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Sample records for cancer cells role

  1. Role of cancer stem cells in hepatocarcinogenesis

    OpenAIRE

    Wang, Bo; Jacob, Samson T.

    2011-01-01

    There has been considerable interest in cancer stem cells (CSCs) among cancer biologists and clinicians, most likely because of their role in the heterogeneity of cancer and their potential application in cancer therapeutics. Recent studies suggest that CSCs play a key role in liver carcinogenesis. A small subpopulation of cancer cells with CSC properties has been identified and characterized from hepatocellular carcinoma (HCC) cell lines, animal models and human primary HCCs. Considering the...

  2. The role of regulatory T cells in cancer immunology

    OpenAIRE

    Whiteside TL

    2015-01-01

    Theresa L Whiteside University of Pittsburgh Cancer Institute, Pittsburgh, PA, US Abstract: Regulatory T cells (Treg) are generally considered to be significant contributors to tumor escape from the host immune system. Emerging evidence suggests, however, that in some human cancers, Treg are necessary to control chronic inflammation, prevent tissue damage, and limit inflammation-associated cancer development. The dual role of Treg in cancer and underpinnings of Treg diversity are not well und...

  3. Role of Inflammation and Substrate Stiffness in Cancer Cell Transmigration

    Science.gov (United States)

    Hamilla, Susan; Stroka, Kimberly; Aranda-Espinoza, Helim

    2013-03-01

    Cancer metastasis, the ability for cancer cells to break away from the primary tumor site and spread to other organs of the body, is one of the main contributing factors to the deadliness of the disease. One of the rate-limiting steps in cancer metastasis that is not well understood is the adhesion of tumor cells to the endothelium followed by transmigration. Other factors include substrate stiffness and inflammation. To test these parameters, we designed an in vitro model of transendothelial migration. Our results suggest that cancer cell transmigration is a two-step process in which they first incorporate into the endothelium before migrating through. It was observed that the cumulative fraction of cancer cells that incorporate into the endothelium increases over time. Unlike leukocytes, which can directly transmigrate through the endothelium, cancer cells appear to have a two-step process of transmigration. Our results indicate that inflammation does not act as a signal for cancer cells to localize at specific sites and transmigrate similarly to leukocytes. Cancer cell transmigration also does not vary with substrate stiffness indicating that tissue stiffness may not play a role in cancer's propensity to metastasize to certain tissues.

  4. Role of pancreatic stellate cells in chemoresistance in pancreatic cancer

    OpenAIRE

    McCarroll, Joshua A.; Naim, Stephanie; Sharbeen, George; Russia, Nelson; Lee, Julia; Kavallaris, Maria; Goldstein, David; Phillips, Phoebe A.

    2014-01-01

    Pancreatic cancer is highly chemoresistant. A major contributing factor is the characteristic extensive stromal or fibrotic reaction, which comprises up to 90% of the tumor volume. Over the last decade there has been intensive research into the role of the pro-fibrogenic pancreatic stellate cells (PSCs) and their interaction with pancreatic cancer cells. As a result of the significant alterations in the tumor microenvironment following activation of PSCs, tumor progression, and chemoresistanc...

  5. Role of Oxidative Stress in Stem, Cancer, and Cancer Stem Cells

    International Nuclear Information System (INIS)

    The term ‘‘oxidative stress” refers to a cell’s state characterized by excessive production of reactive oxygen species (ROS) and oxidative stress is one of the most important regulatory mechanisms for stem, cancer, and cancer stem cells. The concept of cancer stem cells arose from observations of similarities between the self-renewal mechanism of stem cells and that of cancer stem cells, but compared to normal stem cells, they are believed to have no control over the cell number. ROS have been implicated in diverse processes in various cancers, and generally the increase of ROS in cancer cells is known to play an important role in the initiation and progression of cancer. Additionally, ROS have been considered as the most significant mutagens in stem cells; when elevated, blocking self-renewal and at the same time, serving as a signal stimulating stem cell differentiation. Several signaling pathways enhanced by oxidative stress are suggested to have important roles in tumorigenesis of cancer or cancer stem cells and the self-renewal ability of stem or cancer stem cells. It is now well established that mitochondria play a prominent role in apoptosis and increasing evidence supports that apoptosis and autophagy are physiological phenomena closely linked with oxidative stress. This review elucidates the effect and the mechanism of the oxidative stress on the regulation of stem, cancer, and cancer stem cells and focuses on the cell signaling cascades stimulated by oxidative stress and their mechanism in cancer stem cell formation, as very little is known about the redox status in cancer stem cells. Moreover, we explain the link between ROS and both of apoptosis and autophagy and the impact on cancer development and treatment. Better understanding of this intricate link may shed light on mechanisms that lead to better modes of cancer treatment

  6. Targeting cancer stem cells: emerging role of Nanog transcription factor

    Directory of Open Access Journals (Sweden)

    Wang ML

    2013-09-01

    Full Text Available Mong-Lien Wang,1 Shih-Hwa Chiou,2,3 Cheng-Wen Wu1,4–61Institute of Biochemistry and Molecular Biology, 2Institute of Pharmacology, National Yang Ming University, Taipei, Taiwan; 3Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan; 4Institute of Microbiology and Immunology, 5Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan; 6Institute of Biomedical Science, Academia Sinica, Taipei, TaiwanAbstract: The involvement of stemness factors in cancer initiation and progression has drawn much attention recently, especially after the finding that introducing four stemness factors in somatic cells is able to reprogram the cells back to an embryonic stem cell-like state. Following accumulating data revealing abnormal elevated expression levels of key stemness factors, like Nanog, Oct4, and Sox2, in several types of cancer stem cells; the importance and therapeutic potential of targeting these stemness regulators in cancers has turned to research focus. Nanog determines cell fate in both embryonic and cancer stem cells; activating Nanog at an inappropriate time would result in cancer stem cells rather than normal pluripotent stem cells or differentiated somatic cells. Upregulated Nanog is correlated with poor survival outcome of patients with various types of cancer. The discoveries of downstream regulatory pathways directly or indirectly mediated by Nanog indicate that Nanog regulates several aspects of cancer development such as tumor cell proliferation, self-renewal, motility, epithelial-mesenchymal transition, immune evasion, and drug-resistance, which are all defined features for cancer stem cells. The current review paper illustrates the central role of Nanog in the regulatory networks of cancer malignant development and stemness acquirement, as well as in the communication between cancer cells and the surrounding stroma. Though a more defined model is needed to test the

  7. The Role of Treg Cells in the Cancer Immunological Response

    Directory of Open Access Journals (Sweden)

    Stephen M. Ansell

    2009-01-01

    Full Text Available Problem statement: T cell-mediated immunosuppression has been observed for decades without clarification as to which factor was responsible for this observation. The identification of CD4+CD25+ regulatory T (Treg cells represents a milestone in the filed of immunology and provides an explanation for T-cell-mediated immunosuppression. Although Treg cells were originally identified for their ability to prevent organ-specific autoimmune disease in mice, emerging evidence suggests that Treg cells play a pivotal role in tumor immunity and contribute to tumor growth and progression, thereby having an important impact on the outcome of cancer patients. Approach: This article reviewed the medical literature to describe how Treg cells affect anti-tumor immunity. Results: Treg cells suppressed anti-tumor immunity by inhibiting the effector functions of tumor-specific T cells and NK cells. Importantly, tumor cells played an active role in recruiting and generating Treg cells and creating a suppressive tumor microenvironment. Strategies to deplete Treg cells or inhibit their function had yielded promising results by enhancing anti-tumor immunity in experimental studies as well as clinical practice. Conclusion: A better understanding of the pathophysiology of Treg cells not only increased our knowledge in a variety of aspects of immunology but also potentially benefited cancer patients.

  8. Roles of regulatory T cells in cancer immunity.

    Science.gov (United States)

    Takeuchi, Yoshiko; Nishikawa, Hiroyoshi

    2016-08-01

    CD4(+) regulatory T cells (Tregs) expressing the transcription factor FoxP3 are highly immune suppressive and play central roles in the maintenance of self-tolerance and immune homeostasis, yet in malignant tumors they promote tumor progression by suppressing effective antitumor immunity. Indeed, higher infiltration by Tregs is observed in tumor tissues, and their depletion augments antitumor immune responses in animal models. Additionally, increased numbers of Tregs and, in particular, decreased ratios of CD8(+) T cells to Tregs among tumor-infiltrating lymphocytes are correlated with poor prognosis in various types of human cancers. The recent success of cancer immunotherapy represented by immune checkpoint blockade has provided a new insight in cancer treatment, yet more than half of the treated patients did not experience clinical benefits. Identifying biomarkers that predict clinical responses and developing novel immunotherapies are therefore urgently required. Cancer patients whose tumors contain a large number of neoantigens stemming from gene mutations, which have not been previously recognized by the immune system, provoke strong antitumor T-cell responses associated with clinical responses following immune checkpoint blockade, depending on the resistance to Treg-mediated suppression. Thus, integration of a strategy restricting Treg-mediated immune suppression may expand the therapeutic spectrum of cancer immunotherapy towards patients with a lower number of neoantigens. In this review, we address the current understanding of Treg-mediated immune suppressive mechanisms in cancer, the involvement of Tregs in cancer immunotherapy, and strategies for effective and tolerable Treg-targeted therapy. PMID:27160722

  9. DUAL ROLES OF CANCER CELL-EXPRESSED IMMUNOGLOBULINS IN CANCER IMMUNOLOGY

    Directory of Open Access Journals (Sweden)

    Gregory Lee

    2014-01-01

    Full Text Available While the expression of immunoglobulins and T cell receptors on cancer cells has been well-established for decades, the potential roles and mechanisms of action of these cancerous antigen receptors have not been fully elucidated. A monoclonal antibody designated as RP215, which reacts specifically with the carbohydrate-associated epitope located on the heavy chain region of cancerous immunoglobulins and T cell receptors, was used as a unique probe to study the roles of antigen receptors in the immunology of cancer cells. Through extensive cell-based biological and immunological studies, it was found that both anti-antigen receptors and RP215 demonstrated similar actions on the gene regulations involved in the growth/proliferation of cancer cells, as well as on toll-like receptors involved in innate immunity. In addition, RP215-specific cancerous immunoglobulins are believed to capture or neutralize circulating antigen/antibodies which may be harmful to cancer cells within the human body. In contrast to normal B and T cells and their respective receptors in the conventional immune system, cancer cells co-express both immunoglobulins and T cell receptors and immune protection is exercised by unique mechanisms. For example, these cancer cell-expressed antigen receptors display a lack of class switching, limited hyper-mutation, aberrant glycosylations and a strong influence on the toll-like receptors of cancer cells. Therefore, it is hypothesized that both normal and cancerous immune systems may co-exist and operate simultaneously within the human body. The balance of these two immune factors for respective surveillance and protection may be relevant to the outcome of cancer immunotherapy in humans. A potential therapeutic strategy is being developed by using RP215 as a drug candidate to target cancer cells based on these observations.

  10. The role of bisphosphonates in breast cancer: Direct effects of bisphosphonates on breast cancer cells

    International Nuclear Information System (INIS)

    In addition to inhibiting bone resorption, bisphosphonates have also been shown to exhibit antitumour effects. In vitro, bisphosphonates inhibit proliferation and induce apoptosis in cultured human breast cancer cells. In addition, bisphosphonate treatment interferes with breast cancer cell adhesion to bone matrix, and inhibits cell migration and invasion. The combination of bisphosphonates with other anticancer drugs such as the taxoids markedly enhances these effects. These newly recognized direct actions of bisphosphonates on breast cancer cells indicate that these agents may have a greater role to play in treatment of patients suffering from cancers with a propensity to metastasize to bone

  11. The significant role of mast cells in cancer.

    Science.gov (United States)

    Khazaie, Khashayarsha; Blatner, Nichole R; Khan, Mohammad Wasim; Gounari, Fotini; Gounaris, Elias; Dennis, Kristen; Bonertz, Andreas; Tsai, Fu-Nien; Strouch, Matthew J; Cheon, Eric; Phillips, Joseph D; Beckhove, Philipp; Bentrem, David J

    2011-03-01

    Mast cells (MC) are a bone marrow-derived, long-lived, heterogeneous cellular population that function both as positive and negative regulators of immune responses. They are arguably the most productive chemical factory in the body and influence other cells through both soluble mediators and cell-to-cell interaction. MC are commonly seen in various tumors and have been attributed alternatively with tumor rejection or tumor promotion. Tumor-infiltrating MC are derived both from sentinel and recruited progenitor cells. MC can directly influence tumor cell proliferation and invasion but also help tumors indirectly by organizing its microenvironment and modulating immune responses to tumor cells. Best known for orchestrating inflammation and angiogenesis, the role of MC in shaping adaptive immune responses has become a focus of recent investigations. MC mobilize T cells and antigen-presenting dendritic cells. They function as intermediaries in regulatory T cells (Treg)-induced tolerance but can also modify or reverse Treg-suppressive properties. The central role of MC in the control of innate and adaptive immunity endows them with the ability to tune the nature of host responses to cancer and ultimately influence the outcome of disease and fate of the cancer patient. PMID:21287360

  12. Role of nuclear receptors in breast cancer stem cells

    Science.gov (United States)

    Papi, Alessio; Orlandi, Marina

    2016-01-01

    The recapitulation of primary tumour heterogenity and the existence of a minor sub-population of cancer cells, capable of initiating tumour growth in xenografts on serial passages, led to the hypothesis that cancer stem cells (CSCs) exist. CSCs are present in many tumours, among which is breast cancer. Breast CSCs (BCSCs) are likely to sustain the growth of the primary tumour mass, as well as to be responsible for disease relapse and metastatic spreading. Consequently, BCSCs represent the most significant target for new drugs in breast cancer therapy. Both the hypoxic condition in BCSCs biology and pro-inflammatory cytokine network has gained increasing importance in the recent past. Breast stromal cells are crucial components of the tumours milieu and are a major source of inflammatory mediators. Recently, the anti-inflammatory role of some nuclear receptors ligands has emerged in several diseases, including breast cancer. Therefore, the use of nuclear receptors ligands may be a valid strategy to inhibit BCSCs viability and consequently breast cancer growth and disease relapse. PMID:27022437

  13. Role of TAZ in cancer stem cells and Wnt signaling

    OpenAIRE

    Azzolin, Luca

    2013-01-01

    The transcriptional co-activator TAZ, known Hippo transducer together with his paralogue YAP, has recently emerged as important player in processes like organ growth and tumorigenesis. Here we focused on two aspects of TAZ biology: the first regards the role of TAZ as molecular determinant of breast cancer stem cells (CSCs); the second is the characterization of TAZ as downstream mediator of Wnt signaling. Using a bioinformatic approach, we discovered that more-malignant/CSC-enriched prim...

  14. Role of stem cells in cancer therapy and cancer stem cells: a review

    OpenAIRE

    Sales Kevin; Chaib Boussad; Sagar Jayesh; Winslet Marc; Seifalian Alexander

    2007-01-01

    Abstract For over 30 years, stem cells have been used in the replenishment of blood and immune systems damaged by the cancer cells or during treatment of cancer by chemotherapy or radiotherapy. Apart from their use in the immuno-reconstitution, the stem cells have been reported to contribute in the tissue regeneration and as delivery vehicles in the cancer treatments. The recent concept of 'cancer stem cells' has directed scientific communities towards a different wide new area of research fi...

  15. The role of lipolysis stimulated lipoprotein receptor in breast cancer and directing breast cancer cell behavior.

    Directory of Open Access Journals (Sweden)

    Denise K Reaves

    Full Text Available The claudin-low molecular subtype of breast cancer is of particular interest for clinically the majority of these tumors are poor prognosis, triple negative, invasive ductal carcinomas. Claudin-low tumors are characterized by cancer stem cell-like features and low expression of cell junction and adhesion proteins. Herein, we sought to define the role of lipolysis stimulated lipoprotein receptor (LSR in breast cancer and cancer cell behavior as LSR was recently correlated with tumor-initiating features. We show that LSR was expressed in epithelium, endothelium, and stromal cells within the healthy breast tissue, as well as in tumor epithelium. In primary breast tumor bioposies, LSR expression was significantly correlated with invasive ductal carcinomas compared to invasive lobular carcinomas, as well as ERα positive tumors and breast cancer cell lines. LSR levels were significantly reduced in claudin-low breast cancer cell lines and functional studies illustrated that re-introduction of LSR into a claudin-low cell line suppressed the EMT phenotype and reduced individual cell migration. However, our data suggest that LSR may promote collective cell migration. Re-introduction of LSR in claudin-low breast cancer cell lines reestablished tight junction protein expression and correlated with transepithelial electrical resistance, thereby reverting claudin-low lines to other intrinsic molecular subtypes. Moreover, overexpression of LSR altered gene expression of pathways involved in transformation and tumorigenesis as well as enhanced proliferation and survival in anchorage independent conditions, highlighting that reestablishment of LSR signaling promotes aggressive/tumor initiating cell behaviors. Collectively, these data highlight a direct role for LSR in driving aggressive breast cancer behavior.

  16. The role of myeloid cells in cancer therapies.

    Science.gov (United States)

    Engblom, Camilla; Pfirschke, Christina; Pittet, Mikael J

    2016-07-01

    Recent clinical trials have demonstrated the ability to durably control cancer in some patients by manipulating T lymphocytes. These immunotherapies are revolutionizing cancer treatment but benefit only a minority of patients. It is thus a crucial time for clinicians, cancer scientists and immunologists to determine the next steps in shifting cancer treatment towards better cancer control. This Review describes recent advances in our understanding of tumour-associated myeloid cells. These cells remain less studied than T lymphocytes but have attracted particular attention because their presence in tumours is often linked to altered patient survival. Also, experimental studies indicate that myeloid cells modulate key cancer-associated activities, including immune evasion, and affect virtually all types of cancer therapy. Consequently, targeting myeloid cells could overcome limitations of current treatment options. PMID:27339708

  17. The Role of Mesenchymal Stem Cell in Cancer Development

    Directory of Open Access Journals (Sweden)

    Hiroshi eYagi

    2013-11-01

    Full Text Available The role of mesenchymal stem cells (MSCs in cancer development is still controversial. MSCs may promote tumor progression through immune modulation, but other tumor suppressive effects of MSCs have also been described. The discrepancy between these results may arise from issues related to different tissue sources, individual donor variability, and injection timing of MSCs. The expression of critical receptors such as Toll-like receptor (TLR is variable at each time point of treatment, which may also determine the effects of MSCs on tumor progression. However, factors released from malignant cells, as well as surrounding tissues and the vasculature, are still regarded as a black box. Thus, it is still difficult to clarify the specific role of MSCs in cancer development. Whether MSCs support or suppress tumor progression is currently unclear, but it is clear that systemically administered MSCs can be recruited and migrate toward tumors. These findings are important because they can be used as a basis for initiating studies to explore the incorporation of engineered MSCs as novel anti-tumor carriers, for the development of tumor-targeted therapies.

  18. A promoting role of androgen receptor in androgen-sensitive and -insensitive prostate cancer cells

    OpenAIRE

    Li, Tzu-Huey; Zhao, Hongjuan; Peng, Yue; Beliakoff, Jason; James D Brooks; Sun, Zijie

    2007-01-01

    Although the vital role of the androgen receptor (AR) has been well demonstrated in primary prostate cancers, its role in the androgen-insensitive prostate cancers still remains unclear. Here, we used a small hairpin RNA approach to directly assess AR activity in prostate cancer cells. Reduction of AR expression in the two androgen-sensitive prostate cancer cell lines, LNCaP and LAPC4, significantly decreased AR-mediated transcription and cell growth. Intriguingly, in two androgen-insensitive...

  19. Intertwining of Activin A and TGFβ Signaling: Dual Roles in Cancer Progression and Cancer Cell Invasion

    Energy Technology Data Exchange (ETDEWEB)

    Loomans, Holli A. [Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Andl, Claudia D., E-mail: claudia.andl@vanderbilt.edu [Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Vanderbilt Digestive Disease Center, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Vanderbilt Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232 (United States)

    2014-12-30

    In recent years, a significant amount of research has examined the controversial role of activin A in cancer. Activin A, a member of the transforming growth factor β (TGFβ) superfamily, is best characterized for its function during embryogenesis in mesoderm cell fate differentiation and reproduction. During embryogenesis, TGFβ superfamily ligands, TGFβ, bone morphogenic proteins (BMPs) and activins, act as potent morphogens. Similar to TGFβs and BMPs, activin A is a protein that is highly systemically expressed during early embryogenesis; however, post-natal expression is overall reduced and remains under strict spatiotemporal regulation. Of importance, normal post-natal expression of activin A has been implicated in the migration and invasive properties of various immune cell types, as well as endometrial cells. Aberrant activin A signaling during development results in significant morphological defects and premature mortality. Interestingly, activin A has been found to have both oncogenic and tumor suppressor roles in cancer. Investigations into the role of activin A in prostate and breast cancer has demonstrated tumor suppressive effects, while in lung and head and neck squamous cell carcinoma, it has been consistently shown that activin A expression is correlated with increased proliferation, invasion and poor patient prognosis. Activin A signaling is highly context-dependent, which is demonstrated in studies of epithelial cell tumors and the microenvironment. This review discusses normal activin A signaling in comparison to TGFβ and highlights how its dysregulation contributes to cancer progression and cell invasion.

  20. Intertwining of Activin A and TGFβ Signaling: Dual Roles in Cancer Progression and Cancer Cell Invasion

    International Nuclear Information System (INIS)

    In recent years, a significant amount of research has examined the controversial role of activin A in cancer. Activin A, a member of the transforming growth factor β (TGFβ) superfamily, is best characterized for its function during embryogenesis in mesoderm cell fate differentiation and reproduction. During embryogenesis, TGFβ superfamily ligands, TGFβ, bone morphogenic proteins (BMPs) and activins, act as potent morphogens. Similar to TGFβs and BMPs, activin A is a protein that is highly systemically expressed during early embryogenesis; however, post-natal expression is overall reduced and remains under strict spatiotemporal regulation. Of importance, normal post-natal expression of activin A has been implicated in the migration and invasive properties of various immune cell types, as well as endometrial cells. Aberrant activin A signaling during development results in significant morphological defects and premature mortality. Interestingly, activin A has been found to have both oncogenic and tumor suppressor roles in cancer. Investigations into the role of activin A in prostate and breast cancer has demonstrated tumor suppressive effects, while in lung and head and neck squamous cell carcinoma, it has been consistently shown that activin A expression is correlated with increased proliferation, invasion and poor patient prognosis. Activin A signaling is highly context-dependent, which is demonstrated in studies of epithelial cell tumors and the microenvironment. This review discusses normal activin A signaling in comparison to TGFβ and highlights how its dysregulation contributes to cancer progression and cell invasion

  1. Role of plasmacytoid dendritic cells in breast cancer bone dissemination

    OpenAIRE

    Sawant, Anandi; Ponnazhagan, Selvarangan

    2013-01-01

    Elevated levels of plasmacytoid dendritic cells (pDC) have been observed as breast cancer disseminates to the bone. The selective depletion of pDC in mice led to a total abrogation of bone metastasis as well as to an increase in TH1 antitumor response, suggesting that pDC may be considered as a potential therapeutic target for metastatic breast cancer.

  2. Role of dietary factors in cell replication and colon cancer.

    Science.gov (United States)

    Jacobs, R

    1988-09-01

    Human studies and experimental data from animals suggest that high rates of colonic epithelial cell replication enhance the development of colon cancer. Vegetarians and individuals following a prudent diet have lower rates of colorectal cell proliferation than subjects at high risk for colon cancer. Animal studies show that colonic cell proliferation is stimulated by feeding in general and specifically by a number of dietary fibers, fats, bile acids, and short-chain fatty acids. Many of these growth factors also increase the induction of experimental tumorigenesis. On the other hand factors that reduce cell growth, including ascorbic acid and butylated hydroxyanisole, inhibit colon carcinogenesis. These results support the concept that dietary chemoprevention is feasible and could significantly reduce the rate of colon cancer development in high risk populations. PMID:3046307

  3. The role of stem cells in airway repair: implications for the origins of lung cancer

    OpenAIRE

    Mulvihill, Michael S.; Kratz, Johannes R.; Patrick Pham; Jablons, David M.; Biao He

    2013-01-01

    Lung cancer is the leading cause of cancer-related deaths worldwide. Recently, advancements in our ability to identify and study stem cell populations in the lung have helped researchers to elucidate the central role that cells with stem cell-like properties may have in lung tumorigenesis. Much of this research has focused on the use of the airway repair model to study response to injury. In this review, we discuss the primary evidence of the role that cancer stem cells play in lung cancer de...

  4. The role of the tissue microenvironment in the regulation of cancer cell motility and invasion

    Directory of Open Access Journals (Sweden)

    Brábek Jan

    2010-09-01

    Full Text Available Abstract During malignant neoplastic progression the cells undergo genetic and epigenetic cancer-specific alterations that finally lead to a loss of tissue homeostasis and restructuring of the microenvironment. The invasion of cancer cells through connective tissue is a crucial prerequisite for metastasis formation. Although cell invasion is foremost a mechanical process, cancer research has focused largely on gene regulation and signaling that underlie uncontrolled cell growth. More recently, the genes and signals involved in the invasion and transendothelial migration of cancer cells, such as the role of adhesion molecules and matrix degrading enzymes, have become the focus of research. In this review we discuss how the structural and biomechanical properties of extracellular matrix and surrounding cells such as endothelial cells influence cancer cell motility and invasion. We conclude that the microenvironment is a critical determinant of the migration strategy and the efficiency of cancer cell invasion.

  5. Emerging role of microRNAs in cancer stem cells:Implications in cancer therapy

    Institute of Scientific and Technical Information of China (English)

    Minal; Garg

    2015-01-01

    A small subset of cancer cells that act as tumor initiating cells or cancer stem cells(CSCs) maintain self-renewal and growth promoting capabilities of cancer and are responsible for drug/treatment resistance,tumor recurrence and metastasis. Due to their potential clinical importance,many researchers have put their efforts over decades to unravel the molecular mechanisms that regulate CSCs functions. Micro RNAs(mi RNAs) which are 21-23 nucleotide long,endogenous noncoding RNAs,regulate gene expression through gene silencing at post-transcriptional level by binding to the 3’-untranslated regions or the open reading frames of target genes,thereby result in target mR NA degradation or its translational repression and serve important role in several cellular,physiological and developmental processes. Aberrant mi RNAs expression and their implication in CSCs regulation by controlling asymmetric cell division,drug/treatment resistance and metastasis make mi RNAs a tool of great therapeutic potential against cancer. Recent advancements on the biological complexities of CSCs,modulation in CSCs properties by mi RNA network and development of mi RNA based treatment strategies specifically targeting the CSCs as an attractive therapeutic targets for clinical application are being critically analysed.

  6. An Anticancer Role of Hydrogen Sulfide in Human Gastric Cancer Cells

    Directory of Open Access Journals (Sweden)

    Li Zhang

    2015-01-01

    Full Text Available Hydrogen sulfide (H2S can be synthesized in mammalian cells by cystathionine γ-lyase (CSE and/or cystathionine β-synthase (CBS. Both CSE and CBS are expressed in rat gastric tissues but their role in human gastric neoplasia has been unclear. The aims of the present study were to detect CSE and CBS proteins in human gastric cancer and determine the effect of exogenous NaHS on the proliferation of gastric cancer cells. We found that both CSE and CBS proteins were expressed in human gastric cancer cells and upregulated in human gastric carcinoma mucosa compared with those in noncancerous gastric samples. NaHS induced apoptosis of gastric cancer cells by regulating apoptosis related proteins. Also, NaHS inhibited cancer cell migration and invasion. An antigastric cancer role of H2S is thus indicated.

  7. The Role of Lipid Rafts in Cancer Cell Adhesion and Migration

    Directory of Open Access Journals (Sweden)

    Toshiyuki Murai

    2012-01-01

    Full Text Available Lipid rafts are cholesterol-enriched microdomains of the cell membrane and possess a highly dynamic nature. They have been involved in various cellular functions including the regulation of cell adhesion and membrane signaling through proteins within lipid rafts. The dynamic features of the cancer cell surface may modulate the malignant phenotype of cancer, including adhesion disorders and aggressive phenotypes of migration and invasion. Recently, it was demonstrated that lipid rafts play critical roles in cancer cell adhesion and migration. This article summarizes the important roles of lipid rafts in cancer cell adhesion and migration, with a focus on the current state of knowledge. This article will improve the understanding of cancer progression and lead to the development of novel targets for cancer therapy.

  8. Role of p53 in Cell Death and Human Cancers

    International Nuclear Information System (INIS)

    p53 is a nuclear transcription factor with a pro-apoptotic function. Since over 50% of human cancers carry loss of function mutations in p53 gene, p53 has been considered to be one of the classical type tumor suppressors. Mutant p53 acts as the dominant-negative inhibitor toward wild-type p53. Indeed, mutant p53 has an oncogenic potential. In some cases, malignant cancer cells bearing p53 mutations display a chemo-resistant phenotype. In response to a variety of cellular stresses such as DNA damage, p53 is induced to accumulate in cell nucleus to exert its pro-apoptotic function. Activated p53 promotes cell cycle arrest to allow DNA repair and/or apoptosis to prevent the propagation of cells with serious DNA damage through the transactivation of its target genes implicated in the induction of cell cycle arrest and/or apoptosis. Thus, the DNA-binding activity of p53 is tightly linked to its tumor suppressive function. In the present review article, we describe the regulatory mechanisms of p53 and also p53-mediated therapeutic strategies to cure malignant cancers

  9. Role of p53 in Cell Death and Human Cancers

    OpenAIRE

    Toshinori Ozaki; Akira Nakagawara

    2011-01-01

    p53 is a nuclear transcription factor with a pro-apoptotic function. Since over 50% of human cancers carry loss of function mutations in p53 gene, p53 has been considered to be one of the classical type tumor suppressors. Mutant p53 acts as the dominant-negative inhibitor toward wild-type p53. Indeed, mutant p53 has an oncogenic potential. In some cases, malignant cancer cells bearing p53 mutations display a chemo-resistant phenotype. In response to a variety of cellular stresses such as DNA ...

  10. Breast cancers radiation-resistance: key role of the cancer stem cells marker CD24

    International Nuclear Information System (INIS)

    This work focuses on the characterization of radiation-resistant breast cancer cells, responsible for relapse after radiotherapy. The 'Cancer Stem Cells' (CSC) theory describes a radiation-resistant cellular sub-population, with enhanced capacity to induce tumors and proliferate. In this work, we show that only the CSC marker CD24-/low defines a radiation resistant cell population, able to transmit the 'memory' of irradiation, expressed as long term genomic instability in the progeny of irradiated cells. We show that CD24 is not only a marker, but is an actor of radiation-response. So, CD24 expression controls cell proliferation in vitro and in vivo, and ROS level before and after irradiation. As a result, CD24-/low cells display enhanced radiation-resistance and genomic stability. For the first time, our results attribute a role to CD24-/low CSCs in the transmission of genomic instability. Moreover, by providing informations on tumor intrinsic radiation-sensitivity, CD24- marker could help to design new radiotherapy protocols. (author)

  11. Role of Oxidative Stress in Stem, Cancer, and Cancer Stem Cells

    OpenAIRE

    Ahmed Abdal Dayem; Hye-Yeon Choi; Jung-Hyun Kim; Ssang-Goo Cho

    2010-01-01

    The term ‘‘oxidative stress” refers to a cell’s state characterized by excessive production of reactive oxygen species (ROS) and oxidative stress is one of the most important regulatory mechanisms for stem, cancer, and cancer stem cells. The concept of cancer stem cells arose from observations of similarities between the self-renewal mechanism of stem cells and that of cancer stem cells, but compared to normal stem cells, they are believed to have no control over the cell number. ROS have bee...

  12. The role of mismatch repair in small-cell lung cancer cells

    DEFF Research Database (Denmark)

    Hansen, L T; Thykjaer, T; Ørntoft, T F; Rasmussen, L J; Keller, P; Spang-Thomsen, M; Edmonston, T Bocker; Schmutte, C; Fishel, R; Petersen, L Nørgård

    2003-01-01

    The role of mismatch repair (MMR) in small-cell lung cancer (SCLC) is controversial, as the phenotype of a MMR-deficiency, microsatellite instability (MSI), has been reported to range from 0 to 76%. We studied the MMR pathway in a panel of 21 SCLC cell lines and observed a highly heterogeneous...... pattern of MMR gene expression. A significant correlation between the mRNA and protein levels was found. We demonstrate that low hMLH1 gene expression was not linked to promoter CpG methylation. One cell line (86MI) was found to be deficient in MMR and exhibited resistance to the alkylating agent MNNG...

  13. Role of mitochondria-associated hexokinase II in cancer cell death induced by 3-Bromopyruvate

    OpenAIRE

    Chen, Zhao; Zhang, Hui; Lu, Weiqin; Huang, Peng

    2009-01-01

    It has long been observed that cancer cells rely more on glycolysis to generate ATP and actively use certain glycolytic metabolic intermediates for biosynthesis. Hexokinase II (HKII) is a key glycolytic enzyme that plays a role in the regulation of the mitochondria-initiated apoptotic cell death. As a potent inhibitor of hexokinase, 3-bromopyruvate (3-BrPA) is known to inhibit cancer cell energy metabolism and trigger cell death, supposedly through depletion of cellular ATP. The current study...

  14. The role of stem cells in airway repair: implications for the origins of lung cancer

    Institute of Scientific and Technical Information of China (English)

    Michael S.Mulvihill; Johannes R.Kratz; Patrick Pham; David M.Jablons; Biao He

    2013-01-01

    Lung cancer is the leading cause of cancer-related deaths worldwide.Recently,advancements in our ability to identify and study stem cell populations in the lung have helped researchers to elucidate the central role that cells with stem cell-like properties may have in lung tumorigenesis.Much of this research has focused on the use of the airway repair model to study response to injury.In this review,we discuss the primary evidence of the role that cancer stem cells play in lung cancer development.The implications of a stem cell origin of lung cancer are reviewed,and the importance of ongoing research to identify novel therapeutic and prognostic targets is reiterated.

  15. The role of stem cells in airway repair: implications for the origins of lung cancer

    Directory of Open Access Journals (Sweden)

    Michael S. Mulvihill

    2013-02-01

    Full Text Available Lung cancer is the leading cause of cancer-related deaths worldwide. Recently, advancements in our ability to identify and study stem cell populations in the lung have helped researchers to elucidate the central role that cells with stem cell-like properties may have in lung tumorigenesis. Much of this research has focused on the use of the airway repair model to study response to injury. In this review, we discuss the primary evidence of the role that cancer stem cells play in lung cancer development. The implications of a stem cell origin of lung cancer are reviewed, and the importance of ongoing research to identify novel therapeutic and prognostic targets is reiterated.

  16. The role of NANOG transcriptional factor in the development of malignant phenotype of cancer cells.

    Science.gov (United States)

    Gawlik-Rzemieniewska, Natalia; Bednarek, Ilona

    2016-01-01

    NANOG is a transcription factor that is involved in the self-renewal of embryonic stem cells (ES) and is a critical factor for the maintenance of the undifferentiated state of pluripotent cells. Extensive data in the literature show that the NANOG gene is aberrantly expressed during the development of malignancy in cancer cells. ES and cancer stem cells (CSCs), a subpopulation of cancer cells within the tumor, are thought to share common phenotypic properties. This review describes the role of NANOG in cancer cell proliferation, epithelial-mesenchymal transition (EMT), apoptosis and metastasis. In addition, this paper illustrates a correlation between NANOG and signal transducer and activator of transcription 3 (STAT3) in the maintenance of cancer stem cell properties and multidrug resistance. Together, the available data demonstrate that NANOG is strictly involved in the process of carcinogenesis and is a potential prognostic marker of malignant tumors. PMID:26618281

  17. The role of Nanog expression in tamoxifen-resistant breast cancer cells

    Directory of Open Access Journals (Sweden)

    Arif K

    2015-06-01

    Full Text Available Khalid Arif,1 Issam Hussain,1 Carol Rea,1 Mohamed El-Sheemy2 1School of Life Sciences, University of Lincoln, Brayford Pool, 2Lincoln County Hospital, Greetwell Road, Lincoln, Lincolnshire, UK Abstract: There is an accumulation of evidence that shows a significant role of cancer stem cells in tumor initiation, proliferation, relapse, and metastasis. Nanog is the most important core transcription marker of stem cells, known by its role in maintaining pluripotency, proliferation, and differentiation. Therefore, this study aimed to examine the role of Nanog in breast cancer cell tamoxifen resistance and its implications in breast cancer treatment. In this study, the expression of the three core transcription markers Nanog, Oct3/4, and Sox2 were quantitatively evaluated using flow cytometry. Then, small interfering RNA (siRNA against human Nanog was transfected into tamoxifen-resistant breast cancer cells via Lipofectamine 2000. Nanog gene expression in the cells was detected using reverse transcription polymerase chain reaction (RT-PCR. The change in cell proliferation was evaluated using the tetrazolium bromide method. An enzyme-linked immunosorbent assay was used to detect apoptosis of the transfected cells alone and in combination with 4-hydroxytamoxifen. The results showed a high level expression of Nanog, Oct3/4, and Sox2 in MDA-MB-231 and MCF7/tamoxifen resistant cells compared with MCF7/wild-type. siRNA-mediated Nanog gene silencing can efficiently inhibit cell proliferation and induce apoptosis of tamoxifen-resistant breast cancer cells. This study provides a basis for further study of the role of Nanog in developing resistance to tamoxifen, its implication in breast cancer management, and as a new strategy to enhance response to endocrine therapy. Keywords: breast cancer, cancer stem cell, Nanog, tamoxifen, estrogen receptor

  18. The role of estrogen receptor alpha in mediating chemoresistance in breast cancer cells

    Directory of Open Access Journals (Sweden)

    Jiang Zhinong

    2012-05-01

    Full Text Available Abstract Introduction Previous studies suggested that estrogen receptor alpha (ERα plays an important role in the chemoresistance of breast cancers. However, large random trials failed to demonstrate any benefit of the concurrent estrogen antagonist tamoxifen on the chemotherapy efficacy. Thus, in the present study, the importance of the role of ERα in the chemoresistance of breast cancer cells was investigated. Methods The ERα-transfected Bcap37 cells and natural ERα-positive T47D breast cancer cells were treated using chemotherapeutic agents with or without 17-beta estradiol (E2 pretreatment. Their viabilities were assessed using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays. The dead cell rates were determined using propidium iodide dye exclusion tests, and the expression levels of Bcl-2 and Bax were detected through Western blot analysis. The effects of E2 on the growth of breast cancer cells were also determined via cell growth curve and cell cycle analysis. Results ERα activation by E2 increased the sensitivity of natural ERα-positive T47D breast cancer cells to chemotherapeutic agents. However, the increase in ERα expression in ERα-negative Bcap37 breast cancer cells also significantly increased their resistance. These phenomena cannot be explained by asserting that ERα mediated the chemoresistance of breast cancer cells by regulating the expression of Bcl-2 and Bax. Our findings show that ERα activation upregulated the expression of Bcl-2 in natural ERα-positive T47D breast cancer cells, whereas ERα activation by E2 downregulated and upregulated the Bcl-2 and Bax expression levels, respectively, in ERα-transfected Bcap37 cells. This phenomenon was due to the influence of ERα on the growth of breast cancer cells. Specifically, ERα activation enhanced the growth of natural ERα-positive breast cancer cells and thus increased their sensitivity to chemotherapeutic agents. However, ERα activation also

  19. The role of STAT1 for crosstalk between fibroblasts and colon cancer cells

    Directory of Open Access Journals (Sweden)

    Pawan eKaler

    2014-04-01

    Full Text Available Signaling between tumor cells and the associated stroma has an important impact on cancer initiation and progression. The tumor microenvironment has a paradoxical role in tumor progression and fibroblasts, a major component of the tumor stroma, have been shown to either inhibit or promote cancer development. In this study we established that normal intestinal fibroblasts activate STAT1 signaling in colon cancer cells and, in contrast to cancer- associated fibroblasts, inhibit growth of tumor cells. Treatment of 18Co fibroblasts with the proinflammatory cytokine TNF interfered with their ability to trigger STAT1 signaling in cancer cells. Accordingly, intestinal myofibroblasts isolated from patients with Ulcerative colitis (UC or Crohn’s disease (CD, which are activated and produce high levels of TNF, failed to stimulate STAT1 signaling in tumor cells, demonstrating that activated myofibroblasts lose the ability to trigger growth-inhibitory STAT1 signaling in tumor cells. Finally, we confirmed that silencing of STAT1 in tumor cells alters the crosstalk between tumor cells and fibroblasts, suggesting STAT1 as a novel link between intestinal inflammation and colon cancer. We demonstrated that normal fibroblasts restrain the growth of carcinoma cells, at least in part, through the induction of STAT1 signaling in cancer cells. We showed that changes in the microenvironment, as they occur in inflammatory bowel disease, alter the crosstalk between carcinoma cells and fibroblasts, perturb the homeostasis of intestinal tissue and thereby contribute to tumor progression.

  20. Roles of Mir-144-ZFX Pathway in Growth Regulation of Non-Small-Cell Lung Cancer

    OpenAIRE

    Zha, Wangjian; Cao, Liu; Shen, Ying; Mao HUANG

    2013-01-01

    Background Lung cancer is the leading cause of cancer-related death worldwide. Non-small cell lung carcinoma (NSCLC) accounts for most of the lung cancer cases and the prognosis of this disease remains poor despite decades of intensive investigation. Thus new insights into underlying mechanisms by which NSCLC develops are avidly needed as the basis for development of new lines of therapeutic strategies. The past decade has witnessed a growing interest on the regulatory roles of micro RNAs on ...

  1. Induction of Cancer Cell Death by Isoflavone: The Role of Multiple Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Fazlul H. Sarkar

    2011-10-01

    Full Text Available Soy isoflavones have been documented as dietary nutrients broadly classified as “natural agents” which plays important roles in reducing the incidence of hormone-related cancers in Asian countries, and have shown inhibitory effects on cancer development and progression in vitro and in vivo, suggesting the cancer preventive or therapeutic activity of soy isoflavones against cancers. Emerging experimental evidence shows that isoflavones could induce cancer cell death by regulating multiple cellular signaling pathways including Akt, NF-κB, MAPK, Wnt, androgen receptor (AR, p53 and Notch signaling, all of which have been found to be deregulated in cancer cells. Therefore, homeostatic regulation of these important cellular signaling pathways by isoflavones could be useful for the activation of cell death signaling, which could result in the induction of apoptosis of both pre-cancerous and/or cancerous cells without affecting normal cells. In this article, we have attempted to summarize the current state-of-our-knowledge regarding the induction of cancer cell death pathways by isoflavones, which is believed to be mediated through the regulation of multiple cellular signaling pathways. The knowledge gained from this article will provide a comprehensive view on the molecular mechanism(s by which soy isoflavones may exert their effects on the prevention of tumor progression and/or treatment of human malignancies, which would also aid in stimulating further in-depth mechanistic research and foster the initiation of novel clinical trials.

  2. Role of cancer stem cells in racial disparity in colorectal cancer.

    Science.gov (United States)

    Farhana, Lulu; Antaki, Fadi; Anees, Mohammad R; Nangia-Makker, Pratima; Judd, Stephanie; Hadden, Timothy; Levi, Edi; Murshed, Farhan; Yu, Yingjie; Van Buren, Eric; Ahmed, Kulsoom; Dyson, Gregory; Majumdar, Adhip P N

    2016-06-01

    Although African-Americans (AAs) have a higher incidence of colorectal cancer (CRC) than White people, the underlying biochemical mechanisms for this increase are poorly understood. The current investigation was undertaken to examine whether differences in self-renewing cancer stem/stem-like cells (CSCs) in the colonic mucosa, whose stemness is regulated by certain microRNAs (miRs), could partly be responsible for the racial disparity in CRC. The study contains 53 AAs and 47 White people. We found the number of adenomas and the proportion of CD44(+) CD166(-  ) CSC phenotype in the colon to be significantly higher in AAs than White people. MicroRNAs profile in CSC-enriched colonic mucosal cells, expressed as ratio of high-risk (≥3 adenomas) to low-risk (no adenoma) CRC patients revealed an 8-fold increase in miR-1207-5p in AAs, compared to a 1.2-fold increase of the same in White people. This increase in AA was associated with a marked rise in lncRNA PVT1 (plasmacytoma variant translocation 1), a host gene of miR-1207-5p. Forced expression of miR-1207-5p in normal human colonic epithelial cells HCoEpiC and CCD841 produced an increase in stemness, as evidenced by morphologically elongated epithelial mesenchymal transition( EMT) phenotype and significant increases in CSC markers (CD44, CD166, and CD133) as well as TGF-β, CTNNB1, MMP2, Slug, Snail, and Vimentin, and reduction in Twist and N-Cadherin. Our findings suggest that an increase in CSCs, specifically the CD44(+) CD166(-) phenotype in the colon could be a predisposing factor for the increased incidence of CRC among AAs. MicroRNA 1207-5p appears to play a crucial role in regulating stemness in colonic epithelial cells in AAs. PMID:26990997

  3. Chemotherapy for advanced non-small-cell lung cancer: Role of paclitaxel and gemcitabine

    OpenAIRE

    Lam, WK; Tsang, KWT; Ip, MSM

    1999-01-01

    Objective. To review the role of chemotherapy in advanced non-small-cell lung cancer, focusing on cisplatin-based regimens and two new drugs: paclitaxel and gemcitabine. Data sources. Medline search of the relevant English literature. Study selection. Open and randomised comparative (phases II and III) studies, and meta-analyses of cytotoxic drugs/regimens used to treat advanced non-small-cell lung cancer. Data extraction. The following factors were studied and compared: symptomatic response ...

  4. Role of Metallothionein1H in Cisplatin Resistance of Non-Small Cell Lung Cancer Cells

    Institute of Scientific and Technical Information of China (English)

    Xin-fang Hou; Qing-xia Fan; Liu-xing Wang; Shi-xin Lu

    2009-01-01

    Objective: Despite platinum-based adjuvant chemotherapy has improved greatly patients' outcomes, drug resistance poses a major impediment to the successful use of such an effective agent. Metallothioneins(MTs) are known to play putative roles in cancer cell proliferation, apoptosis, differentiation, drug resistance and prognosis. The present studiy was to investigte the role of metallethioein1H(MT1H) in cisplatin resistance of human non-small cell lung cancer(NSCLC) cell lines in vitro or its possible molecular mechanisms. Methods: MT1H mRNA expression in A549 and A549/DDP cells was detected by RT-PCR. A recombinant eukaryotic expression plasmid pcDNA3.1(-)-MT1H was constructed and transfected into A549 cells which express no MT1H. MT1H siRNA was transfected into A549/DDP cells which express MT1H highly. MT1H expression was detected by RT-PCR and Immunoblot. The chemosensitivity to cisplatin was assessed by MTT assay. Apoptosis rate was determined by Tunel and FCM. Bcl-2 and Bax were determined by immunohistochemistry. Results: MT1H mRNA was expressed in A549/DDP but not in A549. After transfection of MT1H, MT1H expression was enhanced and the chemosensitivity to cisplatin was decreased in A549 cells. Inversely, after transfection of MT1H siRNA, MT1H expression was decreased and the chemosensitivity to cisplatin was increased in A549/DDP. The apoptosis rate induced by cisplatin was increased and Bcl-2 was down-regulated but Bax showed little change in A549/DDP cells interferred with MT1H siRNA. Conclusion: MT1H overexpression can promote drug resistance in A549 cells . Down-regulation of MT1H interfered with siRNA can effectively reverses the drug resistance in A549/DDP cells by down-regulating the expression of Bcl-2 and increasing cisplatin induced apoptosis. SiRNA targeting MT1H combined with chemotherapy may be a very promising strategy for treatment of lung cancer.

  5. Role for chondroitin sulfate glycosaminoglycan in NEDD9-mediated breast cancer cell growth

    NARCIS (Netherlands)

    Iida, J.; Dorchak, J.; Clancy, R.; Slavik, J.; Ellsworth, R.; Katagiri, Y.; Pugacheva, E.N.; Kuppevelt, T.H. van; Mural, R.J.; Cutler, M.L.; Shriver, C.D.

    2015-01-01

    There are lines of evidence demonstrating that NEDD9 (Cas-L, HEF-1) plays a key role in the development, progression, and metastasis of breast cancer cells. We previously reported that NEDD9 plays a critical role for promoting migration and growth of MDA-MB-231. In order to further characterize the

  6. Role of nitric oxide in Salmonella typhimurium-mediated cancer cell killing

    International Nuclear Information System (INIS)

    Bacterial targeting of tumours is an important anti-cancer strategy. We previously showed that strain SL7838 of Salmonella typhimurium targets and kills cancer cells. Whether NO generation by the bacteria has a role in SL7838 lethality to cancer cells is explored. This bacterium has the mechanism for generating NO, but also for decomposing it. Mechanism underlying Salmonella typhimurium tumour therapy was investigated through in vitro and in vivo studies. NO measurements were conducted either by chemical assays (in vitro) or using Biosensors (in vivo). Cancer cells cytotoxic assay were done by using MTS. Bacterial cell survival and tumour burden were determined using molecular imaging techniques. SL7838 generated nitric oxide (NO) in anaerobic cell suspensions, inside infected cancer cells in vitro and in implanted 4T1 tumours in live mice, the last, as measured using microsensors. Thus, under these conditions, the NO generating pathway is more active than the decomposition pathway. The latter was eliminated, in strain SL7842, by the deletion of hmp- and norV genes, making SL7842 more proficient at generating NO than SL7838. SL7842 killed cancer cells more effectively than SL7838 in vitro, and this was dependent on nitrate availability. This strain was also ca. 100% more effective in treating implanted 4T1 mouse tumours than SL7838. NO generation capability is important in the killing of cancer cells by Salmonella strains

  7. The Role of Biomaterials on Cancer Stem Cell Enrichment and Behavior

    Science.gov (United States)

    Ordikhani, Faride; Kim, Yonghyun; Zustiak, Silviya P.

    2015-11-01

    The theory of cancer stem cells (CSCs) and their role in cancer metastasis, tumorigenicity and resistance to therapy is slowly shifting the emphasis on the search for cancer cure: more evidence is surfacing that a successful therapy should be geared against this rare cancer cell population. Unfortunately, CSCs are difficult to culture in vitro which severely limits the progress of CSC research. This review gives a brief overview of CSCs and their microenvironment, with particular focus on studies that used in vitro biomaterial-based models and biomaterial/CSC interfaces for the enrichment of CSCs. Biomaterial properties relevant to CSC behaviors are also addressed. While the discussed research field is still in its infancy, it appears that in vitro cancer models that include a biomaterial can support CSC enrichment and this has proved indispensable to the study of their biology as well as the development of novel cancer therapies.

  8. A role for PAX8 in the tumorigenic phenotype of ovarian cancer cells

    International Nuclear Information System (INIS)

    PAX8 is a member of the paired box (Pax) multigene family of transcription factors, which are involved in the developmental and tissue-specific control of the expression of several genes in both vertebrates and invertebrates. Previously, several studies reported that PAX8 is expressed at high levels in specific types of tumors. In particular, PAX8 has been recently reported to be conspicuously expressed in human ovarian cancer, but the functional role of PAX8 in the carcinogenesis of this type of tumor has not been addressed. In this study, we investigated the contribution of PAX8 in ovarian cancer progression. Stable PAX8 depleted ovarian cancer cells were generated using short hairpin RNA (shRNA) constructs. PAX8 mRNA and protein were detected by RT-PCR, immunoblot and immunofluorescence. Cell proliferation, motility and invasion potential of PAX8 silenced cells were analyzed by means of growth curves, wound healing and Matrigel assays. In addition, PAX8 knockdown and control cells were injected into nude mice for xenograft tumorigenicity assays. Finally, qPCR was used to detect the expression levels of EMT markers in PAX8-overexpressing and control cells. Here, we show that PAX8 plays a critical role in the migration, invasion and tumorigenic ability of ovarian cancer cells. Our results show that RNA interference-mediated knockdown of PAX8 expression in SKOV-3 ovarian cancer cells produces a significant reduction of cell proliferation, migration ability and invasion activity compared with control parental SKOV-3 cells. Moreover, PAX8 silencing strongly suppresses anchorage-independent growth in vitro. Notably, tumorigenesis in vivo in a nude mouse xenograft model is also significantly inhibited. Overall, our results indicate that PAX8 plays an important role in the tumorigenic phenotype of ovarian cancer cells and identifies PAX8 as a potential new target for the treatment of ovarian cancer

  9. The Role of Dextran Coatings on the Cytotoxicity Properties of Ceria Nanoparticles Toward Bone Cancer Cells

    Science.gov (United States)

    Yazici, Hilal; Alpaslan, Ece; Webster, Thomas J.

    2015-04-01

    Cerium oxide nanoparticles have demonstrated great potential as antioxidant and radioprotective agents for nanomedicine applications especially for cancer therapy. The surface chemistry of nanoparticles is an important property that has a significant effect on their performance in biological applications including cancer diagnosis, cancer treatment, and bacterial infection. Recently, various nanosized cerium oxide particles with different types of polymer coatings have been developed to improve aqueous solubility and allow for surface functionalization for distinct applications. In this study, the role of ceria nanoparticles coated with dextran on the cytotoxicity properties of bone cancer cells was shown. Specifically, 0.1 M and 0.01 M dextran-coated, bone cancer cells was observed for the 0.01 M dextran coating after 3 days compared with the 0.1 M dextran coating. These results indicated that surface dextran functionalization had a positive impact on the cytotoxicity of cerium oxide nanoparticles against osteosarcoma cells.

  10. The role of SOX2 in small cell lung cancer, lung adenocarcinoma and squamous cell carcinoma of the lung

    OpenAIRE

    Karachaliou, Niki; Rosell, Rafael; Viteri, Santiago

    2013-01-01

    SOX2 is a stem cell transcription factor that plays a crucial role in the regulation of embryonic development. It is one of the genes in a set of factors (Oct4, SOX2, Nanog) that are able to reprogram human somatic cells to pluripotent stem cells. Overexpression of SOX2 has been described in all types of lung cancer tissues, including small cell and squamous cell carcinoma but also adenocarcinoma. An in-depth view of the spectrum of genomic alterations in small cell lung cancer (SCLC) has ide...

  11. Role of ATF5 in the invasive potential of diverse human cancer cell lines.

    Science.gov (United States)

    Nukuda, Akihiro; Endoh, Hiroki; Yasuda, Motoaki; Mizutani, Takeomi; Kawabata, Kazushige; Haga, Hisashi

    2016-06-01

    Activating transcription factor 5 (ATF5) is a member of the ATF/cAMP response element-binding protein family. Our research group recently revealed that ATF5 expression increases the invasiveness of human lung carcinoma cells. However, the effects of ATF5 on the invasive potential of other cancer cells lines remain unclear. Therefore, in this study, we investigated the role of ATF5 in the invasive activity of diverse human cancer cell lines. Invasiveness was assessed using Matrigel invasion assays. ATF5 knockdown resulted in decreased invasiveness in seven of eight cancer cell lines tested. These results suggest that ATF5 promotes invasiveness in several cancer cell lines. Furthermore, the roles of ATF5 in the invasiveness were evaluated in three-dimensional (3D) culture conditions. In 3D collagen gel, HT-1080 and MDA-MB-231 cells exhibited high invasiveness, with spindle morphology and high invasion speed. In both cell lines, knockdown of ATF5 resulted in rounded morphology and decreased invasion speed. Next, we showed that ATF5 induced integrin-α2 and integrin-β1 expression and that the depletion of integrin-α2 or integrin-β1 resulted in round morphology and decreased invasion speed. Our results suggest that ATF5 promotes invasion by inducing the expression of integrin-α2 and integrin-β1 in several human cancer cell lines. PMID:27125458

  12. Role of positron emission tomography-computed tomography in non-small cell lung cancer.

    Science.gov (United States)

    Garg, Pankaj Kumar; Singh, Saurabh Kumar; Prakash, Gaurav; Jakhetiya, Ashish; Pandey, Durgatosh

    2016-03-26

    Lung cancer is the leading cause of cancer-related mortality worldwide. Non-small cell carcinoma and small cell carcinoma are the main histological subtypes and constitutes around 85% and 15% of all lung cancer respectively. Multimodality treatment plays a key role in the successful management of lung cancer depending upon the histological subtype, stage of disease, and performance status. Imaging modalities play an important role in the diagnosis and accurate staging of the disease, in assessing the response to neoadjuvant therapy, and in the follow-up of the patients. Last decade has witnessed voluminous upsurge in the use of positron emission tomography-computed tomography (PET-CT); role of PET-CT has widened exponentially in the management of lung cancer. The present article reviews the role of 18-fluoro-deoxyglucose PET-CT in the management of non small cell lung cancer with emphasis on staging of the disease and the assessment of response to neoadjuvant therapy based on available literature. PMID:27018223

  13. Roles of micro RNA-140 in stem cell-associated early stage breast cancer

    Institute of Scientific and Technical Information of China (English)

    Benjamin; Wolfson; Gabriel; Eades; Qun; Zhou

    2014-01-01

    An increasing body of evidence supports a stepwise model for progression of breast cancer from ductal carcinoma in situ(DCIS) to invasive ductal carcinoma(IDC). Due to the high level of DCIS heterogeneity, we cannot currently predict which patients are at highest risk for disease recurrence or progression. The mechanisms of progression are still largely unknown, however cancer stem cell populations in DCIS lesions may serve as malignant precursor cells intimately involved in progression. While genetic and epigenetic alterations found in DCIS are often shared by IDC, m RNA and mi RNA expression profiles are significantly altered. Therapeutic targeting of cancer stem cell pathways and differentially expressed mi RNA could have significant clinical benefit. As tumor grade increases, mi RNA-140 is progressively downregulated. mi R-140 plays an important tumor suppressive role in the Wnt, SOX2 and SOX9 stem cell regulator pathways. Downregulation of mi R-140 removes inhibition of these pathways, leading to higher cancer stem cell populations and breast cancer progression. mi R-140 downregulation is mediated through both an estrogen response element in the mi R-140 promoter region and differential methylation of Cp G islands. These mechanisms are novel targets for epigenetic therapy to activate tumor suppressor signaling via mi R-140. Additionally, we briefly explored the emerging role of exosomes in mediating intercellular mi R-140 signaling. The purpose of this review is to examine the cancer stem cell signaling pathways involved in breast cancer progression, and the role of dysregulation of mi R-140 in regulating DCIS to IDC transition.

  14. Synergistic role of three dimensional niche and hypoxia on conservation of cancer stem cell phenotype.

    Science.gov (United States)

    Gorgun, Cansu; Ozturk, Sukru; Gokalp, Sevtap; Vatansever, Seda; Gurhan, S Ismet Deliloglu; Urkmez, Aylin Sendemir

    2016-09-01

    Hypoxia is a pathalogical condition in which tissues are deprived of adequate oxygen supply. The hypoxia effect on tumors has a critically important role on maintenance of cancer stem cell phenotype. The aim of this study is to investigate the effects of hypoxia on cancer stem cells on three dimensional (3D) in vitro culture models. Osteosarcoma stem cells characterized by CD133 surface protein were isolated from osteosarcoma cell line (SaOS-2) by magnetic-activated cell sorting (MACS) technique. Isolated CD133(+) and CD133(-) cells were cultivated under hypoxic (1% O2) and normoxic conditions (21% O2) for 3 days. For the 3D model, bacterial cellulose scaffold was used as the culture substrate. 3D morphologies of cells were examined by scanning electron microscopy (SEM); RT-PCR and immunocytochemistry staining were used to demonstrate conservation of the cancer stem cell phenotype in 3D environment under hypoxic conditions. Cell viability was shown by MTT assay on 3. and 7. culture days. This study is seen as an introduction to develop a 3D hypoxic cancer stem cell based tumor model to study CSC behavior and tumor genesis in vitro. PMID:26718870

  15. THE EMERGING ROLE OF INSULIN AND INSULIN-LIKE GROWTH FACTOR SIGNALING IN CANCER STEM CELLS

    Directory of Open Access Journals (Sweden)

    Roberta eMalaguarnera

    2014-02-01

    Full Text Available Cancer cells frequently exploit the IGF signaling, a fundamental pathway mediating development, cell growth and survival. As a consequence, several components of the IGF signaling are deregulated in cancer and sustain cancer progression. However, specific targeting of IGF-IR in humans has resulted efficacious only in small subsets of cancers, making researches wondering whether IGF system targeting is still worth pursuing in the clinical setting. Although no definite answer is yet available, it has become increasingly clear that other components of the IGF signaling pathway, such as IR-A, may substitute for the lack of IGF-IR, and induce cancer resistance and/or clonal selection. Moreover, accumulating evidence now indicates that IGF signaling is a central player in the induction/maintenance of epithelial mesenchymal transition (EMT and cell stemness, two strictly related programs, which play a key role in metastatic spread and resistance to cancer treatments. Here we review the evidences indicating that IGF signaling enhances the expression of transcription factors implicated in the EMT program and has extensive crosstalk with specific pathways involved in cell pluripotency and stemness maintenance. In turn, EMT and cell stemness activate positive feed-back mechanisms causing upregulation of various IGF signaling components. These findings may have novel translational implications.

  16. Role of Calcium Ion in Apoptosis of MD Cancer Cells Induced by Arsenic Trioxide

    Institute of Scientific and Technical Information of China (English)

    ZHANG Jiuli; WANG Jintao; XU Shiwen

    2008-01-01

    In order to observe the role of calcium ion in apoptosis of MD cancer cells induced by arsenic trioxide, inhibition percentage was detected by MTT assay;morphology changes were examined by fluorescence microscope;apoptosis was examined by DNA Ladder;[Ca2+]i was investigated by spectrofluorimeter in vitro on MDCC-MSB1 cells. The results showed that As2O3 inhibited the proliferation of MDCC-MSB1 cells in concentration dependent manner (P<0.05 or P<0.01);typical apoptosis character was observed by fluorescence microscope;DNA Ladder was observed;the [Ca2+]i was elevated significantly after the treatment of As203 (P<0.05 or P<0.01) and showed a dose-dependent manner. It is concluded that the calcium may play an important role in apoptosis of MD cancer cells induced by arsenic trioxide.

  17. PSF3 marks malignant colon cancer and has a role in cancer cell proliferation

    International Nuclear Information System (INIS)

    PSF3 (partner of Sld five 3) is a member of the tetrameric complex termed GINS, composed of SLD5, PSF1, PSF2, and PSF3, and well-conserved evolutionarily. Previous studies suggested that some GINS complex members are upregulated in cancer, but PSF3 expression in colon carcinoma has not been investigated. Here, we established a mouse anti-PSF3 antibody, and examined PSF3 expression in human colon carcinoma cell lines and colon carcinoma specimens. We found that PSF3 is expressed in the crypt region in normal colonic mucosa and that many PSF3-positive cells co-expressed Ki-67. This suggests that PSF3-positivity of normal mucosa is associated with cell proliferation. Expression of the PSF3 protein was greater in carcinoma compared with the adjacent normal mucosa, and even stronger in high-grade malignancies, suggesting that it may be associated with colon cancer progression. PSF3 gene knock-down in human colon carcinoma cell lines resulted in growth inhibition characterized by delayed S-phase progression. These results suggest that PSF3 is a potential biomarker for diagnosis of progression in colon cancer and could be a new target for cancer therapy.

  18. A key role of microRNA-29b for the suppression of colon cancer cell migration by American ginseng.

    Directory of Open Access Journals (Sweden)

    Deepak Poudyal

    Full Text Available Metastasis of colon cancer cells increases the risk of colon cancer mortality. We have recently shown that American ginseng prevents colon cancer, and a Hexane extract of American Ginseng (HAG has particularly potent anti-inflammatory and anti-cancer properties. Dysregulated microRNA (miR expression has been observed in several disease conditions including colon cancer. Using global miR expression profiling, we observed increased miR-29b in colon cancer cells following exposure to HAG. Since miR-29b plays a role in regulating the migration of cancer cells, we hypothesized that HAG induces miR-29b expression to target matrix metalloproteinase-2 (MMP-2 thereby suppressing the migration of colon cancer cells. Results are consistent with this hypothesis. Our study supports the understanding that targeting MMP-2 by miR-29b is a mechanism by which HAG suppresses the migration of colon cancer cells.

  19. Role of Glycans in Cancer Cells Undergoing Epithelial–Mesenchymal Transition

    Science.gov (United States)

    Li, Xiang; Wang, Xin; Tan, Zengqi; Chen, Si; Guan, Feng

    2016-01-01

    The term “cancer” refers to a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. Epithelial–mesenchymal transition (EMT), a process whereby epithelial cells lose their cell polarity and cell–cell adhesion ability, and acquire migratory and invasive properties to gain mesenchymal phenotype, is an important step leading to tumor metastasis. Glycans, such as N-glycans, O-glycans, and glycosphingolipids, are involved in numerous biological processes, including inflammation, virus/bacteria–host interactions, cell–cell interactions, morphogenesis, and cancer development and progression. Aberrant expression of glycans has been observed in several EMT models, and the functional roles of such glycans in cancer development and progression has been investigated. We summarize here recent research progress regarding the functions of glycans in cancer cells undergoing EMT. Better understanding of the mechanisms underlying aberrant glycan patterns in EMT and cancer will facilitate the development of such glycans as cancer biomarkers or as targets in design and synthesis of anti-tumor drugs. PMID:26925388

  20. Studying the role of macrophages in circulating prostate cancer cells by in vivo flow cytometry

    Science.gov (United States)

    Cui, Xiaojun; Guo, Jin; Gu, Zhengqin; Wei, Xunbin

    2012-12-01

    Metastasis is a very complicated multi-step process and accounts for the low survival rate of the cancerous patients. To metastasize, the malignant cells must detach from the primary tumor and migrate to secondary sites in the body through either blood or lymph circulation. Macrophages appear to be directly involved in tumor progression and metastasis. However, the role of macrophages in affecting cancer metastasis has not been fully elucidated. Here, we have utilized an emerging technique, namely in vivo flow cytometry (IVFC) to study the depletion kinetics of circulating prostate cancer cells in mice and how depletion of macrophages by the liposome-encapsulated clodronate affects the depletion kinetics. Our results show different depletion kinetics of PC-3 cells between macrophage-deficient group and the control group. The number of circulating tumor cells (CTCs) in macrophage-deficient group decreases in a slower manner compared to the control mice group. The differences in depletion kinetics indicate that the absence of macrophages facilitates the stay of prostate cancer cells in circulation. We speculate that macrophages might be able to arrest, phagocytose and digest PC-3 cells. Therefore, the phagocytosis may mainly contribute to the depletion kinetic differences. The developed methods here would be useful to study the relationship between macrophages and tumor metastasis in small animal cancer model.

  1. A transcriptional regulatory role of the THAP11-HCF-1 complex in colon cancer cell function.

    Science.gov (United States)

    Parker, J Brandon; Palchaudhuri, Santanu; Yin, Hanwei; Wei, Jianjun; Chakravarti, Debabrata

    2012-05-01

    The recently identified Thanatos-associated protein (THAP) domain is an atypical zinc finger motif with sequence-specific DNA-binding activity. Emerging data suggest that THAP proteins may function in chromatin-dependent processes, including transcriptional regulation, but the roles of most THAP proteins in normal and aberrant cellular processes remain largely unknown. In this work, we identify THAP11 as a transcriptional regulator differentially expressed in human colon cancer. Immunohistochemical analysis of human colon cancers revealed increased THAP11 expression in both primary tumors and metastases. Knockdown of THAP11 in SW620 colon cancer cells resulted in a significant decrease in cell proliferation, and profiling of gene expression in these cells identified a novel gene set composed of 80 differentially expressed genes, 70% of which were derepressed by THAP11 knockdown. THAP11 was found to associate physically with the transcriptional coregulator HCF-1 (host cell factor 1) and recruit HCF-1 to target promoters. Importantly, THAP11-mediated gene regulation and its chromatin association require HCF-1, while HCF-1 recruitment at these genes requires THAP11. Collectively, these data provide the first characterization of THAP11-dependent gene expression in human colon cancer cells and suggest that the THAP11-HCF-1 complex may be an important transcriptional and cell growth regulator in human colon cancer. PMID:22371484

  2. Distinct roles for histone methyltransferases G9a and GLP in cancer germline antigen gene regulation in human cancer cells and murine ES cells

    OpenAIRE

    Link, Petra A.; Gangisetty, Omkaram; James, Smitha R.; Woloszynska-Read, Anna; Tachibana, Makoto; Shinkai, Yoichi; Karpf, Adam R.

    2009-01-01

    The H3K9me2 histone methyltransferases G9a and GLP repress Mage-a class cancer germline (CG) antigen gene expression in murine ES cells but the role of these enzymes in CG antigen gene regulation in human cancer cells is unknown. Here we show that while independent or dual knockdown of G9a and GLP in human cancer cells leads to reduced global and CG antigen promoter-associated H3K9me2 levels it does not activate CG antigen gene expression. Moreover, CG antigen gene repression is maintained fo...

  3. Mammary development and breast cancer: the role of stem cells

    OpenAIRE

    Ercan, C.; J. van Diest, P.; Vooijs, M.

    2011-01-01

    The mammary gland is a highly regenerative organ that can undergo multiple cycles of proliferation, lactation and involution, a process controlled by stem cells. The last decade much progress has been made in the identification of signaling pathways that function in these stem cells to control self-renewal, lineage commitment and epithelial differentiation in the normal mammary gland. The same signaling pathways that control physiological mammary development and homeostasis are also often fou...

  4. The regulatory role of B cells in autoimmunity, infections and cancer: Perspectives beyond IL10 production.

    Science.gov (United States)

    Gorosito Serrán, Melisa; Fiocca Vernengo, Facundo; Beccaria, Cristian G; Acosta Rodriguez, Eva V; Montes, Carolina L; Gruppi, Adriana

    2015-11-14

    The term regulatory B cells (B regs) is ascribed to a heterogeneous population of B cells with the function of suppressing inflammatory responses. They have been described mainly during the last decade in the context of different immune-mediated diseases. Most of the work on B regs has been focused on IL-10-producing B cells. However, B cells can exert regulatory functions independently of IL-10 production. Here we discuss the phenotypes, development and effector mechanisms of B regs and advances in their role in autoimmunity, infections and cancer. PMID:26424657

  5. Role of macrophages in circulating prostate cancer cells studied by in vivo flow cytometry

    Science.gov (United States)

    Liu, Rongrong; Guo, Jin; Gu, Zhengqin; Wei, Xunbin

    2013-02-01

    Macrophages appear to be directly involved in cancer progression and metastasis. However, the role of macrophages in influencing tumor metastasis has not been fully understood. Here, we have used an emerging technique, namely in vivo flow cytometry (IVFC) to study the depletion kinetics of circulating prostate cancer cells in mice and how depletion of macrophages by the liposome-encapsulated clodronate affects the depletion kinetics. Our results show different depletion kinetics of PC-3 prostate cancer cells between macrophage-deficient group and the control group. The number of circulating tumor cells (CTCs) in macrophage-deficient group decreases in a slower manner compared to the control mice group. The differences in depletion kinetics indicate that the absence of macrophages might facilitate the stay of prostate tumor cells in circulation. We speculate that macrophages might be able to arrest, phagocytose and digest PC-3 cancer cells. Therefore, the phagocytosis may mainly contribute to the differences in depletion kinetics. The developed methods here would be useful to study the relationship between macrophages and cancer metastasis in small animal tumor model.

  6. The Role of Immunoglobulin Superfamily Cell Adhesion Molecules in Cancer Metastasis

    Directory of Open Access Journals (Sweden)

    Chee Wai Wong

    2012-01-01

    Full Text Available Metastasis is a major clinical problem and results in a poor prognosis for most cancers. The metastatic pathway describes the process by which cancer cells give rise to a metastatic lesion in a new tissue or organ. It consists of interconnecting steps all of which must be successfully completed to result in a metastasis. Cell-cell adhesion is a key aspect of many of these steps. Adhesion molecules belonging to the immunoglobulin superfamily (Ig-SF commonly play a central role in cell-cell adhesion, and a number of these molecules have been associated with cancer progression and a metastatic phenotype. Surprisingly, the contribution of Ig-SF members to metastasis has not received the attention afforded other cell adhesion molecules (CAMs such as the integrins. Here we examine the steps in the metastatic pathway focusing on how the Ig-SF members, melanoma cell adhesion molecule (MCAM, L1CAM, neural CAM (NCAM, leukocyte CAM (ALCAM, intercellular CAM-1 (ICAM-1 and platelet endothelial CAM-1 (PECAM-1 could play a role. Although much remains to be understood, this review aims to raise the profile of Ig-SF members in metastasis formation and prompt further research that could lead to useful clinical outcomes.

  7. Damaged DNA binding protein 2 plays a role in breast cancer cell growth.

    Directory of Open Access Journals (Sweden)

    Zilal Kattan

    Full Text Available The Damaged DNA binding protein 2 (DDB2, is involved in nucleotide excision repair as well as in other biological processes in normal cells, including transcription and cell cycle regulation. Loss of DDB2 function may be related to tumor susceptibility. However, hypothesis of this study was that DDB2 could play a role in breast cancer cell growth, resulting in its well known interaction with the proliferative marker E2F1 in breast neoplasia. DDB2 gene was overexpressed in estrogen receptor (ER-positive (MCF-7 and T47D, but not in ER-negative breast cancer (MDA-MB231 and SKBR3 or normal mammary epithelial cell lines. In addition, DDB2 expression was significantly (3.0-fold higher in ER-positive than in ER-negative tumor samples (P = 0.0208 from 16 patients with breast carcinoma. Knockdown of DDB2 by small interfering RNA in MCF-7 cells caused a decrease in cancer cell growth and colony formation. Inversely, introduction of the DDB2 gene into MDA-MB231 cells stimulated growth and colony formation. Cell cycle distribution and 5 Bromodeoxyuridine incorporation by flow cytometry analysis showed that the growth-inhibiting effect of DDB2 knockdown was the consequence of a delayed G1/S transition and a slowed progression through the S phase of MCF-7 cells. These results were supported by a strong decrease in the expression of S phase markers (Proliferating Cell Nuclear Antigen, cyclin E and dihydrofolate reductase. These findings demonstrate for the first time that DDB2 can play a role as oncogene and may become a promising candidate as a predictive marker in breast cancer.

  8. Dual Roles of Immune Cells and Their Factors in Cancer Development and Progression

    Directory of Open Access Journals (Sweden)

    Brian F. Zamarron, WanJun Chen

    2011-01-01

    Full Text Available Traditional wisdom holds that intact immune responses, such as immune surveillance or immunoediting, are required for preventing and inhibiting tumor development; but recent evidence has also indicated that unresolved immune responses, such as chronic inflammation, can promote the growth and progression of cancer. Within the immune system, cytotoxic CD8+ and CD4+ Th1 T cells, along with their characteristically produced cytokine IFN-γ, function as the major anti-tumor immune effector cells, whereas tumor associated macrophages (TAM or myeloid-derived suppressive cells (MDSC and their derived cytokines IL-6, TNF, IL-1β and IL-23 are generally recognized as dominant tumor-promoting forces. However, the roles played by Th17 cells, CD4+ CD25+ Foxp3+ regulatory T lymphocytes and immunoregulatory cytokines such as TGF-β in tumor development and survival remain elusive. These immune cells and the cellular factors produced from them, including both immunosuppressive and inflammatory cytokines, play dual roles in promoting or discouraging cancer development, and their ultimate role in cancer progression may rely heavily on the tumor microenvironment and the events leading to initial propagation of carcinogenesis.

  9. Apoptotic potential role of Agave palmeri and Tulbaghia violacea extracts in cervical cancer cells.

    Science.gov (United States)

    Mthembu, Nonkululeko N; Motadi, Lesetja Raymond

    2014-09-01

    Cervical cancer, a gynaecological malignant disorder, is a common cause of death in females in Sub-Saharan Africa, striking nearly half a million of lives each year worldwide. Currently, more than 50 % of all modern drugs in clinical use are of natural products, many of which have an ability to control cancer cells (Madhuri and Pandey, Curr Sci 96:779-783, 2009; Richter, Traditional medicines and traditional healers in South Africa, 2003). In South Africa, plants used to treat cancer are rare even though majority of our population continue to put their trust in traditional medicine. In this study we aimed to screen Agave palmeri (AG) and Tulbaghia violacea (TV) for potential role in inducing cell death in cervical cancer cell lines HeLa and ME-180, and in normal human fibroblast cell line KMST-6 cell lines. To achieve this, AG and TV crude extracts were utilized to screen for apoptosis induction, inhibition of cell proliferation followed by elucidation of the role of Bax, Bcl-2, p53, Rb, RBBP and Mdm2 genes in cervical cancer. In brief, plant leaves and roots were collected, crushed and methanolic extracts obtained. Different concentrations of the stock extracts were used to treat cancer cells and measure cell death using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay and flow cytometry. Western blot was applied to measure gene expression at protein level using RBBP6, p53, Mdm2, Rb, Bax, Bcl-2 and β-actin mouse monoclonal primary antibodies (IgG) and goat anti mouse coupled with horseradish peroxidase secondary antibody from Santa Cruz Biotechnology and real time-PCR was used for mRNA expression level. Plant extracts of AG and TV were time (24 h) and dose (50, 100, 150 μg/ml) dependent in their induction of cell death with an IC50 ~ 150 μg/ml. A further mixed respond by several genes was observed following treatment with the two plant extracts where RBBP6 was seen to be spliced in cancer cells while Bax was induced and Bcl-2 was

  10. Matrix metalloproteases as maestros for the dual role of LPS- and IL-10-stimulated macrophages in cancer cell behaviour

    OpenAIRE

    Ana P. Cardoso; Pinto, Marta L.; Pinto, Ana T.; Pinto, Marta T.; Monteiro, Cátia; Oliveira, Marta I; Santos, Susana G.; Relvas, João B.; Seruca, Raquel; Mantovani, Alberto; Mareel, Marc; Barbosa, Mário A.; Oliveira, Maria J.

    2015-01-01

    Background The interactions established between macrophages and cancer cells are largely dependent on instructions from the tumour microenvironment. Macrophages may differentiate into populations with distinct inflammatory profiles, but knowledge on their role on cancer cell activities is still very scarce. In this work, we investigated the influence of pro-inflammatory (LPS-stimulated) and anti-inflammatory (IL-10-stimulated) macrophages on gastric and colorectal cancer cell invasion, motili...

  11. Crucial role of HMGA1 in the self-renewal and drug resistance of ovarian cancer stem cells

    Science.gov (United States)

    Kim, Dae Kyoung; Seo, Eun Jin; Choi, Eun J; Lee, Su In; Kwon, Yang Woo; Jang, Il Ho; Kim, Seung-Chul; Kim, Ki-Hyung; Suh, Dong-Soo; Seong-Jang, Kim; Lee, Sang Chul; Kim, Jae Ho

    2016-01-01

    Cancer stem cells are a subpopulation of cancer cells characterized by self-renewal ability, tumorigenesis and drug resistance. The aim of this study was to investigate the role of HMGA1, a chromatin remodeling factor abundantly expressed in many different cancers, in the regulation of cancer stem cells in ovarian cancer. Spheroid-forming cancer stem cells were isolated from A2780, SKOV3 and PA1 ovarian cancer cells by three-dimensional spheroid culture. Elevated expression of HMGA1 was observed in spheroid cells along with increased expression of stemness-related genes, such as SOX2, KLF4, ALDH, ABCB1 and ABCG2. Furthermore, spheroid A2780 cells, compared with adherent cells, showed higher resistance to chemotherapeutic agents such as paclitaxel and doxorubicin. HMGA1 knockdown in spheroid cells reduced the proliferative advantage and spheroid-forming efficiency of the cells and the expression of stemness-related genes. HMGA1 overexpression in adherent A2780 cells increased cancer stem cell properties, including proliferation, spheroid-forming efficiency and the expression of stemness-related genes. In addition, HMGA1 regulated ABCG2 promoter activity through HMGA1-binding sites. Knockdown of HMGA1 in spheroid cells reduced resistance to chemotherapeutic agents, whereas the overexpression of HMGA1 in adherent ovarian cancer cells increased resistance to chemotherapeutic agents in vitro. Furthermore, HMGA1-overexpressing A2780 cells showed a significant survival advantage after chemotherapeutic agent treatment in a xenograft tumorigenicity assay. Together, our results provide novel insights regarding the critical role of HMGA1 in the regulation of the cancer stem cell characteristics of ovarian cancer cells, thus suggesting that HMGA1 may be an important target in the development of therapeutics for ovarian cancer patients. PMID:27561949

  12. mTOR plays critical roles in pancreatic cancer stem cells through specific and stemness-related functions

    Science.gov (United States)

    Matsubara, Shyuichiro; Ding, Qiang; Miyazaki, Yumi; Kuwahata, Taisaku; Tsukasa, Koichiro; Takao, Sonshin

    2013-11-01

    Pancreatic cancer is characterized by near-universal mutations in KRAS. The mammalian target of rapamycin (mTOR), which functions downstream of RAS, has divergent effects on stem cells. In the present study, we investigated the significance of the mTOR pathway in maintaining the properties of pancreatic cancer stem cells. The mTOR inhibitor, rapamycin, reduced the viability of CD133+ pancreatic cancer cells and sphere formation which is an index of self-renewal of stem-like cells, indicating that the mTOR pathway functions to maintain cancer stem-like cells. Further, rapamycin had different effects on CD133+ cells compared to cyclopamine which is an inhibitor of the Hedgehog pathway. Thus, the mTOR pathway has a distinct role although both pathways maintain pancreatic cancer stem cells. Therefore, mTOR might be a promising target to eliminate pancreatic cancer stem cells.

  13. Prostate cancer stem cells: the role of androgen and estrogen receptors

    OpenAIRE

    Di Zazzo, Erika; Galasso, Giovanni; Giovannelli, Pia; Di Donato, Marzia; Di Santi, Annalisa; Cernera, Gustavo; Rossi, Valentina; Abbondanza, Ciro; Moncharmont, Bruno; Sinisi, Antonio Agostino; Castoria, Gabriella; Migliaccio, Antimo

    2015-01-01

    Prostate cancer is one of the most commonly diagnosed cancers in men, and androgen deprivation therapy still represents the primary treatment for prostate cancer patients. This approach, however, frequently fails and patients develop castration-resistant prostate cancer, which is almost untreatable. Cancer cells are characterized by a hierarchical organization, and stem/progenitor cells are endowed with tumor-initiating activity. Accumulating evidence indicates that prostate cancer stem cells...

  14. The Role of Merkel Cell Polyomavirus and Other Human Polyomaviruses in Emerging Hallmarks of Cancer

    Directory of Open Access Journals (Sweden)

    Ugo Moens

    2015-04-01

    Full Text Available Polyomaviruses are non-enveloped, dsDNA viruses that are common in mammals, including humans. All polyomaviruses encode the large T-antigen and small t-antigen proteins that share conserved functional domains, comprising binding motifs for the tumor suppressors pRb and p53, and for protein phosphatase 2A, respectively. At present, 13 different human polyomaviruses are known, and for some of them their large T-antigen and small t-antigen have been shown to possess oncogenic properties in cell culture and animal models, while similar functions are assumed for the large T- and small t-antigen of other human polyomaviruses. However, so far the Merkel cell polyomavirus seems to be the only human polyomavirus associated with cancer. The large T- and small t-antigen exert their tumorigenic effects through classical hallmarks of cancer: inhibiting tumor suppressors, activating tumor promoters, preventing apoptosis, inducing angiogenesis and stimulating metastasis. This review elaborates on the putative roles of human polyomaviruses in some of the emerging hallmarks of cancer. The reciprocal interactions between human polyomaviruses and the immune system response are discussed, a plausible role of polyomavirus-encoded and polyomavirus-induced microRNA in cancer is described, and the effect of polyomaviruses on energy homeostasis and exosomes is explored. Therapeutic strategies against these emerging hallmarks of cancer are also suggested.

  15. A role for collagen XXIII in cancer cell adhesion, anchorage-independence, and metastasis

    OpenAIRE

    Spivey, Kristin A.; Chung, Ivy; Banyard, Jacqueline; Adini, Irit; Feldman, Henry A.; Bruce R Zetter

    2011-01-01

    Collagen XXIII is a transmembrane collagen previously shown to be upregulated in metastatic prostate cancer that has been used as a tissue and fluid biomarker for non-small cell lung cancer and prostate cancer. To determine whether collagen XXIII facilitates cancer cell metastasis in vivo and to establish a function for collagen XXIII in cancer progression, collagen XXIII knockdown cells were examined for alterations in in vivo metastasis as well as in vitro cell adhesion. In experimental and...

  16. The role of RAD51 in etoposide (VP16) resistance in small cell lung cancer

    DEFF Research Database (Denmark)

    Hansen, Lasse Tengbjerg; Lundin, Cecilia; Spang-Thomsen, Mogens;

    2003-01-01

    investigated DSB repair and cellular VP16 sensitivity of SCLC cells. VP16 sensitivity and RAD51, DNA-PK(cs), topoisomerase IIalpha and P-glycoprotein protein levels were determined in 17 SCLC cell lines. In order to unravel the role of RAD51 in VP16 resistance, we cloned the human RAD51 gene, transfected SCLC......Etoposide (VP16) is a potent inducer of DNA double-strand breaks (DSBs) and is efficiently used in small cell lung cancer (SCLC) therapy. However, acquired VP16 resistance remains an important barrier to effective treatment. To understand the underlying mechanisms for VP16 resistance in SCLC, we...

  17. The diverse and contrasting effects of using human prostate cancer cell lines to study androgen receptor roles in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Sheng-Qiang Yu; Kuo-Pao Lai; Shu-Jie Xia; Hong-Chiang Chang; Chawnshang Chang; Shuyuan Yeh

    2009-01-01

    The androgen receptor (AR) plays an important role in the development and progression of prostate cancer (PCa).Androgen deprivation therapy is initially effective in blocking tumor growth,but it eventually leads to the hormonerefractory state.The detailed mechanisms of the conversion from androgen dependence to androgen independence remain unclear.Several PCa cell lines were established to study the role of AR in PCa,but the results were often inconsistent or contrasting in different cell lines,or in the same cell line grown under different conditions.The cellular and molecular alteration of epithelial cells and their microenvironments are complicated,and it is difficult to use a single cell line to address this important issue and also to study the pathophysiological effects of AR.In this paper,we summarize the different effects of AR on multiple cell lines and show the disadvantages of using a single human PCa cell line to study AR effects on PCa.We also discuss the advantages of widely used epithelium-stroma co-culture systems,xenograft mouse models,and genetically engineered PCa mouse models.The combination of in vitro cell line studies and in vivo mouse models might lead to more credible results and better strategies for the study of AR roles in PCa.

  18. PUTATIVE ROLE OF ADIPOSE TISSUE IN GROWTH AND METABOLISM OF COLON CANCER CELLS

    Directory of Open Access Journals (Sweden)

    BettySchwartz

    2014-06-01

    Given that adipocytes are a major source of adipokines and energy for the cancer cell, understanding the mechanisms of metabolic symbiosis between cancer cells and adipocytes should reveal new therapeutic possibilities.

  19. The role of natural polyphenols in cell signaling and cytoprotection against cancer development.

    Science.gov (United States)

    Lewandowska, Hanna; Kalinowska, Monika; Lewandowski, Włodzimierz; Stępkowski, Tomasz M; Brzóska, Kamil

    2016-06-01

    The cytoprotective and anticancer action of dietary in-taken natural polyphenols has for long been attributed only to their direct radical scavenging activities. Currently it is well supported that those compounds display a broad spectrum of biological and pharmacological outcomes mediated by their complex metabolism, interaction with gut microbiota as well as direct interactions of their metabolites with key cellular signaling proteins. The beneficial effects of natural polyphenols and their synthetic derivatives are extensively studied in context of cancer prophylaxis and therapy. Herein we focus on cell signaling to explain the beneficial role of polyphenols at the three stages of cancer development: we review the recent proceedings about the impact of polyphenols on the cytoprotective antioxidant response and their proapoptotic action at the premalignant stage, and finally we present data showing how phenolic acids (e.g., caffeic, chlorogenic acids) and flavonols (e.g., quercetin) hamper the development of metastatic cancer. PMID:27142731

  20. The increasing role of amphiregulin in non-small cell lung cancer.

    OpenAIRE

    Busser, Benoît; Coll, Jean-Luc; Hurbin, Amandine

    2009-01-01

    International audience Non-small cell lung cancers present a 5-year survival rate below 12%. Such a poor prognosis may be explained by non small cell lung cancer cells evasion to apoptosis and resistance to treatments. Amphiregulin, an epidermal growth factor-related growth factor is secreted by non-small cell lung cancer cells in an autocrine/paracrine manner to promote autonomous growth of tumor cells and to provide resistance to apoptosis. Furthermore, amphiregulin is involved in non-sm...

  1. Studies into characteristics of cancer stem cells and their role in the origin of epithelial tumours.

    OpenAIRE

    Burkert, J.

    2008-01-01

    Tumours are organised in a cellular hierarchy, originating in and maintained by a minority of cells with stem cell characteristics, so-called 'cancer stem cells'. The Side Population (SP) phenotype, distinguished by its ability to efflux the nucleic acid dye Hoechst 33342, as well as surface markers CD44 and CD133 were evaluated as potential cancer stem cell markers in human colorectal cancer cell lines and primary adenocarcinomas by testing sorted cell fractions for phenotypical and behaviou...

  2. The role of Kif4A in doxorubicin-induced apoptosis in breast cancer cells.

    Science.gov (United States)

    Wang, Hui; Lu, Changqing; Li, Qing; Xie, Jun; Chen, Tongbing; Tan, Yan; Wu, Changping; Jiang, Jingting

    2014-11-01

    This study was to investigate the mechanism and role of Kif4A in doxorubicin-induced apoptosis in breast cancer. Using two human breast cancer cell lines MCF-7 (with wild-type p53) and MDA-MB-231 (with mutant p53), we quantitated the expression levels of kinesin super-family protein 4A (Kif4A) and poly (ADP-ribose) Polymerase-1 (PARP-1) by Western blot after doxorubicin treatment and examined the apoptosis by flow cytometry after treatment with doxorubicin and PARP-1 inhibitor, 3-Aminobenzamide (3-ABA). Our results showed that doxorubicin treatment could induce the apoptosis of MCF-7 and MDA-MB-231 cells, the down-regulation of Kif4A and upregulation of poly(ADP-ribose) (PAR). The activity of PARP-1 or PARP-1 activation was significantly elevated by doxorubicin treatment in dose- and time-dependent manners (P 0.05). We further demonstrated that overexpression of Kif4A could reduce the level of PAR and significantly increase apoptosis. The effect of doxorubicin on apoptosis was more profound in MCF-7 cells compared with MDA-MB-231 cells (P breast cancer cells is achieved by inhibiting the activity of PARP-1. PMID:25377255

  3. Roles of EGFR and KRAS and their downstream signaling pathways in pancreatic cancer and pancreatic cancer stem cells.

    Science.gov (United States)

    Fitzgerald, Timothy L; Lertpiriyapong, Kvin; Cocco, Lucio; Martelli, Alberto M; Libra, Massimo; Candido, Saverio; Montalto, Giuseppe; Cervello, Melchiorre; Steelman, Linda; Abrams, Stephen L; McCubrey, James A

    2015-09-01

    Pancreatic cancer is currently the fourth most common cancer, is increasing in incidence and soon will be the second leading cause of cancer death in the USA. This is a deadly malignancy with an incidence that approximates the mortality with 44,000 new cases and 36,000 deaths each year. Surgery, although only modestly successful, is the only curative option. However, due the locally aggressive nature and early metastasis, surgery can be performed on less than 20% of patients. Cytotoxic chemotherapy is palliative, has significant toxicity and improves survival very little. Thus new treatment paradigms are needed desperately. Due to the extremely high frequency of KRAS gene mutations (>90%) detected in pancreatic cancer patients, the roles of the epidermal growth factor receptor (EGFR), Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTORC1/GSK-3 pathways have been investigated in pancreatic cancer for many years. Constitutively active Ras can activate both of these pathways and there is cross talk between Ras and EGFR which is believed to be important in driving metastasis. Mutant KRAS may also drive the expression of GSK-3 through Raf/MEK/ERK-mediated effects on GSK-3 transcription. GSK-3 can then regulate the expression of NF-kappaB which is important in modulating pancreatic cancer chemoresistance. While the receptors and many downstream signaling molecules have been identified and characterized, there is still much to learn about these pathways and how their deregulation can lead to cancer. Multiple inhibitors to EGFR, PI3K, mTOR, GSK-3, Raf, MEK and hedgehog (HH) have been developed and are being evaluated in various cancers. Current research often focuses on the role of these pathways in cancer stem cells (CSC), with the goal to identify sites where therapeutic resistance may develop. Relatively novel fields of investigation such as microRNAs and drugs used for other diseases e.g., diabetes, (metformin) and malaria (chloroquine) have provided new information about

  4. ROLE OF PANCREATIC STELLATE CELLS AND GALECTIN-3 ON PROLIFERATION AND INFILTRATION OF HUMAN PANCREATIC CANCER CELL LINE SW1990

    Institute of Scientific and Technical Information of China (English)

    JIANG Hai-biao; XU Ming; WANG Xing-peng

    2008-01-01

    Objective To investigate the role of pancreatic stellate cells (PSCs) and galectin-3 (GAL-3)on the proliferation and infiltration of pancreatic cancer cell line SW1990. Methods Human pancreatic cancercell line SW1990 and PSCs were cultured in vitro. Supernatant of cultured PSCs and SW1990 cells was collected.Expressions of GAL-3 in SW1990 cells and PSCs were detected by ELISA, RT-PCR and Western blot. Theproliferation of those cultured PSCs and SW1990 cells were measured by MTT assay and flowcytometry. Infiltrationof SW1990 cells was detected by cell infiltration kit. Results SW1990 cells expressed GAL-3 and the expressionwas up-regulated by the supernatant fluid of cultured PSCs. PSCs did not express GAL-3. SW1990 cells couldstimulate the proliferation of PSCs via GAL-3. GAL-3 antibody could inhibit SW1990 cells proliferation andinfiltration, which indicated that supernatant of PSCs might stimulate the proliferation of SW1990 cells through theinteraction with GAL-3 protein. The supernatant fluid of PSCs could enhance the invasiveness of SW1990 cellsthrough the interaction with GAL-3. Conclusion GAL-3 and PSCs was involved in the proliferation andinfiltration process of pancreatic cancer.

  5. The emerging role of extracellular vesicle-derived miRNAs: implication in cancer progression and stem cell related diseases

    OpenAIRE

    Yang, Qiwei; Diamond, Michael P.; Al-Hendy, Ayman

    2016-01-01

    Cells release into the extracellular environment, diverse types of membrane vesicles of endosomal and plasma membrane origin called exosomes and microvesicles. A number of studies indicate that these extracellular vehicles (EVs) mediate the interaction between cancer cells and their microenvironment; and thereby, play a critical role in the development of cancers. EVs contain cargo which consist of proteins, lipids, mRNAs, and miRNAs that can be delivered to different types of cells in nascen...

  6. Role of CD44high/CD133high HCT-116 cells in the tumorigenesis of colon cancer.

    Science.gov (United States)

    Zhou, Jin-Yong; Chen, Min; Ma, Long; Wang, Xiaoxiao; Chen, Yu-Gen; Liu, Shen-Lin

    2016-02-16

    This study aimed to explore cell surface biomarkers related to cancer stem cells (CSCs) and their role in the tumorigenesis of colon cancer. Various colon cancer cell lines were screened for CD133 and CD44 expression. CD44high/CD133high and CD44low/CD133low cells were separately isolated by Fluorescence-Activated Cell Sorting (FACS). The cell proliferation, colony formation, cell cycle characteristics, and tumorigenic properties in CD44high/CD133high and CD44low/CD133low cells were investigated through in vitro experiments and in vivo tumor xenograft models. The expression profiles of stem cell-related genes were examined by RT-PCR. With HCT-116 cells, flow cytometry analysis revealed that CD44high/CD133high cells had higher proliferation potency than CD44low/CD133low cells. Compared to CD44low/CD133low cells, CD44high/CD133high cells had more stem cell-related genes, and displayed increased tumorigenic ability. In summary, CD44high/CD133high cells isolated from HCT-116 cells harbor CSC properties that may be related to the tumor growth of colon cancer. These results suggest that CD44 and CD133 could be strong markers of colorectal cancer stem cells. PMID:26840024

  7. Role of cytokines in promoting immune escape of FasL-expressing human colon cancer cells

    Institute of Scientific and Technical Information of China (English)

    Tong Xu; Bao-Cun Sun; Qiang Li; Xi-Shan Hao

    2005-01-01

    AIM: To investigate the potential role of cytokines in promoting Fas ligand (FasL)-expressing colon cancer cells.METHODS: Immunohistochemical SABC method was used to observe the expression of Fas receptor and ligand in SW620 colon cancer cell line and Jurkat T cells in order to provide the morphological evidence for the functions of Fas receptor and ligand. To examine the cytotoxicity of effector cells, CytoTox96(R) non-radioactive cytotoxicity assay was adopted to measure the lactate dehydrogenase-releasing value after SW620 cells were co-cultured with Jurkat T lymphocytes.RESULTS: The FasL of colon cancer SW620 cells was positive. The positive substances were distributed in the cell membrane and cytoplasm. The Fas receptor of colon cancer SW620 cells was negative. The Fas receptor and ligand of Jurkat T lymphocytes tumed out to be positive. The positive substances were distributed in the cell membrane.After phytohemagglutinin (PHA)-stimulated Jurkat T lymphocytes were co-cultured with phorbol 12-myristate 13-acetate (PMA)-plus-ionomycin-stimulated (for 48 h) SW620ceils or tumor necrosis factor-alpha (TNF-α)-stimulated (for 48 h) SW620 cells or unstimulated SW620 cells for 4 h,the cytotoxicity of SW620 cells to PHA-stimulated Jurkat cells at effector-to-target ratios of 10:1, 5:1, 2.5:1, and 1.25:1was 74.6%, 40.8%, 32.4%, and 10.9% (F= 8.19, P<0.05);or 54.9%, 35.3%, 22.0%, and 10.3% (F= 11.12, P<0.05);or 14.9%, 10.5%, 6.9%, and 5.8% (F= 3.45, P<0.05).After PHA-stimulated Jurkat T lymphocytes were co-cultured with unstimulated SW620 cells for 8 h, the cytotoxicity of SW620 cells to PHA-stimulated Jurkat cells at effector-totarget ratios of 5:1, 2.5:1, and 1.25:1 from the experiment was 83.9%, 74.1%, and 28.5% (F= 137.04, P<0.05)respectively. Non-radioactive cytotoxicity assay showed that the apoptotic rate of Jurkat cells remarkably increased with the increase of planting concentration of SW620 cells and co-culture time after the SW620 cells were co

  8. Butyrate plays differential roles in cellular signaling in cancerous HCT116 and noncancerous NCM460 colon cells

    Science.gov (United States)

    Butyrate, an intestinal microbiota metabolite of dietary fiber, exhibits chemoprevention effects in colon. However, the mechanistic action of butyrate at the cellular level remains to be determined. We hypothesize that butyrate plays differential roles in cancerous and non-cancerous cells through si...

  9. Nerve growth factor: role in growth, differentiation and controlling cancer cell development.

    Science.gov (United States)

    Aloe, Luigi; Rocco, Maria Luisa; Balzamino, Bijorn Omar; Micera, Alessandra

    2016-01-01

    Recent progress in the Nerve Growth Factor (NGF) research has shown that this factor acts not only outside its classical domain of the peripheral and central nervous system, but also on non-neuronal and cancer cells. This latter observation has led to divergent hypothesis about the role of NGF, its specific distribution pattern within the tissues and its implication in induction as well as progression of carcinogenesis. Moreover, other recent studies have shown that NGF has direct clinical relevance in certain human brain neuron degeneration and a number of human ocular disorders. These studies, by suggesting that NGF is involved in a plethora of physiological function in health and disease, warrant further investigation regarding the true role of NGF in carcinogenesis. Based on our long-lasting experience in the physiopathology of NGF, we aimed to review previous and recent in vivo and in vitro NGF studies on tumor cell induction, progression and arrest. Overall, these studies indicate that the only presence of NGF is unable to generate cell carcinogenesis, both in normal neuronal and non-neuronal cells/tissues. However, it cannot be excluded the possibility that the co-expression of NGF and pro-carcinogenic molecules might open to different consequence. Whether NGF plays a direct or an indirect role in cell proliferation during carcinogenesis remains to demonstrate. PMID:27439311

  10. The Role of Tumor-Infiltrating Lymphocytes in Development, Progression, and Prognosis of Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Bremnes, Roy M; Busund, Lill-Tove; Kilvær, Thomas L; Andersen, Sigve; Richardsen, Elin; Paulsen, Erna Elise; Hald, Sigurd; Khanehkenari, Mehrdad Rakaee; Cooper, Wendy A; Kao, Steven C; Dønnem, Tom

    2016-06-01

    A malignant tumor is not merely an accumulation of neoplastic cells, but constitutes a microenvironment containing endothelial cells, fibroblasts, structural components, and infiltrating immune cells that impact tumor development, invasion, metastasis, and outcome. Hence, the evolution of cancers reflects intricate cellular and molecular interactions between tumor cells and constituents of the tumor microenvironment. Recent studies have shed new light on this complex interaction between tumor and host immune cells and the resulting immune response. The composition of the immune microenvironment differs across patients as well as in cancers of the same type, including various populations of T cells, B cells, dendritic cells, natural killer cells, myeloid-derived suppressor cells, neutrophils, and macrophages. The type, density, location, and organization of immune cells within solid tumors define the immune contexture, which has proved to be a major determinant of tumor characteristics and patient outcome. Lung cancer consists mostly of non-small cell lung cancer (85%); it is our most deadly malignant disease, with the 5-year survival rate being merely 15%. This review focuses on the immune contexture; the tumor-suppressing roles of tumor-infiltrating lymphocytes; and the relevance of this immune contexture for cancer diagnostics, prognostication, and treatment allocation, with an emphasis on non-small cell lung cancer. PMID:26845192

  11. Cancer stem cell subsets and their relationships

    OpenAIRE

    Pan Yi-Fei; Yang Han; Chen Chong; Liu Hai-Guang; Zhang Xiao-Hua

    2011-01-01

    Abstract Emerging evidence suggests that cancer stem cells account for the initiation and progression of cancer. While many types of cancer stem cells with specific markers have been isolated and identified, a variety of differences among them began to be appreciated. Cancer stem cells are hierarchical populations that consist of precancerous stem cells, primary cancer stem cells, migrating cancer stem cells and chemoradioresistant cancer stem cells, playing different roles in cancer initiati...

  12. The role of microRNA-1274a in the tumorigenesis of gastric cancer: Accelerating cancer cell proliferation and migration via directly targeting FOXO4

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Guo-Jun, E-mail: wwangguojun@163.com; Liu, Guang-Hui; Ye, Yan-Wei; Fu, Yang; Zhang, Xie-Fu

    2015-04-17

    MicroRNAs (miRNAs) are a series of 18–25 nucleotides length non-coding RNAs, which play critical roles in tumorigenesis. Previous study has shown that microRNA-1274a (miR-1274a) is upregulated in human gastric cancer. However, its role in gastric cancer progression remains poorly understood. Therefore, the current study was aimed to examine the effect of miR-1274a on gastric cancer cells. We found that miR-1274a was overexpressed in gastric cancer tissues or gastric cancer cells including HGC27, MGC803, AGS, and SGC-7901 by qRT-PCR analysis. Transfection of miR-1274a markedly promoted gastric cancer cells proliferation and migration as well as induced epithelial–mesenchymal transition (EMT) of cancer cells. Our further examination identified FOXO4 as a target of miR-1274a, which did not influence FOXO4 mRNA expression but significantly inhibited FOXO4 protein expression. Moreover, miR-1274a overexpression activated PI3K/Akt signaling and upregulated cyclin D1, MMP-2 and MMP-9 expressions. With tumor xenografts in mice models, we also showed that miR-1274a promoted tumorigenesis of gastric cancer in vivo. In all, our study demonstrated that miR-1274a prompted gastric cancer cells growth and migration through dampening FOXO4 expression thus provided a potential target for human gastric cancer therapy. - Highlights: • MiR-1274a expression was augmented in gastric cancer. • MiR-1274a promoted proliferation, migration and induced EMT in cancer cells. • MiR-1274a directly targeted FOXO4 expression. • MiR-1274a triggered PI3K/Akt signaling in cancer cells. • MiR-1274a significantly increased tumor xenografts growth.

  13. The role of microRNA-1274a in the tumorigenesis of gastric cancer: Accelerating cancer cell proliferation and migration via directly targeting FOXO4

    International Nuclear Information System (INIS)

    MicroRNAs (miRNAs) are a series of 18–25 nucleotides length non-coding RNAs, which play critical roles in tumorigenesis. Previous study has shown that microRNA-1274a (miR-1274a) is upregulated in human gastric cancer. However, its role in gastric cancer progression remains poorly understood. Therefore, the current study was aimed to examine the effect of miR-1274a on gastric cancer cells. We found that miR-1274a was overexpressed in gastric cancer tissues or gastric cancer cells including HGC27, MGC803, AGS, and SGC-7901 by qRT-PCR analysis. Transfection of miR-1274a markedly promoted gastric cancer cells proliferation and migration as well as induced epithelial–mesenchymal transition (EMT) of cancer cells. Our further examination identified FOXO4 as a target of miR-1274a, which did not influence FOXO4 mRNA expression but significantly inhibited FOXO4 protein expression. Moreover, miR-1274a overexpression activated PI3K/Akt signaling and upregulated cyclin D1, MMP-2 and MMP-9 expressions. With tumor xenografts in mice models, we also showed that miR-1274a promoted tumorigenesis of gastric cancer in vivo. In all, our study demonstrated that miR-1274a prompted gastric cancer cells growth and migration through dampening FOXO4 expression thus provided a potential target for human gastric cancer therapy. - Highlights: • MiR-1274a expression was augmented in gastric cancer. • MiR-1274a promoted proliferation, migration and induced EMT in cancer cells. • MiR-1274a directly targeted FOXO4 expression. • MiR-1274a triggered PI3K/Akt signaling in cancer cells. • MiR-1274a significantly increased tumor xenografts growth

  14. Roles of Mir-144-ZFX pathway in growth regulation of non-small-cell lung cancer.

    Directory of Open Access Journals (Sweden)

    Wangjian Zha

    Full Text Available BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. Non-small cell lung carcinoma (NSCLC accounts for most of the lung cancer cases and the prognosis of this disease remains poor despite decades of intensive investigation. Thus new insights into underlying mechanisms by which NSCLC develops are avidly needed as the basis for development of new lines of therapeutic strategies. The past decade has witnessed a growing interest on the regulatory roles of micro RNAs on various categories of malignancies. Related data has been well documented in carcinogenesis and pathophysiology of a variety of malignancies. Even so, there is a relative lack of data on roles of mir-144 in tumor biology and there has been no report showing the involvement of mir-144 in NSCLC development. METHODS/PRINCIPAL FINDING: From human NSCLC tumor tissue samples and cell culture samples, we found that the expression of mir-144 is associated with malignant phenotype of NSCLC. Further investigations showed that ectopic mir-144 expression dramatically inhibits NSCLC tumor cell growth and induces apoptosis as manifested by elevated apoptotic protein markers and flowcytometry change. Moreover, we also found that ZFX protein expression is also associated with malignant phenotype of NSCLC and knockdown of ZFX protein results in a similar effect as of ectopic mir-144 expression. Finally, we found that ZFX expression is highly adjustable upon presence of mir-144 and ectopic expression of ZFX dramatically dampens mir-144 action of tumor inhibition. CONCLUSIONS: Our results for the first time showed mir-144-ZFX pathway is involved in the development of NSCLC, which sheds a light for further investigations on underlying mechanisms toward better understanding and management of NSCLC.

  15. Role of phosphoproteins involved in chemoresistance of colorectal cancer stem cells and immuno phenotypic comparative analysis

    International Nuclear Information System (INIS)

    Recent studies demonstrated that colon cancers contain a cellular subpopulation, with stem cell-like proprieties, able to initiate and sustain tumour growth. These cells, so-called Cancer Initiating Cells (CICs), express the transmembrane antigen CD133. CD133 positive cells show slow proliferation rate, high expression of ABC (ATP-binding cassette) transporters and anti-apoptotic factors making them resistant to conventional therapies

  16. The Role of Colorectal Cancer Stem Cells in Metastatic Disease and Therapeutic Response

    OpenAIRE

    Wong, Melissa H.; Levin, Trevor G.; Anderson, Eric C.; Crystal Hessman; Monroe, Marcus M.

    2011-01-01

    Colorectal cancer is the third-leading cause of cancer related mortality in the United States. The intricate molecular mechanisms involved in the regenerative process of the normal intestine and the identity of putative somatic intestinal stem cells have become clear. In parallel with this, experiment evidence has emerged supporting the century old hypothesis that solid tumor initiation, progression, chemoresistance and recurrence is the result of a small population of cancer cells with self-...

  17. New targeted treatments for non-small-cell lung cancer - role of nivolumab.

    Science.gov (United States)

    Zago, Giulia; Muller, Mirte; van den Heuvel, Michel; Baas, Paul

    2016-01-01

    Non-small-cell lung cancer (NSCLC) is often diagnosed at an advanced stage of disease, where it is no longer amenable to curative treatment. During the last decades, the survival has only improved significantly for lung cancer patients who have tumors harboring a driver mutation. Therefore, there is a clear unmet need for effective therapies for patients with no mutation. Immunotherapy has emerged as an effective treatment for different cancer types. Nivolumab, a monoclonal inhibitory antibody against PD-1 receptor, can prolong survival of NSCLC patients, with a manageable toxicity profile. In two Phase III trials, nivolumab was compared to docetaxel in patients with, respectively, squamous (CheckMate 017) and non-squamous NSCLC (CheckMate 057). In both trials, nivolumab significantly reduced the risk of death compared to docetaxel (41% and 27% lower risk of death for squamous and non-squamous NSCLC, respectively). Therefore, nivolumab has been approved in the US and in Europe as second-line treatment for advanced NSCLC. Unfortunately, accurate predictive factors for patient selection are lacking, making it difficult to decide who will benefit and who will not. Currently, there are many ongoing trials that evaluate the efficacy of nivolumab in different settings and in combination with other agents. This paper reviews the present literature about the role of nivolumab in the treatment of NSCLC. Particular attention has been given to efficacy studies, toxicity profile, and current and emerging predictive factors. PMID:27536062

  18. Depressed immune surveillance against cancer: role of deficient T cell: extracellular matrix interactions.

    Science.gov (United States)

    Górski, A; Castronovo, V; Stepień-Sopniewska, B; Grieb, P; Ryba, M; Mrowiec, T; Korczak-Kowalska, G; Wierzbicki, P; Matysiak, W; Dybowska, B

    1994-07-01

    Although T cells infiltrate malignant tumors, the local immune response is usually inefficient and tumors escape destruction. While extracellular matrix proteins strongly costimulate T cell responses in normal individuals, our studies indicate that peripheral blood T cells from cancer patients and tumor infiltrating cells respond poorly or are resistant to stimulative signals mediated by collagen I and IV and fibronectin. Moreover, the adhesive properties of cancer T cells are markedly depressed. Those functional deficiencies are paralleled by variable deficits in integrin and non-integrin T cell receptors for extracellular matrix. Immunotherapy with BCG causes a dramatic but transient increase in T cell: ECM interactions. PMID:7827959

  19. Epidermal stem cells - role in normal, wounded and pathological psoriatic and cancer skin

    DEFF Research Database (Denmark)

    Kamstrup, M.; Faurschou, A.; Gniadecki, R.;

    2008-01-01

    In this review we focus on epidermal stem cells in the normal regeneration of the skin as well as in wounded and psoriatic skin. Furthermore, we discuss current data supporting the idea of cancer stem cells in the pathogenesis of skin carcinoma and malignant melanoma. Epidermal stem cells present...... stem cells or transit amplifying cells constitute a primary pathogenetic factor in the epidermal hyperproliferation seen in psoriasis. In cutaneous malignancies mounting evidence supports a stem cell origin in skin carcinoma and malignant melanoma and a possible existence of cancer stem cells...

  20. Prostate cancer stem cells: the role of androgen and estrogen receptors.

    Science.gov (United States)

    Di Zazzo, Erika; Galasso, Giovanni; Giovannelli, Pia; Di Donato, Marzia; Di Santi, Annalisa; Cernera, Gustavo; Rossi, Valentina; Abbondanza, Ciro; Moncharmont, Bruno; Sinisi, Antonio Agostino; Castoria, Gabriella; Migliaccio, Antimo

    2016-01-01

    Prostate cancer is one of the most commonly diagnosed cancers in men, and androgen deprivation therapy still represents the primary treatment for prostate cancer patients. This approach, however, frequently fails and patients develop castration-resistant prostate cancer, which is almost untreatable.Cancer cells are characterized by a hierarchical organization, and stem/progenitor cells are endowed with tumor-initiating activity. Accumulating evidence indicates that prostate cancer stem cells lack the androgen receptor and are, indeed, resistant to androgen deprivation therapy. In contrast, these cells express classical (α and/or β) and novel (GPR30) estrogen receptors, which may represent new putative targets in prostate cancer treatment.In the present review, we discuss the still-debated mechanisms, both genomic and non-genomic, by which androgen and estradiol receptors (classical and novel) mediate the hormonal control of prostate cell stemness, transformation, and the continued growth of prostate cancer. Recent preclinical and clinical findings obtained using new androgen receptor antagonists, anti-estrogens, or compounds such as enhancers of androgen receptor degradation and peptides inhibiting non-genomic androgen functions are also presented. These new drugs will likely lead to significant advances in prostate cancer therapy. PMID:26506594

  1. Role of Chemokines in Non-Small Cell Lung Cancer: Angiogenesis and Inflammation

    OpenAIRE

    Rivas-Fuentes, Selma; Salgado-Aguayo, Alfonso; Pertuz Belloso, Silvana; Gorocica Rosete, Patricia; Alvarado-Vásquez, Noé; Aquino-Jarquin, Guillermo

    2015-01-01

    Non-small cell lung cancer (NSCLC) is one of the most common types of aggressive cancer. The tumor tissue, which shows an active angiogenesis, is composed of neoplastic and stromal cells, and an abundant inflammatory infiltrate. Angiogenesis is important to support tumor growth, while infiltrating cells contribute to the tumor microenvironment through the secretion of growth factors, cytokines and chemokines, important molecules in the progression of the disease. Chemokines are important in d...

  2. Lessons from development: A role for asymmetric stem cell division in cancer

    OpenAIRE

    Powell, Anne E.; Shung, Chia-Yi; Saylor, Katherine W.; Müllendorf, Karin A.; Weiss, Joseph B.; Wong, Melissa H.

    2009-01-01

    Asymmetric stem cell division has emerged as a major regulatory mechanism for physiologic control of stem cell numbers. Reinvigoration of the cancer stem cell theory suggests that tumorigenesis may be regulated by maintaining the balance between asymmetric and symmetric cell division. Therefore, mutations affecting this balance could result in aberrant expansion of stem cells. Although a number of molecules have been implicated in regulation of asymmetric stem cell division, here, we highligh...

  3. The Role of HPV in Head and Neck Cancer Stem Cell Formation and Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Mark S. Swanson

    2016-02-01

    Full Text Available The cancer stem cell (CSC theory proposes that a minority of tumor cells are capable of self-replication and tumorigenesis. It is these minority of cells that are responsible for cancer metastasis and recurrence in head and neck squamous cell cancers (HNSCC. Human papilloma virus (HPV-related cancer of the oropharynx is becoming more prevalent, which makes understanding of the relationship between HPV and CSCs more important than ever. This relationship is critical because CSC behavior can be predicted based on cell surface markers, which makes them a suitable candidate for targeted therapy. New therapies are an exciting opportunity to advance past the stalled outcomes in HNSCC that have plagued patients and clinicians for several decades.

  4. Atypical role of sprouty in p21 dependent inhibition of cell proliferation in colorectal cancer.

    Science.gov (United States)

    Zhang, Qiong; Shim, Katherine; Wright, Kevin; Jurkevich, Alexander; Khare, Sharad

    2016-09-01

    Sprouty (SPRY) appears to act as a tumor suppressor in cancer, whereas we reported that SPRY2 functions as a putative oncogene in colorectal cancer (CRC) [Oncogene, 2010, 29: 5241-5253]. In general, various studies established inhibition of cell proliferation by SPRY in cancer. The mechanisms by which SPRY regulates cell proliferation in CRC are investigated. We demonstrate, for the first time, suppression of SPRY2 augmented EGF-dependent oncogenic signaling, however, surprisingly decreased cell proliferation in colon cancer cells. Our data suggest that cell cycle inhibitor p21(WAF1/CIP1) transcriptional activity being regulated by SPRY2. Indeed, suppression of SPRY2 significantly increased p21(WAF1/CIP1) mRNA and protein expression as well as p21(WAF1/CIP1) promoter activity. Conversely, overexpressing SPRY2 triggered a decrease in p21(WAF1/CIP1) promoter activity. Concurrent down-regulation of both SPRY1 and SPRY2 also increased p21(WAF1/CIP1) expression in colon cancer cells. Increased nuclear localization of p21(WAF1/CIP1) in SPRY2 downregulated colon cancer cells may explain the inhibition of cell proliferation in colon cancer cells. Underscoring the biological relevance of these findings in SPRY1 and SPRY2 mutant mouse, recombination of floxed SPRY1 and SPRY2 alleles in mouse embryonic fibroblasts (MEFs) resulted in increased expression and nuclear localization of p21(WAF1/CIP1) and decreased cell proliferation. In CRC, the relationship of SPRY with p21 may provide unique strategies for cancer prevention and treatment. © 2015 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc. PMID:26293890

  5. Ectopic Expression of Testis Germ Cell Proteins in Cancer and Its Potential Role in Genomic Instability

    OpenAIRE

    Aaraby Yoheswaran Nielsen; Morten Frier Gjerstorff

    2016-01-01

    Genomic instability is a hallmark of human cancer and an enabling factor for the genetic alterations that drive cancer development. The processes involved in genomic instability resemble those of meiosis, where genetic material is interchanged between homologous chromosomes. In most types of human cancer, epigenetic changes, including hypomethylation of gene promoters, lead to the ectopic expression of a large number of proteins normally restricted to the germ cells of the testis. Due to the ...

  6. The role of annexin A1 in expression of matrix metalloproteinase-9 and invasion of breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Hyereen [Department of Medicine, Graduate School, University of Ulsan, Pungnap-2 dong, Songpa-gu, Seoul (Korea, Republic of); Ko, Jesang [School of Life Sciences and Biotechnology, Korea University, Seoul 136-701 (Korea, Republic of); Jang, Sung-Wuk, E-mail: swjang@amc.seoul.kr [Department of Medicine, Graduate School, University of Ulsan, Pungnap-2 dong, Songpa-gu, Seoul (Korea, Republic of)

    2012-06-22

    Highlights: Black-Right-Pointing-Pointer We evaluated the effect of ANXA1 on promoting migration and invasion in MDA-MB-231 cells. Black-Right-Pointing-Pointer ANXA1 siRNA inhibits invasion and migration. Black-Right-Pointing-Pointer ANXA1 regulates MMP-9 expression and activity. Black-Right-Pointing-Pointer ANX-1 siRNA inhibits the activation of NF-{kappa}B in MDA-MB-231 cells. -- Abstract: Matrix metalloproteinase-9 (MMP-9) plays an important role in the invasion and metastasis of cancer cells. However, the regulatory mechanism of MMP-9 expression and its biological effects on breast cancer development remain obscure. In the current study, we examined the potential role of annexin A1 (ANXA1) in regulating migration and invasion in breast cancer cell lines. Both ANXA1 mRNA and protein are expressed in the highly invasive, hormone-insensitive human breast cancer cell lines MDA-MB-231 and SKBr3, but not in the hormone-responsive cell lines MCF-7 and T47D. Downregulation of ANXA1 expression with specific small interfering RNAs (ANXA1 siRNA) in MDA-MB-231 cells resulted in decreased cancer cell migration and invasion. Ablation of ANXA1 expression decreases the expression of MMP-9 at both the mRNA and protein levels and also reduces the proteolytic activity of MMP-9 in MDA-MB-231 cells. Moreover, silencing ANXA1 also decreases the transcriptional activity of MMP-9 by the suppression of nuclear factor kappa-B (NF-{kappa}B) activity. Collectively, these results indicate that ANXA1 functions as a positive regulator of MMP-9 expression and invasion of breast cancer cells through specific activation of the NF-{kappa}B signaling pathway.

  7. Regulatory role of hexosamine biosynthetic pathway on hepatic cancer stem cell marker CD133 under low glucose conditions

    Science.gov (United States)

    Lin, Shu-Hai; Liu, Tengfei; Ming, Xiaoyan; Tang, Zhi; Fu, Li; Schmitt-Kopplin, Philippe; Kanawati, Basem; Guan, Xin-Yuan; Cai, Zongwei

    2016-02-01

    Cancer was hypothesized to be driven by cancer stem cells (CSCs), but the metabolic determinants of CSC-like phenotype still remain elusive. Here, we present that hexosamine biosynthetic pathway (HBP) at least in part rescues cancer cell fate with inactivation of glycolysis. Firstly, metabolomic analysis profiled cellular metabolome in CSCs of hepatocellular carcinoma using CD133 cell-surface marker. The metabolic signatures of CD133-positive subpopulation compared to CD133-negative cells highlighted HBP as one of the distinct metabolic pathways, prompting us to uncover the role of HBP in maintenance of CSC-like phenotype. To address this, CSC-like phenotypes and cell survival were investigated in cancer cells under low glucose conditions. As a result, HBP inhibitor azaserine reduced CD133-positive subpopulation and CD133 expression under high glucose condition. Furthermore, treatment of N-Acetylglucosamine in part restores CD133-positive subpopulation when either 2.5 mM glucose in culture media or glycolytic inhibitor 2-deoxy-D-glucose in HCC cell lines was applied, enhancing CD133 expression as well as promoting cancer cell survival. Together, HBP might be a key metabolic determinant in the functions of hepatic CSC marker CD133.

  8. A role for IGF-1R-targeted therapies in small-cell lung cancer?

    LENUS (Irish Health Repository)

    Gately, Kathy

    2012-02-01

    BACKGROUND: Small-cell lung cancer (SCLC) is an aggressive disease with a poor prognosis. The insulin-like growth factor-1 receptor (IGF-1R) is an autocrine growth factor and an attractive therapeutic target in many solid tumors, but particularly in lung cancer. PATIENTS AND METHODS: This study examined tumor samples from 23 patients diagnosed with SCLC, 11 resected specimens and 12 nodal biopsies obtained by mediastinoscopy, for expression of IGF-1R using the monoclonal rabbit anti-IGF-1R (clone G11, Ventana Medical Systems, Tucson, AZ) and standard immunohistochemistry (IHC). RESULTS: All 23 tumor samples expressed IGF-1R with a range of stain intensity from weak (1+) to strong (3+). Ten tumors had a score of 3+, 7 tumors 2+, and 6 tumors 1+. Patient survival data were available for all 23 patients. Two patients died < 30 days post biopsy, therefore, the intensity of anti-IGF-1R immunostaining for 21 patients was correlated to survival. Patients with 3+ immunostaining had a poorer prognosis (P = .003). The overall survival of patients who underwent surgical resection was significantly better (median survival not reached) than patients who were not resected (median survival, 7.4 months) (P = .006). CONCLUSION: IGF-1R targeted therapies may have a role in the treatment of SCLC in combination with chemotherapy or as maintenance therapy. Further studies on the clinical benefit of targeting IGF-1R in SCLC are needed.

  9. Differential Roles for DUSP Family Members in Epithelial-to-Mesenchymal Transition and Cancer Stem Cell Regulation in Breast Cancer.

    Science.gov (United States)

    Boulding, Tara; Wu, Fan; McCuaig, Robert; Dunn, Jennifer; Sutton, Christopher R; Hardy, Kristine; Tu, Wenjuan; Bullman, Amanda; Yip, Desmond; Dahlstrom, Jane E; Rao, Sudha

    2016-01-01

    Dual-specificity phosphatases (DUSPs) dephosphorylate threonine/serine and tyrosine residues on their substrates. Here we show that DUSP1, DUSP4, and DUSP6 are involved in epithelial-to-mesenchymal transition (EMT) and breast cancer stem cell (CSC) regulation. DUSP1, DUSP4, and DUSP6 are induced during EMT in a PKC pathway signal-mediated EMT model. We show for the first time that the key chromatin-associated kinase PKC-θ directly regulates a subset of DUSP family members. DUSP1, DUSP4, and DUSP6 globally but differentially co-exist with enhancer and permissive active histone post-translational modifications, suggesting that they play distinct roles in gene regulation in EMT/CSCs. We show that nuclear DUSP4 associates with the key acetyltransferase p300 in the context of the chromatin template and dynamically regulates the interplay between two key phosphorylation marks: the 1834 (active) and 89 (inhibitory) residues central to p300's acetyltransferase activity. Furthermore, knockdown with small-interfering RNAs (siRNAs) shows that DUSP4 is required for maintaining H3K27ac, a mark mediated by p300. DUSP1, DUSP4, and DUSP6 knockdown with siRNAs shows that they participate in the formation of CD44hi/CD24lo/EpCAM+ breast CSCs: DUSP1 knockdown reduces CSC formation, while DUSP4 and DUSP6 knockdown enhance CSC formation. Moreover, DUSP6 is overexpressed in patient-derived HER2+ breast carcinomas compared to benign mammary tissue. Taken together, these findings illustrate novel pleiotropic roles for DUSP family members in EMT and CSC regulation in breast cancer. PMID:26859151

  10. Differential Roles for DUSP Family Members in Epithelial-to-Mesenchymal Transition and Cancer Stem Cell Regulation in Breast Cancer.

    Directory of Open Access Journals (Sweden)

    Tara Boulding

    Full Text Available Dual-specificity phosphatases (DUSPs dephosphorylate threonine/serine and tyrosine residues on their substrates. Here we show that DUSP1, DUSP4, and DUSP6 are involved in epithelial-to-mesenchymal transition (EMT and breast cancer stem cell (CSC regulation. DUSP1, DUSP4, and DUSP6 are induced during EMT in a PKC pathway signal-mediated EMT model. We show for the first time that the key chromatin-associated kinase PKC-θ directly regulates a subset of DUSP family members. DUSP1, DUSP4, and DUSP6 globally but differentially co-exist with enhancer and permissive active histone post-translational modifications, suggesting that they play distinct roles in gene regulation in EMT/CSCs. We show that nuclear DUSP4 associates with the key acetyltransferase p300 in the context of the chromatin template and dynamically regulates the interplay between two key phosphorylation marks: the 1834 (active and 89 (inhibitory residues central to p300's acetyltransferase activity. Furthermore, knockdown with small-interfering RNAs (siRNAs shows that DUSP4 is required for maintaining H3K27ac, a mark mediated by p300. DUSP1, DUSP4, and DUSP6 knockdown with siRNAs shows that they participate in the formation of CD44hi/CD24lo/EpCAM+ breast CSCs: DUSP1 knockdown reduces CSC formation, while DUSP4 and DUSP6 knockdown enhance CSC formation. Moreover, DUSP6 is overexpressed in patient-derived HER2+ breast carcinomas compared to benign mammary tissue. Taken together, these findings illustrate novel pleiotropic roles for DUSP family members in EMT and CSC regulation in breast cancer.

  11. Lung cancer - small cell

    Science.gov (United States)

    Cancer - lung - small cell; Small cell lung cancer; SCLC ... About 15% of all lung cancer cases are SCLC. Small cell lung cancer is slightly more common in men than women. Almost all cases of SCLC ...

  12. Lung cancer - small cell

    Science.gov (United States)

    Cancer - lung - small cell; Small cell lung cancer; SCLC ... About 15% of all lung cancer cases are SCLC. Small cell lung cancer is slightly more common in men than women. Almost all cases of SCLC are ...

  13. The role of mesenchymal stem cells in promoting the transformation of androgen-dependent human prostate cancer cells into androgen-independent manner

    OpenAIRE

    Jiwen Cheng; Keqin Yang; Qingyun Zhang; Yang Yu; Qinggui Meng; Ning Mo; Yang Zhou; Xianlin Yi; Chengzhong Ma; Aming Lei; Yan Liu

    2016-01-01

    Mesenchymal stem cells (MSCs) play an important role in the development of human prostate cancer (PCa). However, the role of MSCs in the transformation of androgen-dependent human PCa cells into androgen-independent manner has been poorly understood. In this study, we investigated the underlying mechanism of MSCs in promoting PCa cells from androgen-dependent into androgen-independent manner. Firstly, we demonstrated that MSCs could affect the transformation of androgen-dependent human PCa ce...

  14. Ectopic Expression of Testis Germ Cell Proteins in Cancer and Its Potential Role in Genomic Instability.

    Science.gov (United States)

    Nielsen, Aaraby Yoheswaran; Gjerstorff, Morten Frier

    2016-01-01

    Genomic instability is a hallmark of human cancer and an enabling factor for the genetic alterations that drive cancer development. The processes involved in genomic instability resemble those of meiosis, where genetic material is interchanged between homologous chromosomes. In most types of human cancer, epigenetic changes, including hypomethylation of gene promoters, lead to the ectopic expression of a large number of proteins normally restricted to the germ cells of the testis. Due to the similarities between meiosis and genomic instability, it has been proposed that activation of meiotic programs may drive genomic instability in cancer cells. Some germ cell proteins with ectopic expression in cancer cells indeed seem to promote genomic instability, while others reduce polyploidy and maintain mitotic fidelity. Furthermore, oncogenic germ cell proteins may indirectly contribute to genomic instability through induction of replication stress, similar to classic oncogenes. Thus, current evidence suggests that testis germ cell proteins are implicated in cancer development by regulating genomic instability during tumorigenesis, and these proteins therefore represent promising targets for novel therapeutic strategies. PMID:27275820

  15. The Role and Clinical Relevance of Disseminated Tumor Cells in Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Banys, Malgorzata, E-mail: maggybanys@yahoo.de [Department of Obstetrics and Gynecology, University of Duesseldorf, Duesseldorf D-40225 (Germany); Department of Obstetrics and Gynecology, Marienkrankenhaus Hamburg, Hamburg D-22087 (Germany); Krawczyk, Natalia; Fehm, Tanja [Department of Obstetrics and Gynecology, University of Duesseldorf, Duesseldorf D-40225 (Germany)

    2014-01-15

    Tumor cell dissemination is a common phenomenon observed in most cancers of epithelial origin. One-third of breast cancer patients present with disseminated tumor cells (DTCs) in bone marrow at time of diagnosis; these patients, as well as patients with persistent DTCs, have significantly worse clinical outcome than DTC-negative patients. Since DTC phenotype may differ from the primary tumor with regard to ER and HER2 status, reevaluation of predictive markers on DTCs may optimize treatment choices. In the present review, we report on the clinical relevance of DTC detection in breast cancer.

  16. The Role and Clinical Relevance of Disseminated Tumor Cells in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Malgorzata Banys

    2014-01-01

    Full Text Available Tumor cell dissemination is a common phenomenon observed in most cancers of epithelial origin. One-third of breast cancer patients present with disseminated tumor cells (DTCs in bone marrow at time of diagnosis; these patients, as well as patients with persistent DTCs, have significantly worse clinical outcome than DTC-negative patients. Since DTC phenotype may differ from the primary tumor with regard to ER and HER2 status, reevaluation of predictive markers on DTCs may optimize treatment choices. In the present review, we report on the clinical relevance of DTC detection in breast cancer.

  17. Role of Fbxw7 in the maintenance of normal stem cells and cancer-initiating cells

    OpenAIRE

    Takeishi, S; Nakayama, K I

    2014-01-01

    In addition to the properties of self-renewal and multipotency, stem cells are characterised by their distinct cell cycle status. Somatic stem cells are maintained in a quiescent state but switch reversibly from quiescence to proliferation as needed. On the other hand, embryonic stem cells and induced pluripotent stem cells proliferate rapidly until the induction of differentiation results in inhibition of cell cycle progression. Uncovering the mechanisms underlying cell cycle control in stem...

  18. Breast cancer stem cells

    Directory of Open Access Journals (Sweden)

    MatthewJNaylor

    2013-08-01

    Full Text Available Cancer metastasis, resistance to therapies and disease recurrence are significant hurdles to successful treatment of breast cancer. Identifying mechanisms by which cancer spreads, survives treatment regimes and regenerates more aggressive tumours are critical to improving patient survival. Substantial evidence gathered over the last 10 years suggests that breast cancer progression and recurrence is supported by cancer stem cells (CSCs. Understanding how CSCs form and how they contribute to the pathology of breast cancer will greatly aid the pursuit of novel therapies targeted at eliminating these cells. This review will summarise what is currently known about the origins of breast CSCs, their role in disease progression and ways in which they may be targeted therapeutically.

  19. Migration-promoting role of VEGF-C and VEGF-C binding receptors in human breast cancer cells

    OpenAIRE

    Timoshenko, A V; Rastogi, S; P. K. Lala

    2007-01-01

    Vascular endothelial growth factor C (VEGF-C) is a lymphangiogenic factor over-expressed in highly metastatic, cyclooxygenase (COX)-2 expressing breast cancer cells. We tested the hypothesis that tumour-derived VEGF-C may play an autocrine role in metastasis by promoting cellular motility through one or more VEGF-C-binding receptors VEGFR-2, VEGFR-3, neuropilin (NRP)-1, NRP-2, and integrin α9β1. We investigated the expression of these receptors in several breast cancer cell lines (MDA-MB-231,...

  20. A Transcriptional Regulatory Role of the THAP11–HCF-1 Complex in Colon Cancer Cell Function

    Science.gov (United States)

    Parker, J. Brandon; Palchaudhuri, Santanu; Yin, Hanwei; Wei, Jianjun

    2012-01-01

    The recently identified Thanatos-associated protein (THAP) domain is an atypical zinc finger motif with sequence-specific DNA-binding activity. Emerging data suggest that THAP proteins may function in chromatin-dependent processes, including transcriptional regulation, but the roles of most THAP proteins in normal and aberrant cellular processes remain largely unknown. In this work, we identify THAP11 as a transcriptional regulator differentially expressed in human colon cancer. Immunohistochemical analysis of human colon cancers revealed increased THAP11 expression in both primary tumors and metastases. Knockdown of THAP11 in SW620 colon cancer cells resulted in a significant decrease in cell proliferation, and profiling of gene expression in these cells identified a novel gene set composed of 80 differentially expressed genes, 70% of which were derepressed by THAP11 knockdown. THAP11 was found to associate physically with the transcriptional coregulator HCF-1 (host cell factor 1) and recruit HCF-1 to target promoters. Importantly, THAP11-mediated gene regulation and its chromatin association require HCF-1, while HCF-1 recruitment at these genes requires THAP11. Collectively, these data provide the first characterization of THAP11-dependent gene expression in human colon cancer cells and suggest that the THAP11–HCF-1 complex may be an important transcriptional and cell growth regulator in human colon cancer. PMID:22371484

  1. Drug resistance, and the role of p53, in lung cancer cell lines

    OpenAIRE

    Breen, Laura

    2005-01-01

    This thesis sets out to increase our knowledge of mechanisms by which lung cancer cells develop resistance to chemotherapeutic agents. The involvement of the tumour suppressor p53 in the development of drug resistance in lung cancer cell lines was investigated. p53 is a tumour suppressor gene, which is mutated in more than half of all tumours. Most chemotherapeutic drugs cause DNA damage that is sensed by p53, which either arrests the cell cycle to allow DNA repair or induces apoptosis. Wildt...

  2. Cell adhesion molecule CD44: its functional roles in prostate cancer

    OpenAIRE

    Iczkowski, Kenneth A

    2010-01-01

    CD44 is a cell adhesion glycoprotein that also governs cell signaling. Dysregulated CD44 expression characterizes most human cancers, including prostate cancer (PCa). PCa loses expression of CD44 standard (CD44s) that is present in benign epithelium, and overexpresses the novel splice variant (v) isoform, CD44v7-10. We studied CD44 in PCa for more than a decade, and in a series of papers, established its functional significance. Using retrovi-ral gene delivery to PC-3M PCa cells, we expressed...

  3. The role of colorectal cancer stem cells in metastatic disease and therapeutic response.

    Science.gov (United States)

    Anderson, Eric C; Hessman, Crystal; Levin, Trevor G; Monroe, Marcus M; Wong, Melissa H

    2011-01-01

    Colorectal cancer is the third-leading cause of cancer related mortality in the United States. The intricate molecular mechanisms involved in the regenerative process of the normal intestine and the identity of putative somatic intestinal stem cells have become clear. In parallel with this, experiment evidence has emerged supporting the century old hypothesis that solid tumor initiation, progression, chemoresistance and recurrence is the result of a small population of cancer cells with self-renewal and pluripotency capabilities. These "cancer stem cells" (CSCs) present a unique opportunity to better understand the biology of solid tumors in general, as well as targets for future therapeutics. In this review, we will summarize the current understanding of intestinal stem cell biology and translate it to colorectal CSCs to provide a basis for understanding chemoresistance, cancer recurrence and metastasis. A more complete understanding of the biology of colorectal CSCs will translate into the development of better chemotherapeutic and biological agents for the treatment of colorectal cancer. PMID:21318087

  4. COPD promotes migration of A549 lung cancer cells: the role of chemokine CCL21

    Directory of Open Access Journals (Sweden)

    Kuźnar-Kamińska B

    2016-05-01

    Full Text Available Barbara Kuźnar-Kamińska,1 Justyna Mikuła-Pietrasik,2 Patrycja Sosińska,2 Krzysztof Książek,2 Halina Batura-Gabryel1 1Department of Pulmonology, Allergology and Respiratory Oncology, 2Department of Pathophysiology, Poznań University of Medical Sciences, Poznań, Poland Abstract: Patients with COPD develop lung cancer more frequently than healthy smokers. At the same time, molecular mediators promoting various aspects of cancer cell progression are still elusive. In this report, we examined whether COPD can be coupled with increased migration of non-small-cell lung cancer cells A549 and, if so, whether this effect may be related to altered production and activity of chemokines CCL21, CXCL5, and CXCL12. The study showed that the migration of A549 cells through the polycarbonate membrane and basement membrane extract toward a chemotactic gradient elicited by serum from patients with COPD was markedly higher as compared with serum from healthy donors. The concentration of CCL21 and CXCL12, but not CXCL5, in serum from patients with COPD was also increased. Experiments in which CCL21- and CXCL12-dependent signaling was blocked revealed that increased migration of the cancer cells upon treatment with serum from patients with COPD was mediated exclusively by CCL21. Collectively, our results indicate that COPD may contribute to the progression of lung cancer via CCL21-dependent intensification of cancer cell migration. Keywords: chemokines, COPD, lung cancer, migration

  5. The role of monocarboxylate transporters in 3-bromopyruvate effect in cancer cells

    OpenAIRE

    Silva, João Pedro Azevedo

    2016-01-01

    Tese de Doutoramento em Biologia Molecular e Ambiental (área de especialização em Biologia Molecular e Saúde). Cancer is one of the world leading causes of death, being characterized by a set of hallmarks which confer an uncontrolled cellular growth. One of these alterations represents a metabolic reprogramming in which cells rely on glycolysis for energy production over oxidative phosphorylation, even in the presence of oxygen. In several cancers, this activity leads to the production of ...

  6. New targeted treatments for non-small-cell lung cancerrole of nivolumab

    OpenAIRE

    Baas, Paul; Muller,Mirte; van den Heuvel,Michel; Zago,Giulia

    2016-01-01

    Giulia Zago,1,2,* Mirte Muller,1,* Michel van den Heuvel,1 Paul Baas1 1Department of Thoracic Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek (NKI-AvL), Amsterdam, the Netherlands; 2Medical Oncology 2, Istituto Oncologico Veneto (IOV), Padova, Italy *These authors contributed equally to this work Abstract: Non-small-cell lung cancer (NSCLC) is often diagnosed at an advanced stage of disease, where it is no longer amenable to curative treatment. During the last decades, the ...

  7. The Role of Colorectal Cancer Stem Cells in Metastatic Disease and Therapeutic Response

    Directory of Open Access Journals (Sweden)

    Melissa H. Wong

    2011-01-01

    Full Text Available Colorectal cancer is the third-leading cause of cancer related mortality in the United States. The intricate molecular mechanisms involved in the regenerative process of the normal intestine and the identity of putative somatic intestinal stem cells have become clear. In parallel with this, experiment evidence has emerged supporting the century old hypothesis that solid tumor initiation, progression, chemoresistance and recurrence is the result of a small population of cancer cells with self-renewal and pluripotency capabilities. These “cancer stem cells” (CSCs present a unique opportunity to better understand the biology of solid tumors in general, as well as targets for future therapeutics. In this review, we will summarize the current understanding of intestinal stem cell biology and translate it to colorectal CSCs to provide a basis for understanding chemoresistance, cancer recurrence and metastasis. A more complete understanding of the biology of colorectal CSCs will translate into the development of better chemotherapeutic and biological agents for the treatment of colorectal cancer.

  8. Inhibitory role of TRIP-Br1 oncoprotein in hypoxia-induced apoptosis in breast cancer cell lines.

    Science.gov (United States)

    Li, Chengping; Jung, Samil; Yang, Young; Kim, Keun-Il; Lim, Jong-Seok; Cheon, Chung-Il; Lee, Myeong-Sok

    2016-06-01

    TRIP-Br1 oncoprotein is known to be involved in many vital cellular functions. In this study, we examined the role of TRIP-Br1 in hypoxia-induced cell death. Exposure to the overcrowded and CoCl2-induced hypoxic conditions increased TRIP-Br1 expression at the protein level in six breast cancer cell lines (MCF7, MDA-MB-231, T47D, Hs578D, BT549, and MDA-MB-435) but resulted in no significant change in three normal cell lines (MCF10A, MEF and NIH3T3). Our result revealed that CoCl2-induced hypoxia stimulated apoptosis and autophagy, in which TRIP-Br1 expression was found to be upregulated. Interestingly, TRIP-Br1 silencing in the MCF7 and MDA-MB-231 cancer cells accelerated apoptosis and destabilization of XIAP under the CoCl2-induced hypoxic condition, implying that TRIP-Br1 may render cancer cells resistant to apoptosis through the stabilization of XIAP. We also propose that TRIP-Br1 seems to be upregulated at least partly as a result of the inhibition of PI3K/AKT signaling pathway and the overexpression of HIF-1α. In conclusion, our findings suggest that TRIP-Br1 functions as an oncogenic protein by providing cancer cells resistance to the hypoxia-induced cell death. PMID:27035851

  9. Critical role of Spns2, a sphingosine-1-phosphate transporter, in lung cancer cell survival and migration.

    Directory of Open Access Journals (Sweden)

    Eric Bradley

    Full Text Available The sphingosine-1-phosphate (S1P transporter Spns2 regulates myocardial precursor migration in zebrafish and lymphocyte trafficking in mice. However, its function in cancer has not been investigated. We show here that ectopic Spns2 expression induced apoptosis and its knockdown enhanced cell migration in non-small cell lung cancer (NSCLC cells. Metabolically, Spns2 expression increased the extracellular S1P level while its knockdown the intracellular. Pharmacological inhibition of S1P synthesis abolished the augmented cell migration mediated by Spns2 knockdown, indicating that intracellular S1P plays a key role in this process. Cell signaling studies indicated that Spns2 expression impaired GSK-3β and Stat3 mediated pro-survival pathways. Conversely, these pathways were activated by Spns2 knockdown, which explains the increased cell migration since they are also crucial for migration. Alterations of Spns2 were found to affect several enzymes involved in S1P metabolism, including sphingosine kinases, S1P phosphatases, and S1P lyase 1. Genetically, Spns2 mRNA level was found to be reduced in advanced lung cancer (LC patients as quantified by using a small scale qPCR array. These data show for the first time that Spns2 plays key roles in regulating the cellular functions in NSCLC cells, and that its down-regulation is a potential risk factor for LC.

  10. Role of volume-regulated and calcium-activated anion channels in cell volume homeostasis, cancer and drug resistance

    DEFF Research Database (Denmark)

    Hoffmann, Else Kay; Sørensen, Belinda Halling; Sauter, Daniel Rafael Peter;

    2015-01-01

    Volume-regulated channels for anions (VRAC) / organic osmolytes (VSOAC) play essential roles in cell volume regulation and other cellular functions, e.g. proliferation, cell migration and apoptosis. LRRC8A, which belongs to the leucine rich-repeat containing protein family, was recently shown to be...... an essential component of both VRAC and VSOAC. Reduced VRAC and VSOAC activities are seen in drug resistant cancer cells. ANO1 is a calcium-activated chloride channel expressed on the plasma membrane of e.g. secretory epithelia. ANO1 is amplified and highly expressed in a large number of carcinomas...... important cellular functions as well as their role in cancer and drug resistance....

  11. From milk to malignancy: the role of mammary stem cells in development, pregnancy and breast cancer

    Institute of Scientific and Technical Information of China (English)

    Benjamin Tiede; Yibin Kang

    2011-01-01

    Adult stem cells of the mammary gland (MaSCs) are a highly dynamic population of cells that are responsible for the generation of the gland during puberty and its expansion during pregnancy, in recent years significant advances have been made in understanding how these cells are regulated during these developmentally important processes both in humans and in mice. Understanding how MaSCs are regulated is becoming a particularly important area of research, given that they may be particularly susceptible targets for transformation in breast cancer. Here, we summarize the identification of MaSCs, how they are regulated and the evidence for their serving as the origins of breast cancer, in particular, we focus on how changes in MaSC populations may explain both the increased risk of developing aggressive ERJPR(-) breast cancer shortly after pregnancy and the long-term decreased risk of developing ER/ PR(+) tumors.

  12. Transmembrane transporters ABCC – structure, function and role in multidrug resistance of cancer cells

    Directory of Open Access Journals (Sweden)

    Sylwia Dębska

    2011-08-01

    Full Text Available Resistance to cytotoxic drugs is a significant problem of systemic treatment of cancers. Apart from drug inactivation, changes in target enzymes and proteins, increased DNA repair and suppression of apoptosis, an important mechanism of resistance is an active drug efflux from cancer cells. Drug efflux across the cell membrane is caused by transport proteins such as ABC proteins (ATP-binding cassette. This review focuses on the ABCC protein subfamily, whose members are responsible for multidrug cross-resistance of cancer cells to cytotoxic agents. The authors discuss the structure of ABCC proteins, their physiological function and diseases provoked by mutations of respective genes, their expression in many different malignancies and its connection with resistance to anticancer drugs, as well as methods of reversion of such resistance.

  13. Dendritic cells are defective in breast cancer patients: a potential role for polyamine in this immunodeficiency

    International Nuclear Information System (INIS)

    Dendritic cells (DCs) are antigen-presenting cells that are currently employed in cancer clinical trials. However, it is not clear whether their ability to induce tumour-specific immune responses when they are isolated from cancer patients is reduced relative to their ability in vivo. We determined the phenotype and functional activity of DCs from cancer patients and investigated the effect of putrescine, a polyamine molecule that is released in large amounts by cancer cells and has been implicated in metastatic invasion, on DCs. The IL-4/GM-CSF (granulocyte–macrophage colony-stimulating factor) procedure for culturing blood monocyte-derived DCs was applied to cells from healthy donors and patients (17 with breast, 7 with colorectal and 10 with renal cell carcinoma). The same peroxide-treated tumour cells (M74 cell line) were used for DC pulsing. We investigated the effects of stimulation of autologous lymphocytes by DCs pulsed with treated tumour cells (DC-Tu), and cytolytic activity of T cells was determined in the same target cells. Certain differences were observed between donors and breast cancer patients. The yield of DCs was dramatically weaker, and expression of MHC class II was lower and the percentage of HLA-DR-Lin- cells higher in patients. Whatever combination of maturating agents was used, expression of markers of mature DCs was significantly lower in patients. Also, DCs from patients exhibited reduced ability to stimulate cytotoxic T lymphocytes. After DC-Tu stimulation, specific cytolytic activity was enhanced by up to 40% when DCs were from donors but only up to 10% when they were from patients. IFN-γ production was repeatedly found to be enhanced in donors but not in patients. By adding putrescine to DCs from donors, it was possible to enhance the HLA-DR-Lin- cell percentage and to reduce the final cytolytic activity of lymphocytes after DC-Tu stimulation, mimicking defective DC function. These putrescine-induced deficiencies were reversed by

  14. Conformational changes and translocation of tissue-transglutaminase to the plasma membranes: role in cancer cell migration

    International Nuclear Information System (INIS)

    Tissue-transglutaminase (TG2), a dual function G-protein, plays key roles in cell differentiation and migration. In our previous studies we reported the mechanism of TG2-induced cell differentiation. In present study, we explored the mechanism of how TG2 may be involved in cell migration. To study the mechanism of TG2-mediated cell migration, we used neuroblastoma cells (SH-SY5Y) which do not express TG2, neuroblastoma cells expressing exogenous TG2 (SHYTG2), and pancreatic cancer cells which express high levels of endogenous TG2. Resveratrol, a natural compound previously shown to inhibit neuroblastoma and pancreatic cancer in the animal models, was utilized to investigate the role of TG2 in cancer cell migration. Immunofluorescence assays were employed to detect expression and intracellular localization of TG2, and calcium levels in the migrating cells. Native gel electrophoresis was performed to analyze resveratrol-induced cellular distribution and conformational states of TG2 in migrating cells. Data are presented as the mean and standard deviation of at least 3 independent experiments. Comparisons were made among groups using one-way ANOVA followed by Tukey-Kramer ad hoc test. TG2 containing cells (SHYTG2 and pancreatic cancer cells) exhibit increased cell migration and invasion in collagen-coated and matrigel-coated transwell plate assays, respectively. Resveratrol (1 μM-10 μM) prevented migration of TG2-expressing cells. During the course of migration, resveratrol increased the immunoreactivity of TG2 without affecting the total TG2 protein level in migrating cells. In these cells, resveratrol increased calcium levels, and depletion of intracellular calcium by a calcium chelator, BAPTA, attenuated resveratrol-enhanced TG2 immunoreactivity. In native-polyacrylamide gels, we detected an additional TG2 protein band with slower migration in total cell lysates of resveratrol treated cells. This TG2 form is non-phosphorylated, exclusively present in plasma

  15. A role for PP1/NIPP1 in steering migration of human cancer cells.

    Directory of Open Access Journals (Sweden)

    Cristina Martin-Granados

    Full Text Available Electrical gradients are present in many developing and regenerating tissues and around tumours. Mimicking endogenous electric fields in vitro has profound effects on the behaviour of many cell types. Intriguingly, specific cell types migrate cathodally, others anodally and some polarise with their long axis perpendicular to the electric vector. These striking phenomena are likely to have in vivo relevance since one of the determining factors during cancer metastasis is the ability to switch between attractive and repulsive migration in response to extracellular guidance stimuli. We present evidence that the cervical cancer cell line HeLa migrates cathodally in a direct current electric field of physiological intensity, while the strongly metastatic prostate cancer cell line PC-3-M migrates anodally. Notably, genetic disruption of protein serine/threonine phosphatase-1 (PP1 and its regulator NIPP1 decrease directional migration in these cell lines. Conversely, the inducible expression of NIPP1 switched the directional response of HeLa cells from cathodal to slightly anodal in a PP1-dependent manner. Remarkably, induction of a hyperactive PP1/NIPP1 holoenzyme, further shifted directional migration towards the anode. We show that PP1 association with NIPP1 upregulates signalling by the GTPase Cdc42 and demonstrate that pharmacological inhibition of Cdc42 in cells overexpressing NIPP1 recovered cathodal migration. Taken together, we provide the first evidence for regulation of directional cell migration by NIPP1. In addition, we identify PP1/NIPP1 as a novel molecular compass that controls directed cell migration via upregulation of Cdc42 signalling and suggest a way by which PP1/NIPP1 may contribute to the migratory properties of cancer cells.

  16. The secret role of microRNAs in cancer stem cell development and potential therapy: A Notch-pathway approach.

    Directory of Open Access Journals (Sweden)

    Marianna eProkopi

    2015-02-01

    Full Text Available MicroRNAs (miRNAs have been implicated in the development of some if not all cancer types and have been identified as attractive targets for prognosis, diagnosis and therapy of the disease. MiRNAs are a class of small non-coding RNAs (20-22 nucleotides in length that bind imperfectly to the 3’-untranslated region of target mRNA regulating gene expression. Aberrantly expressed miRNAs in cancer, sometimes known as oncomiRNAs, have been shown to play a major role in oncogenesis, metastasis and drug resistance. Amplification of oncomiRNAs during cancer development correlates with the silencing of tumor suppressor genes; on the other hand, down-regulation of miRNAs has also been observed in cancer and cancer stem cells (CSCs. In both cases, miRNA regulation is inversely correlated with cancer progression. Growing evidence indicates that miRNAs are also involved in the metastatic process by either suppressing or promoting metastasis-related genes leading to the reduction or activation of cancer cell migration and invasion processes. In particular, circulating miRNAs (vesicle-encapsulated or non-encapsulated have significant effects on tumorigenesis: membrane-particles, apoptotic bodies and exosomes have been described as providers of a cell-to-cell communication system transporting oncogenic miRNAs from tumors to neighboring cells and distant metastatic sites. It is hypothesized that MiRNAs control cancer development in a traditional manner, by regulating signaling pathways and factors. In addition, recent developments indicate a non-conventional mechanism of cancer regulation by stem cell reprogramming via a regulatory network consisting of miRNAs and Wnt/β-catenin, Notch, and Hedgehog signaling pathways, all of which are involved in controlling stem cell functions of CSCs. In this review, we focus on the role of miRNAs in the Notch pathway and how they regulate CSC self-renewal, differentiation and tumorigenesis by direct/indirect targeting of

  17. Stem Cells and Cancer

    International Nuclear Information System (INIS)

    Stem cell research has thrived over the last years due to their therapeutic and regenerative potential. Scientific breakthroughs in the field are immediately translated from the scientific journals to the mass media, which is not surprising as the characterisation of the molecular mechanisms that regulate the biology of stem cells is crucial for the treatment of degenerative and cardiovascular diseases, as well as cancer. In the Molecular Oncology Unit at Ciemat we work to unravel the role of cancer stem cells in tumour development, and to find new antitumor therapies. (Author)

  18. Roles of ERβ and GPR30 in Proliferative Response of Human Bladder Cancer Cell to Estrogen

    Directory of Open Access Journals (Sweden)

    Weiren Huang

    2015-01-01

    Full Text Available Bladder cancer belongs to one of the most common cancers and is a leading cause of deaths in our society. Urothelial carcinoma of the bladder (UCB is the main type of this cancer, and the estrogen receptors in UCB remain to be studied. Our experiment aimed to investigate the possible biological effect of 17β-estradiol on human bladder-derived T24 carcinoma cells and to indicate its related mechanisms. T24 cells were treated with various doses of 17β-estradiol, and cell proliferation was detected using MTT assays. 17β-estradiol promoted T24 cell proliferation independent of ERβ/GPR30-regulated EGFR-MAPK pathway, while it inhibited cell growth via GPR30. Furthermore, the expression levels of downstream genes (c-FOS, BCL-2, and CYCLIN D1 were increased by 17β-estradiol and this effect was independently associated with activity of the EGFR-MAPK pathway. The two estrogen receptors might be potential therapeutic targets for the treatment of bladder cancer.

  19. Roles of dCK Ser-74 in radiation-induced cell death in breast cancer cells

    International Nuclear Information System (INIS)

    Objective: To investigate the roles of dCK Ser-74 in radiation-induced cell death in breast cancer cells. Methods: Different phenotypes of dCK plasmids were transfected into MCF-7 cells by liposome transfection, including dCK-Vector, dCK-WT (wild type), dCK-S74A (non-phosphorylation) and dCK-S74E (hyper-phosphorylation). All these cells were irradiated by 0, 2, 4, 6, 8 Gy X-rays, respectively. The transcriptional and translational level of dCK were detected with real time-PCR and Western blot, respectively. Radiosensitivity was analyzed using cell counting kit (CCK-8) and colony formation assays. Monodansylcadaverine staining (MDC) and flow cytometry were used to detect autophagy and apoptosis,respectively. Results: Four phenotypes of dCK cell models were established successfully. After irradiation, the cell viabilities of MCF-7 and dCK-Vector decreased significantly as compared with mock group (t=14.469 and 9.357, P<0.05), the cell viabilities of dCK-WT, dCK-S74A and dCK-S74E showed no changes (P>0.05). The total mortalities of dCK-WT and dCK-S74E decreased significantly as compared with dCK-Vector (χ2=3.857-3.971, P<0.05), but no changes in dCK-S74A cells (P>0.05). The apoptosis rates in dCK-S74A, dCK-Vector and control group were up-regulated after irradiation (t=-4.531, -3.688 and-7.076, P<0.05), and the irradiation-induced apoptosis was reversed in dCK-WT and dCK-S74E (66% and 68% of the increase level in dCK-Vector group). The autophagy in dCK-WT and dCK-S74E increased by 22% and 26% (t=-9.051 and-8.411, P<0.01), but no changes were observed in dCK-S74A, dCK-Vector and control groups (P>0.05). Conclusions: The dCK-WT and dCK-S74E could reverse the irradiation-induced apoptosis, increase the autophagy occurrence, and decrease the total mortality, indicating that the phosphorylation of dCK at Ser-74 sites is related to the radiosensitivity of MCF-7 cells. (authors)

  20. Sensitization of ovarian cancer cells to cisplatin by genistein: the role of NF-kappaB

    Directory of Open Access Journals (Sweden)

    Solomon Leigh A

    2008-11-01

    Full Text Available Abstract Background Platinum-resistance (PR continues to be a major problem in the management of epithelial ovarian cancer (EOC. Response to various chemotherapeutic agents is poor in patients deemed PR. Genistein, a soy isoflavone has been shown to enhance the effect of chemotherapy in prostate and pancreatic cancer cells in vitro and in vivo by reversing chemo-resistance phenotype. The goal of this study was to investigate the effects of combination therapy with genistein and cisplatin as well as other cytotoxic conventional chemotherapeutic agents in platinum-sensitive (PS and resistant EOC cells. Methods The PS human ovarian cancer cell line A2780 and its PR clone C200 cells were pretreated with genistein, followed by the combination of genistein and either cisplatin, taxotere or gemcitabine. Cell survival and apoptosis was assessed by MTT and histone-DNA ELISA. Electrophoretic mobility shift assay (EMSA was used to evaluate NF-κB DNA binding activity. Western blot analysis was performed with antibodies to Bcl-2, Bcl-xL, survivin, c-IAP and PARP. Results Reduction in cell viability, and corresponding induction of apoptosis was observed with genistein pretreatment followed by combination treatment with each of the drugs in both cell lines. The PS cell line was pretreated for 24 hours; in contrast, the PR cell line required 48 hours pretreatment to achieve a response. The anti-apoptotic genes c-IAP1, Bcl-2, Bcl-xL, survivin and NF-κB DNA binding activity were all found to be down-regulated in the combination groups. Conclusion This study convincingly demonstrated that the current strategy can be translated in a pre-clinical animal model, and thus it should stimulate future clinical trial for the treatment of drug-resistant ovarian cancer.

  1. Squamous cell skin cancer

    Science.gov (United States)

    ... earliest form of squamous cell cancer is called Bowen disease (or squamous cell carcinoma in situ). This type ... cancer; Squamous cell carcinoma of the skin Images Bowen's disease on the hand Keratoacanthoma Keratoacanthoma Skin cancer, squamous ...

  2. Potential role of nuclear PD-L1 expression in cell-surface vimentin positive circulating tumor cells as a prognostic marker in cancer patients.

    Science.gov (United States)

    Satelli, Arun; Batth, Izhar Singh; Brownlee, Zachary; Rojas, Christina; Meng, Qing H; Kopetz, Scott; Li, Shulin

    2016-01-01

    Although circulating tumor cells (CTCs) have potential as diagnostic biomarkers for cancer, determining their prognostic role in cancer patients undergoing treatment is a challenge. We evaluated the prognostic value of programmed death-ligand 1 (PD-L1) expression in CTCs in colorectal and prostate cancer patients undergoing treatment. Peripheral blood samples were collected from 62 metastatic colorectal cancer patients and 30 metastatic prostate cancer patients. CTCs were isolated from the samples using magnetic separation with the cell-surface vimentin(CSV)-specific 84-1 monoclonal antibody that detects epithelial-mesenchymal transitioned (EMT) CTCs. CTCs were enumerated and analyzed for PD-L1 expression using confocal microscopy. PD-L1 expression was detectable in CTCs and was localized in the membrane and/or cytoplasm and nucleus. CTC detection alone was not associated with poor progression-free or overall survival in colorectal cancer or prostate cancer patients, but nuclear PD-L1 (nPD-L1) expression in these patients was significantly associated with short survival durations. These results demonstrated that nPD-L1 has potential as a clinically relevant prognostic biomarker for colorectal and prostate cancer. Our data thus suggested that use of CTC-based models of cancer for risk assessment can improve the standard cancer staging criteria and supported the incorporation of nPD-L1 expression detection in CTCs detection in such models. PMID:27363678

  3. Potential role of nuclear PD-L1 expression in cell-surface vimentin positive circulating tumor cells as a prognostic marker in cancer patients

    Science.gov (United States)

    Satelli, Arun; Batth, Izhar Singh; Brownlee, Zachary; Rojas, Christina; Meng, Qing H.; Kopetz, Scott; Li, Shulin

    2016-01-01

    Although circulating tumor cells (CTCs) have potential as diagnostic biomarkers for cancer, determining their prognostic role in cancer patients undergoing treatment is a challenge. We evaluated the prognostic value of programmed death-ligand 1 (PD-L1) expression in CTCs in colorectal and prostate cancer patients undergoing treatment. Peripheral blood samples were collected from 62 metastatic colorectal cancer patients and 30 metastatic prostate cancer patients. CTCs were isolated from the samples using magnetic separation with the cell-surface vimentin(CSV)-specific 84-1 monoclonal antibody that detects epithelial-mesenchymal transitioned (EMT) CTCs. CTCs were enumerated and analyzed for PD-L1 expression using confocal microscopy. PD-L1 expression was detectable in CTCs and was localized in the membrane and/or cytoplasm and nucleus. CTC detection alone was not associated with poor progression-free or overall survival in colorectal cancer or prostate cancer patients, but nuclear PD-L1 (nPD-L1) expression in these patients was significantly associated with short survival durations. These results demonstrated that nPD-L1 has potential as a clinically relevant prognostic biomarker for colorectal and prostate cancer. Our data thus suggested that use of CTC-based models of cancer for risk assessment can improve the standard cancer staging criteria and supported the incorporation of nPD-L1 expression detection in CTCs detection in such models. PMID:27363678

  4. Key cell signaling pathways modulated by zerumbone: role in the prevention and treatment of cancer.

    Science.gov (United States)

    Prasannan, Remya; Kalesh, Karunakaran A; Shanmugam, Muthu K; Nachiyappan, Alamelu; Ramachandran, Lalitha; Nguyen, An H; Kumar, Alan Prem; Lakshmanan, Manikandan; Ahn, Kwang Seok; Sethi, Gautam

    2012-11-15

    Phytochemicals and their synthetic derivatives are making a significant contribution in modern drug discovery programs by targeting several human diseases, including cancer. Most of these natural compounds are often multitargeted in nature, which is generally a very desirable property for cancer therapy, as carcinomas typically involve dysregulation of multiple genes and associated cell-signaling pathways at various stages of initiation, progression and metastasis. Additionally, these natural agents generally have lower side-effects, are readily available and hence are cost effective. One such natural compound is zerumbone, a cyclic eleven-membered sesquiterpene, isolated from the tropical plant Zingiber zerumbet Smith that has attracted great attention recently for its potent anticancer activities in several tumor models. This review summarizes the data based on various in vitro and in vivo studies related to the effects of zerumbone on numerous pivotal molecular targets in cancer and its reported chemopreventive/therapeutic effects in different models of cancer. PMID:22842489

  5. Human NK cells selective targeting of colon cancer-initiating cells: A role for natural cytotoxicity receptors and MHC class i molecules

    KAUST Repository

    Tallerico, Rossana

    2013-01-23

    Tumor cell populations have been recently proposed to be composed of two compartments: tumor-initiating cells characterized by a slow and asymmetrical growth, and the "differentiated" cancer cells with a fast and symmetrical growth. Cancer stem cells or cancer-initiating cells (CICs) play a crucial role in tumor recurrence. The resistance of CICs to drugs and irradiation often allows them to survive traditional therapy. NK cells are potent cytotoxic lymphocytes that can recognize tumor cells. In this study, we have analyzed the NK cell recognition of tumor target cells derived from the two cancer cell compartments of colon adenocarcinoma lesions. Our data demonstrate that freshly purified allogeneic NK cells can recognize and kill colorectal carcinoma- derived CICs whereas the non-CIC counterpart of the tumors (differentiated tumor cells), either autologous or allogeneic, is less susceptible to NK cells. This difference in the NK cell susceptibility correlates with higher expression on CICs of ligands for NKp30 and NKp44 in the natural cytotoxicity receptor (NCR) group of activating NK receptors. In contrast, CICs express lower levels of MHC class I, known to inhibit NK recognition, on their surface than do the "differentiated" tumor cells. These data have been validated by confocal microscopy where NCR ligands and MHC class I molecule membrane distribution have been analyzed. Moreover, NK cell receptor blockade in cytotoxicity assays demonstrates that NCRs play a major role in the recognition of CIC targets. This study strengthens the idea that biology-based therapy harnessing NK cells could be an attractive opportunity in solid tumors. Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved.

  6. Targeting the MET receptor tyrosine kinase in non-small cell lung cancer: emerging role of tivantinib

    International Nuclear Information System (INIS)

    MET receptor tyrosine kinase and its natural ligand, hepatocyte growth factor, have been implicated in a variety of cancers, including non-small cell lung cancer (NSCLC). Mechanisms by which cellular deregulation of MET occurs include overexpression, genomic amplification, mutation, or alternative splicing. MET overexpression or activation is a known cause of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in NSCLC. Inhibition of MET signaling in these EGFR tyrosine kinase inhibitor-resistant cells may potentially restore sensitivity to EGFR inhibitors. Tivantinib (ARQ 197), reported as a small-molecule MET inhibitor, has demonstrated antitumor activity in early clinical studies. This review focuses on MET and lung cancer, the clinical development of tivantinib, the clinical trials of tivantinib in NSCLC to date, its current/emerging role in the management of NSCLC, and future directions

  7. Development of a highly metastatic model that reveals a crucial role of fibronectin in lung cancer cell migration and invasion

    International Nuclear Information System (INIS)

    The formation of metastasis is the most common cause of death in patients with lung cancer. A major implement to understand the molecular mechanisms involved in lung cancer metastasis has been the lack of suitable models to address it. In this study, we aimed at establishing a highly metastatic model of human lung cancer and characterizing its metastatic properties and underlying mechanisms. The human lung adeno-carcinoma SPC-A-1 cell line was used as parental cells for developing of highly metastatic cells by in vivo selection in NOD/SCID mice. After three rounds of selection, a new SPC-A-1sci cell line was established from pulmonary metastatic lesions. Subsequently, the metastatic properties of this cell line were analyzed, including optical imaging of in vivo metastasis, immunofluorescence and immunohistochemical analysis of several epithelial mesenchymal transition (EMT) makers and trans-well migration and invasion assays. Finally, the functional roles of fibronectin in the invasive and metastatic potentials of SPC-A-1sci cells were determined by shRNA analysis. A spontaneously pulmonary metastatic model of human lung adeno-carcinoma was established in NOD/SCID mice, from which a new lung cancer cell line, designated SPC-A-1sci, was isolated. Initially, the highly metastatic behavior of this cell line was validated by optical imaging in mice models. Further analyses showed that this cell line exhibit phenotypic and molecular alterations consistent with EMT. Compared with its parent cell line SPC-A-1, SPC-A-1sci was more aggressive in vitro, including increased potentials for cell spreading, migration and invasion. Importantly, fibronectin, a mesenchymal maker of EMT, was found to be highly expressed in SPC-A-1sci cells and down-regulation of it can decrease the in vitro and in vivo metastatic abilities of this cell line. We have successfully established a new human lung cancer cell line with highly metastatic potentials, which is subject to EMT and possibly

  8. A Role for PP1/NIPP1 in Steering Migration of Human Cancer Cells

    OpenAIRE

    Martin-Granados, Cristina; Prescott, Alan R.; Van Dessel, Nele; Van Eynde, Aleyde; Arocena, Miguel; Klaska, Izabela P.; Görnemann, Janina; Beullens, Monique; Bollen, Mathieu; Forrester, John V.; McCaig, Colin D.

    2012-01-01

    Electrical gradients are present in many developing and regenerating tissues and around tumours. Mimicking endogenous electric fields in vitro has profound effects on the behaviour of many cell types. Intriguingly, specific cell types migrate cathodally, others anodally and some polarise with their long axis perpendicular to the electric vector. These striking phenomena are likely to have in vivo relevance since one of the determining factors during cancer metastasis is the ability to switch ...

  9. Role of reactive oxygen species in cis-dichlorodiammineplatinum-induced cytotoxicity on bladder cancer cells.

    OpenAIRE

    Miyajima, A; Nakashima, J.; Yoshioka, K; Tachibana, M.; Tazaki, H.; Murai, M

    1997-01-01

    This study was undertaken to investigate the intracellular induction of reactive oxygen species (ROS) by cis-dichlorodiammineplatinum (CDDP) and the augmentation of their cytotoxicity in bladder cancer cells (KU7) by enhancement of ROS generation by the glutathione (GSH) depletors buthionine sulphoximine (BSO) and diethylmaleate (DEM). CDDP-induced cytotoxicity in KU7 cells and its modulation by GSH depletors were determined using spectrophotometric measurement with crystal violet staining. T...

  10. Anthracycline resistance mediated by reductive metabolism in cancer cells: The role of aldo-keto reductase 1C3

    Energy Technology Data Exchange (ETDEWEB)

    Hofman, Jakub; Malcekova, Beata; Skarka, Adam; Novotna, Eva; Wsol, Vladimir, E-mail: wsol@faf.cuni.cz

    2014-08-01

    Pharmacokinetic drug resistance is a serious obstacle that emerges during cancer chemotherapy. In this study, we investigated the possible role of aldo-keto reductase 1C3 (AKR1C3) in the resistance of cancer cells to anthracyclines. First, the reducing activity of AKR1C3 toward anthracyclines was tested using incubations with a purified recombinant enzyme. Furthermore, the intracellular reduction of daunorubicin and idarubicin was examined by employing the transfection of A549, HeLa, MCF7 and HCT 116 cancer cells with an AKR1C3 encoding vector. To investigate the participation of AKR1C3 in anthracycline resistance, we conducted MTT cytotoxicity assays with these cells, and observed that AKR1C3 significantly contributes to the resistance of cancer cells to daunorubicin and idarubicin, whereas this resistance was reversible by the simultaneous administration of 2′-hydroxyflavanone, a specific AKR1C3 inhibitor. In the final part of our work, we tracked the changes in AKR1C3 expression after anthracycline exposure. Interestingly, a reciprocal correlation between the extent of induction and endogenous levels of AKR1C3 was recorded in particular cell lines. Therefore, we suggest that the induction of AKR1C3 following exposure to daunorubicin and idarubicin, which seems to be dependent on endogenous AKR1C3 expression, eventually might potentiate an intrinsic resistance given by the normal expression of AKR1C3. In conclusion, our data suggest a substantial impact of AKR1C3 on the metabolism of daunorubicin and idarubicin, which affects their pharmacokinetic and pharmacodynamic behavior. In addition, we demonstrate that the reduction of daunorubicin and idarubicin, which is catalyzed by AKR1C3, contributes to the resistance of cancer cells to anthracycline treatment. - Highlights: • Metabolism of anthracyclines by AKR1C3 was studied at enzyme and cellular levels. • Anthracycline resistance mediated by AKR1C3 was demonstrated in cancer cells. • Induction of AKR1C3

  11. Anthracycline resistance mediated by reductive metabolism in cancer cells: The role of aldo-keto reductase 1C3

    International Nuclear Information System (INIS)

    Pharmacokinetic drug resistance is a serious obstacle that emerges during cancer chemotherapy. In this study, we investigated the possible role of aldo-keto reductase 1C3 (AKR1C3) in the resistance of cancer cells to anthracyclines. First, the reducing activity of AKR1C3 toward anthracyclines was tested using incubations with a purified recombinant enzyme. Furthermore, the intracellular reduction of daunorubicin and idarubicin was examined by employing the transfection of A549, HeLa, MCF7 and HCT 116 cancer cells with an AKR1C3 encoding vector. To investigate the participation of AKR1C3 in anthracycline resistance, we conducted MTT cytotoxicity assays with these cells, and observed that AKR1C3 significantly contributes to the resistance of cancer cells to daunorubicin and idarubicin, whereas this resistance was reversible by the simultaneous administration of 2′-hydroxyflavanone, a specific AKR1C3 inhibitor. In the final part of our work, we tracked the changes in AKR1C3 expression after anthracycline exposure. Interestingly, a reciprocal correlation between the extent of induction and endogenous levels of AKR1C3 was recorded in particular cell lines. Therefore, we suggest that the induction of AKR1C3 following exposure to daunorubicin and idarubicin, which seems to be dependent on endogenous AKR1C3 expression, eventually might potentiate an intrinsic resistance given by the normal expression of AKR1C3. In conclusion, our data suggest a substantial impact of AKR1C3 on the metabolism of daunorubicin and idarubicin, which affects their pharmacokinetic and pharmacodynamic behavior. In addition, we demonstrate that the reduction of daunorubicin and idarubicin, which is catalyzed by AKR1C3, contributes to the resistance of cancer cells to anthracycline treatment. - Highlights: • Metabolism of anthracyclines by AKR1C3 was studied at enzyme and cellular levels. • Anthracycline resistance mediated by AKR1C3 was demonstrated in cancer cells. • Induction of AKR1C3

  12. The Role of Mitochondrial NADPH-Dependent Isocitrate Dehydrogenase in Cancer Cells

    Czech Academy of Sciences Publication Activity Database

    Smolková, Katarína; Ježek, Petr

    2012-01-01

    Roč. 2012, č. 2012 (2012), ID273947. ISSN 1687-8876 R&D Projects: GA ČR GPP301/12/P381; GA ČR(CZ) GAP302/10/0346 Institutional research plan: CEZ:AV0Z50110509 Institutional support: RVO:67985823 Keywords : isocitrate dehydrogenase 2 * Krebs cycle * cancer cells Subject RIV: ED - Physiology

  13. Fibroblast growth factor signaling and inhibition in non-small cell lung cancer and their role in squamous cell tumors

    International Nuclear Information System (INIS)

    With the introduction of targeted agents primarily applicable to non-small cell lung cancer (NSCLC) of adenocarcinoma histology, there is a heightened unmet need in the squamous cell carcinoma population. Targeting the angiogenic fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling pathway is among the strategies being explored in squamous NSCLC; these efforts are supported by growth-promoting effects of FGF signaling in preclinical studies (including interactions with other pathways) and observations suggesting that FGF/FGFR-related aberrations may be more common in squamous versus adenocarcinoma and other histologies. A number of different anti-FGF/FGFR approaches have shown promise in preclinical studies. Clinical trials of two multitargeted tyrosine kinase inhibitors are restricting enrollment to patients with squamous NSCLC: a phase I/II trial of nintedanib added to first-line gemcitabine/cisplatin and a phase II trial of ponatinib for previously treated advanced disease, with the latter requiring not only squamous disease but also a confirmed FGFR kinase amplification or mutation. There are several ongoing clinical trials of multitargeted agents in general NSCLC populations, including but not limited to patients with squamous disease. Other FGF/FGFR-targeted agents are in earlier clinical development. While results are awaited from these clinical investigations in squamous NSCLC and other disease settings, additional research is needed to elucidate the role of FGF/FGFR signaling in the biology of NSCLC of different histologies

  14. The Role of MET Receptor Tyrosine Kinase in Non-Small Cell Lung Cancer and Clinical Development of Targeted Anti-MET Agents

    OpenAIRE

    Robinson, Kyle W.; Sandler, Alan B.

    2013-01-01

    The role of MET in the pathophysiology of non-small cell lung cancer and in acquired resistance to epidermal growth factor receptor inhibitors is summarized. An update on progress in the clinical development of inhibitors of MET for treatment of non-small cell lung cancer is provided.

  15. PGC-1 family coactivators and cell fate: roles in cancer, neurodegeneration, cardiovascular disease and retrograde mitochondria-nucleus signalling.

    OpenAIRE

    Jones, A W; Z. Yao; Vicencio, J. M.; Karkucinska-Wieckowska, A.; Szabadkai, G.

    2012-01-01

    Over the past two decades, a complex nuclear transcriptional machinery controlling mitochondrial biogenesis and function has been described. Central to this network are the PGC-1 family coactivators, characterised as master regulators of mitochondrial biogenesis. Recent literature has identified a broader role for PGC-1 coactivators in both cell death and cellular adaptation under conditions of stress, here reviewed in the context of the pathology associated with cancer, neurodegeneration and...

  16. COPD promotes migration of A549 lung cancer cells: the role of chemokine CCL21

    OpenAIRE

    Kuznar-Kaminska, Barbara

    2016-01-01

    Barbara Kuźnar-Kamińska,1 Justyna Mikuła-Pietrasik,2 Patrycja Sosińska,2 Krzysztof Książek,2 Halina Batura-Gabryel1 1Department of Pulmonology, Allergology and Respiratory Oncology, 2Department of Pathophysiology, Poznań University of Medical Sciences, Poznań, Poland Abstract: Patients with COPD develop lung cancer more frequently than healthy smokers. At the same time, molecular mediators promoting various aspects of cancer cell progression are still elusive. In t...

  17. COPD promotes migration of A549 lung cancer cells: the role of chemokine CCL21

    OpenAIRE

    Kuźnar-Kamińska B; Mikuła-Pietrasik J; Sosińska P; Książek K; Batura-Gabryel H

    2016-01-01

    Barbara Kuźnar-Kamińska,1 Justyna Mikuła-Pietrasik,2 Patrycja Sosińska,2 Krzysztof Książek,2 Halina Batura-Gabryel1 1Department of Pulmonology, Allergology and Respiratory Oncology, 2Department of Pathophysiology, Poznań University of Medical Sciences, Poznań, Poland Abstract: Patients with COPD develop lung cancer more frequently than healthy smokers. At the same time, molecular mediators promoting various aspects of cancer cell progression are still elusive. In this report, we e...

  18. Role of replication protein A in the radioresistance of esophageal cancer cell line and its mechanism

    International Nuclear Information System (INIS)

    Objective: To evaluate the effect of replication protein A (RPA) gene suppression on the radiosensitivity of esophageal cancer cells (TE-1R) and underlying mechanism. Methods: A radioresistant human esophageal cancer cell line TE-1 R was screened out by fractionated irradiation to TE-1 cells, then siRPA1 or siRPa2 was transfected to TE-1R cells. The untransfected (Con) group and nonsense siRNA transfected (NC) group were set as control groups. The survival was measured with colony-forming assay and the cell cycle distribution was measured with flow cytometry. Results: Compared with the Con and NC groups, the protein expression of RPA1 and RPA2 decreased significantly 48 h after siRPA1 and siRPA2 transfection. The D0, Dq, and SF2 values reduced from 2.09, 1.70, 0.85 in NC group to 1.67, 0.71, 0.44 and 1.82, 0.89, 0.51 in siRPAl and siRPA2 transfection groups, respectively. Accordingly, the sensitization enhancement ratios of Dq were 2.39 and 1.91, respectively. The G2/M arrest in siRPA1 and siRPA2 transfection groups increased from (18.701 3.14)% of NC group to (26.95 ± 3.96)% and (25.28 ± 2.74) % (t=2.827, 2.853, P<0.05), respectively. Conclusions: Knocking down of RPA1 or RPA2 genes can enhance the radiosensitivity of human esophageal cancer cells TE-1R, where the inhibition of radiation-induced sublethal damage repair may be involved. Accordingly, RPA may become a new target of radiosensitization in esophageal cancer. (authors)

  19. Age determines the prognostic role of the cancer stem cell marker aldehyde dehydrogenase-1 in breast cancer

    Directory of Open Access Journals (Sweden)

    Mieog J Sven D

    2012-01-01

    Full Text Available Abstract Background The purpose of this study was to compare the expression and the prognostic effect of the breast cancer stem cell marker aldehyde dehydrogenase-1 (ALDH1 in young and elderly breast cancer patients. Methods The study population (N = 574 consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1994. Median follow-up was 17.9 years (range: 0.1 to 23.5. Tissue microarray slides were immunohistochemically stained for ALDH1 expression and quantified by two independent observers who were blinded to clinical outcome. Assessment of the prognostic effect of ALDH1 expression was stratified according to age and systemic treatment. Results Complete lack of expression of ALDH1 was found in 40% of tumors. With increasing age more tumors showed complete absence of ALDH1 expression (P 65 years, ALDH1 status was not associated with any clinical outcome. Conversely, in patients aged P = .021 and relative survival (relative excess risks of death = 2.36 (95% CI, 1.22 to 3.68; P = .016. Ten-year relative survival risk was 57% in ALDH1-positive patients compared to 83% in ALDH1-negative patients. Conclusion ALDH1 expression and its prognostic effect are age-dependent. Our results support the hypothesis that breast cancer biology is different in elderly patients compared to their younger counterparts and emphasizes the importance of taking into consideration age-specific interactions in breast cancer research.

  20. Human epididymis protein 4 (HE4) plays a key role in ovarian cancer cell adhesion and motility

    International Nuclear Information System (INIS)

    Highlights: ► We generated stable transduced HE4 overexpression and knockdown cells. ► HE4 was associated with EOC cell adhesion and motility. ► HE4 might have some effects on activation of EGFR-MAPK signaling pathway. ► HE4 play an important role in EOC tumorigenicity. -- Abstract: Human epididymis protein 4 (HE4) is a novel and specific biomarker for epithelial ovarian cancer (EOC). We previously demonstrated that serum HE4 levels were significantly elevated in the majority of EOC patients but not in subjects with benign disease or healthy controls. However, the precise mechanism of HE4 protein function is unknown. In this study, we generated HE4-overexpressing SKOV3 cells and found that stably transduced cells promoted cell adhesion and migration. Knockdown of HE4 expression was achieved by stable transfection of SKOV3 cells with a construct encoding a short hairpin DNA directed against the HE4 gene. Correspondingly, the proliferation and spreading ability of HE4-expressed cells were inhibited by HE4 suppression. Mechanistically, impaired EGFR and Erk1/2 phosphorylation were observed in cells with HE4 knockdown. The phosphorylation was restored when the knockdown cells were cultured in conditioned medium containing HE4. Moreover, in vivo tumorigenicity showed that HE4 suppression markedly inhibited the growth of tumors. This suggests that expression of HE4 is associated with cancer cell adhesion, migration and tumor growth, which can be related to its effects on the EGFR-MAPK signaling pathway. Our results provide evidence of the cellular and molecular mechanisms that may underlie the motility-promoting role of HE4 in EOC progression. The role of HE4 as a target for gene-based therapy might be considered in future studies.

  1. Roles of noncoding RNAs in metastasis of nonsmall cell lung cancer: A mini review

    Directory of Open Access Journals (Sweden)

    Tao Wu

    2015-01-01

    Full Text Available Recent advances in genome-wide sequencing and gene expression profiling technologies has facilitated the discovery of a huge amount of long noncoding RNA (lncRNA transcripts. In general, these lncRNAs have been reported to participate in multiple biological processes and human diseases through transcriptional, posttranscriptional and epigenetic pathway. Furthermore, emerging evidence has suggested that dysregulation of lncRNA contributes to the development and progression of human malignancies, notably lung cancer, which is one of the leading causes of cancer-related death. In this review, we will summarize the functions of lncRNAs from recent reports in human nonsmall cell lung cancer (NSCLC research, especially in the metastasis of NSCLC, and highlight the future opportunities and challenges in diagnostics and therapy of NSCLC patients.

  2. Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

    OpenAIRE

    Deschoolmeester, Vanessa; Baay, Marc; Lardon, Filip; Pauwels, Patrick; Peeters, Marc

    2011-01-01

    There is growing evidence that both local and systemic inflammatory responses play an important role in the progression of a variety of solid tumors. Colorectal cancer (CRC) results from the cumulative effect of sequential genetic alterations, leading to the expression of tumor-associated antigens possibly inducing a cellular anti-tumor immune response. It is well recognized that cytotoxic lymphocytes (CTLs) constitute one of the most important effector mechanisms of anti-tumor-immunity. Howe...

  3. Migration-promoting role of VEGF-C and VEGF-C binding receptors in human breast cancer cells

    Science.gov (United States)

    Timoshenko, A V; Rastogi, S; Lala, P K

    2007-01-01

    Vascular endothelial growth factor C (VEGF-C) is a lymphangiogenic factor over-expressed in highly metastatic, cyclooxygenase (COX)-2 expressing breast cancer cells. We tested the hypothesis that tumour-derived VEGF-C may play an autocrine role in metastasis by promoting cellular motility through one or more VEGF-C-binding receptors VEGFR-2, VEGFR-3, neuropilin (NRP)-1, NRP-2, and integrin α9β1. We investigated the expression of these receptors in several breast cancer cell lines (MDA-MB-231, Hs578T, SK-BR-3, T-47D, and MCF7) and their possible requirement in migration of two VEGF-C-secreting, highly metastatic lines MDA-MB-231 and Hs578T. While cell lines varied significantly in their expression of above VEGF-C receptors, migratory activity of MDA-MB-231 and Hs578T cells was linked to one or more of these receptors. Depletion of endogenous VEGF-C by treatments with a neutralising antibody, VEGF-C siRNA or inhibitors of Src, EGFR/Her2/neu and p38 MAP kinases which inhibited VEGF-C production, inhibited cellular migration, indicating the requirement of VEGF-C for migratory function. Migration was differentially attenuated by blocking or downregulation of different VEGF-C receptors, for example treatment with a VEGFR-2 tyrosine kinase inhibitor, NRP-1 and NRP-2 siRNA or α9β1 integrin antibody, indicating the participation of one or more of the receptors in cell motility. This novel role of tumour-derived VEGF-C indicates that breast cancer metastasis can be promoted by coordinated stimulation of lymphangiogenesis and enhanced migratory activity of breast cancer cells. PMID:17912247

  4. Role of ATG10 expression quantitative trait loci in non-small cell lung cancer survival.

    Science.gov (United States)

    Xie, Kaipeng; Liang, Cheng; Li, Qin; Yan, Caiwang; Wang, Cheng; Gu, Yayun; Zhu, Meng; Du, Fangzhi; Wang, Hui; Dai, Juncheng; Liu, Xiao'an; Jin, Guangfu; Shen, Hongbing; Ma, Hongxia; Hu, Zhibin

    2016-10-01

    The aim of this article was to evaluate whether genetic variants in autophagy-related genes affect the overall survival (OS) of non-small cell lung cancer (NSCLC) patients. We analyzed 14 single nucleotide polymorphisms (SNPs) in core autophagy-related genes for OS in 1,001 NSCLC patients. Three promising SNPs in ATG10 were subsequently annotated by the expression quantitative trait loci (eQTL) and methylation quantitative trait loci (meQTL) analyses based on Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. We observed that the variants of rs10514231, rs1864182 and rs1864183 were associated with poor lung cancer survival (HR = 1.33, 95% CI = 1.07-1.65; HR = 1.43, 95% CI = 1.13-1.81; HR = 1.38, 95% CI = 1.14-1.68, respectively) and positively correlated with ATG10 expression (all p lung cancer patients in TCGA dataset (HR = 2.10, 95% CI = 1.33-3.29). Moreover, the variants of rs10514231 and rs1864182 were associated with the increased methylation levels of cg17942617 (meQTL), which in turn contributed to the elevated ATG10 expression and decreased survival time. Further functional assays revealed that ATG10 facilitated lung cancer cell proliferation and migration. Our findings suggest that eQTL/meQTL variations of ATG10 could influence lung cancer survival through regulating ATG10 expression. PMID:27225307

  5. Roles of Galectin-7 in Cancer.

    Science.gov (United States)

    Kaur, Manpreet; Kaur, Tarnjeet; Kamboj, Sukhdev Singh; Singh, Jatinder

    2016-01-01

    Galectins are β-galactoside binding lectins that contain one or more carbohydrate recognition domains. As a consequence of sugar-binding properties, galectins exhibit a variety of interactions with glycoproteins, thus playing important roles in various pathological processes. A number of studies have shown roles of galectins in cancer. Galectin-7 is a prototype member of the galectin family implicated in epithelial stratification and cell migration. It can act as a potent dual regulator in different types of cancer. Galectin-7 may contribute either to neoplastic transformation and tumour progression through regulation of cell growth, cell cycle, angiogenesis, apoptosis and cell migration or may have a protective effect in cancer depending on the tissue type. A perusal of the literature indicates particular roles of galectin-7 in carcinomas and melanomas, while contributions await greater exploration in other types of cancers including sarcomas and leukemia. This review collectively summarizes available literature on expression and roles of galectin-7 in different cancers. PMID:26925627

  6. Role of NKG2D-Expressing NK Cells and sMICA in Immune Surveillance of Advanced Lung Cancer

    Directory of Open Access Journals (Sweden)

    Jing LIANG

    2009-01-01

    Full Text Available Background and objective NKG2D-expressing NK cells and soluble major histocompatibility complex class Ⅰ-related chain A (sMICA is one of aroused general interests in tumor research area recently. The aimof the study is to investigate the levels of NKG2D-expressing NK cells and sMICA in peripheral blood of advanced lung cancer which are remarkably related to clinical significance and analyse the role of NKG2D-expressing NK cells and sMICA in immune surveillance. Methods Flow cytometry was used to determine the percentage of NKG2D-expressing NK cells, T cell subsets, NK cells, and ELISA was used to mesure the levels of sMICA in peripheral blood of 115 advanced lung cancer patients and 50 healthy controls. Results Compared with control group, the levels of sMICA、CD8+T cells, NK cells increased, while the levels of NKG2D-expressing NK cells, CD3+ T cells, CD4+ T cells, CD4+ T/CD8+ T in experimental group decreased. NKG2D-expressing NK cells had a perfect negative correlation with sMICA (r =-0.319, P <0.05. NKG2D-expressing NK cells had positive correlation with CD4+ T cells, CD4+ T/CD8+ T and negative correlationwith CD8+ T cells (P <0.05, sMICA had negative correlation with CD4+ T cells, CD4+ T/CD8+ T and positive correlation with CD8+ T cells (P <0.05, they had no significant correlation with CD3+ T cells, NK cells respectively (P <0.05. Conclusion Accumulation of sMICA in serum may lead to the down-modulation of NKG2D-expressing NK which has been proposed to be a novel mechanism used by cancer cells to evade the tumor immunosurveillance. They may be potential indicators investigating immune functions and helpful in the evaluation of their happening and proceeding.

  7. The Role of Surface Receptor Density in Surface-Initiated Polymerizations for Cancer Cell Isolation.

    Science.gov (United States)

    Lilly, Jacob L; Berron, Brad J

    2016-06-01

    Fluid biopsies potentially offer a minimally invasive alternative to traditional tissue biopsies for the continual monitoring of metastatic cancer. Current established technologies for isolating circulating tumor cells (CTCs) suffer from poor purity and yield and require fixatives that preclude the collection of viable cells for longitudinal analyses of biological function. Antigen specific lysis (ASL) is a rapid, high-purity method of cell isolation based on targeted protective coatings on antigen-presenting cells and lysis depletion of unprotected antigen-negative cells. In ASL, photoinitiators are specifically labeled on cell surfaces that enable subsequent surface-initiated polymerization. Critically, the significant determinants of process yield have yet to be investigated for this emerging technology. In this work, we show that the labeling density of photoinitiators is strongly correlated with the yield of intact cells during ASL by flow cytometry analysis. Results suggest ASL is capable of delivering ∼25% of targeted cells after isolation using traditional antibody labeling approaches. Monomer formulations of two molecular weights of PEG-diacrylate (Mn ∼ 575 and 3500) are examined. The gelation response during ASL polymerization is also investigated via protein microarray analogues on planar glass. Finally, a density threshold of photoinitiator labeling required for protection during lysis is determined for both monomer formulations. These results indicate ASL is a promising technology for high yield CTC isolation for rare-cell function assays and fluid biopsies. PMID:27206735

  8. Roles of Fas signaling pathway in vitamin E succinate-induced apoptosis in human gastric cancer SGC-7901 cells

    Institute of Scientific and Technical Information of China (English)

    Kun Wu; Yao Li; Yan Zhao; Yu-Juan Shan; Wei Xia; Wei-Ping Yu; Lan Zhao

    2002-01-01

    AIM: To investigate the roles of Fas signaling pathway in vitamin E succinate-induced apoptosis in human gastric cancer SGC-7901 cells.METHODS: Human gastric cancer SGC-7901 cells were treated with VES at 5, 10, 20 mg@L-1, succinic acid and vitamin E as vehicle control and condition media only as untreated (UT) control. Apoptotic morphology was observed by DAPI staining. Western blot analysis was applied to measure the expression of Fas, FADD and caspase-8 proteins. After the cells were transiently transfected with Fas and FADD antisense oligonucleotides, respectively, caspase-8 activity was determined by flurometric method.RESULTS: The morphologically apoptotic changes were observed after VES treatment by DAPI staining. 23.7 % and 89.6 % apoptosis occurred after 24 h and 48 h of 20 mg@L-1 VES treatment, respectively. The protein levels of Fas, FADD and caspase-8 were evidently increased in a dose-dependent manner after 24 h of VES treatment. The blockage of Fas by transfection with Fas antisense oligonucleotides obviously inhibited the expression of FADD protein. After SGC-7901 cells were transfected with Fas and FADD antisense oligonucleotides, caspase-8 activity was obviously decreased (P<0.01), whereas Fas blocked more than FADD.CONCLUSION: VES-induced apoptosis in human gastric cancer SGC-7901 cells involves Fas signaling pathway including the interaction of Fas, FADD and caspase-8.

  9. Mechanism of Akt1 inhibition of breast cancer cell invasionreveals a protumorigenic role for TSC2

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Hong; Radisky, Derek C.; Nelson, Celeste M.; Zhang, Hui; Fata, Jimmie; Roth, Richard A.; Bissell, Mina J.

    2006-02-07

    Akt1 is frequently upregulated in human tumors, and has been shown to accelerate cell proliferation and to suppress programmed cell death; consequently, inhibiting the activity of Akt1 has been seen as an attractive target for therapeutic intervention. Paradoxically, hyperactivation of the Akt1 oncogene can also prevent the invasive behavior that underlies progression to metastasis. Here we show that overexpression of activated myr-Akt1 in human breast cancer cells phosphorylates and thereby targets the tumor suppressor tuberous sclerosis complex 2 (TSC2) for degradation, leading to reduced Rho-GTPase activity, decreased actin stress fibers and focal adhesions, and reduced motility and invasion. Overexpression of TSC2 rescues the migration phenotype of myr-Akt1-expressing tumor cells, and high levels of TSC2 in breast cancer patients correlate with increased metastasis and reduced survival. These data indicate that the functional properties of genes designated as oncogenes or tumor suppressor genes depends on the context of the cell type and the tissues studied, and suggest the need for caution in designing therapies targeting the function of individual genes in epithelial tissues.

  10. [The structure of cellular vaults, their role in the normal cell and in the multidrug resistance of cancer].

    Science.gov (United States)

    Szaflarski, Witold; Nowicki, Michał; Zabel, Maciej

    2011-01-01

    The cellular vaults have been described for the first time in 1986 as ribonucleoprotein complexes composed of three proteins, MVP, TEP1 and vPARP and several vRNA strains. Biochemical and structural studies revealed their ubiquitous existence in the cytoplasm of many eukaryotic cells and their barrel-like structure indicating their engagement in the intracellular transport. Furthermore, the high homology between MVP and LRP which was already known to be involved in multidrug resistance mechanism opened a discussion about the role of vaults in both normal and cancer cells. The histopathology research demonstrated an increased amount of MVP/LRP proteins in the cancer as well as showed translocation possibility between cytoplasm and nuclear envelope, which can be of crucial point in the prevention of nucleus against anticancer drugs. PMID:22235652

  11. Role of ErbB receptors in cancer cell migration and invasion

    Directory of Open Access Journals (Sweden)

    Aline eAppert-Collin

    2015-11-01

    Full Text Available Growth factors mediate their diverse biologic responses (regulation of cellular proliferation, differentiation, migration and survival by binding to and activating cell-surface receptors with intrinsic protein kinase activity named Receptor Tyrosine Kinases (RTKs. About 60 RTKs have been identified and can be classified into more than 16 different receptor families. Their activity is normally tightly controlled and regulated. Overexpression of RTK proteins or functional alterations caused by mutations in the corresponding genes or abnormal stimulation by autocrine growth factor loops contribute to constitutive RTK signaling, resulting in alterations in the physiological activities of cells. The ErbB receptor family of RTKs comprises four distinct receptors: the EGFR (also known as ErbB1/HER1, ErbB2 (neu, HER2, ErbB3 (HER3 and ErbB4 (HER4. ErbB family members are often overexpressed, amplified, or mutated in many forms of cancer, making them important therapeutic targets. EGFR has been found to be amplified in gliomas and non-small-cell lung carcinoma while ErbB2 amplifications are seen in breast, ovarian, bladder, non-small-cell lung carcinoma, as well as several other tumor types. Several data have shown that ErbB receptor family and its downstream pathway regulate epithelial-mesenchymal transition, migration, and tumor invasion by modulating extracellular matrix components. Recent findings indicate that extracellular matrix components such as matrikines bind specifically to EGF receptor and promote cell invasion. In this review, we will present an in-depth overview of the structure, mechanisms, cell signaling, and functions of ErbB family receptors in cell adhesion and migration. Furthermore, we will describe in a last part the new strategies developed in anti-cancer therapy to inhibit ErbB family receptor activation.

  12. Oct4 plays a crucial role in the maintenance of gefitinib-resistant lung cancer stem cells.

    Science.gov (United States)

    Kobayashi, Isao; Takahashi, Fumiyuki; Nurwidya, Fariz; Nara, Takeshi; Hashimoto, Muneaki; Murakami, Akiko; Yagishita, Shigehiro; Tajima, Ken; Hidayat, Moulid; Shimada, Naoko; Suina, Kentaro; Yoshioka, Yasuko; Sasaki, Shinichi; Moriyama, Mariko; Moriyama, Hiroyuki; Takahashi, Kazuhisa

    2016-04-22

    Several recent studies have suggested that cancer stem cells (CSCs) are involved in resistance to gefitinib in non-small cell lung cancer (NSCLC). Oct4, a member of the POU-domain transcription factor family, has been shown to be involved in CSC properties of various cancers. We previously reported that Oct4 and the putative lung CSC marker CD133 were highly expressed in gefitinib-resistant persisters (GRPs) in NSCLC cells, and GRPs exhibited characteristic features of the CSCs phenotype. The aim of this study was to elucidate the role of Oct4 in the resistance to gefitinib in NSCLC cells with an activating epidermal growth factor receptor (EGFR) mutation. NSCLC cell lines, PC9, which express the EGFR exon 19 deletion mutation, were transplanted into NOG mice, and were treated with gefitinib in vivo. After 14-17 days of gefitinib treatment, the tumors still remained; these tumors were referred to as gefitinib-resistant tumors (GRTs). PC9-GRTs showed higher expression of Oct4 and CD133. To investigate the role of Oct4 in the maintenance of gefitinib-resistant lung CSCs, we introduced the Oct4 gene into PC9 and HCC827 cells carrying an activating EGFR mutation by lentiviral infection. Transfection of Oct4 significantly increased CD133-positive GRPs and the number of sphere formation, reflecting the self-renewal activity, of PC9 and HCC827 cells under the high concentration of gefitinib in vitro. Furthermore, Oct4-overexpressing PC9 cells (PC9-Oct4) significantly formed tumors at 1 × 10 cells/injection in NOG mice as compared to control cells. In addition, PC9-Oct4 tumors were more resistant to gefitinib treatment as compared to control cells in vivo. Finally, immunohistochemical analysis revealed that Oct4 was highly expressed in tumor specimens of EGFR-mutant NSCLC patients with acquired resistance to gefitinib. Collectively, these findings suggest that Oct4 plays a pivotal role in the maintenance of lung CSCs resistant to gefitinib in EGFR mutation

  13. A role of ZnO nanoparticle electrostatic properties in cancer cell cytotoxicity

    Science.gov (United States)

    Wingett, Denise; Louka, Panagiota; Anders, Catherine B; Zhang, Jianhui; Punnoose, Alex

    2016-01-01

    ZnO nanoparticles (NPs) have previously been shown to exhibit selective cytotoxicity against certain types of cancerous cells suggesting their potential use in biomedical applications. In this study, we investigate the effect of surface modification of ZnO NPs on their cytotoxicity to both cancerous and primary T cells. Our results show that polyacrylic acid capping produces negatively charged ZnO NPs that are significantly more toxic compared to uncapped positively charged NPs of identical size and composition. In contrast, the greatest selectivity against cancerous cells relative to normal cells is observed with cationic NPs. In addition, differences in NP cytotoxicity inversely correlate with NP hydrodynamic size, propensity for aggregation, and dissolution profiles. The generation of reactive oxygen species (ROS) was also observed in the toxicity mechanism with anionic NPs generating higher levels of mitochondrial superoxide without appreciably affecting glutathione levels. Additional experiments evaluated the combined effects of charged ZnO NPs and nontoxic cationic or anionic CeO2 NPs. Results show that the CeO2 NPs offer protective effects against cytotoxicity from anionic ZnO NPs via antioxidant properties. Altogether, study data indicate that surface modification of NPs and resulting changes in their surface charge affect the level of intracellular ROS production, which can be ameliorated by the CeO2 ROS scavenger, suggesting that ROS generation is a dominant mechanism of ZnO NP cytotoxicity. These findings demonstrate the importance of surface electrostatic properties for controlling NP toxicity and illustrate an approach for engineering NPs with desired properties for potential use in biological applications. PMID:27486313

  14. The Role of Postoperative Radiotherapy on Stage N2 Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Fangfang DU

    2009-11-01

    Full Text Available Background and objective The clinical value of postoperative radiotherapy (PORT in stage N2 nonsmall-cell lung cancer (NSCLC is controversy. The aim of this study is to analyze the efficacy of PORT in subgroup of stage N2 NSCLC, which can help clinicians to choose proper patients for PORT. Methods Clinical data of 359 patients with stage N2 NSCLC treated with radical surgery between Mar. 2000 and Jul. 2005 were retrospectively reviewed. Two hundred and seven patients received adjuvant chemotherapy and one hundred and four patients received adjuvant radiotherapy. First, the group of patients were analyzed to evaluate the factors affecting the overall survival. The all patients were divided based on tumor size and the number of lymph node metastasis station (single station or multiple station so as to evaluate the role of PORT. The endpoint was overall survival (OS and local recurrence-free survival (LRFS. Kaplan-Meier method was used to calculate the OS, LRFS and Log-rank was used to compare the difference in OS and LRFS between different groups. Results The median duration of follow-up was 2.3 years. 224 patients died. The median survival was 1.5 years and 1, 3, 5-year survival were 78%, 38% and 26%. Univariate analysis showed tumor size, the number of lymph node metastasis station and PORT were correlated with OS. Among patients, 5-year survival rates in PORT and non-PORT were 29% and 24% (P=0.047 respectively. In subgroups, PORT was related with high survival in patients with multiple station N2 compared to non-PORT: 36% vs 20% (P=0.013 and 33% vs 15% (P=0.002 in patients in patients with tumor size > 3 cm. Also, it was related with low local recurrence compared to non-PORT: 65% vs 48% (P=0.006 and 62% vs 48% (P=0.033. Conclusion PORT can improve overall survival for N2 NSCLC, especially the patients with the factors as follows: tumor size > 3 cm and multiple station N2 can benefit from PORT more or less.

  15. Unusual roles of caspase-8 in triple-negative breast cancer cell line MDA-MB-231.

    Science.gov (United States)

    De Blasio, Anna; Di Fiore, Riccardo; Morreale, Marco; Carlisi, Daniela; Drago-Ferrante, Rosa; Montalbano, Mauro; Scerri, Christian; Tesoriere, Giovanni; Vento, Renza

    2016-06-01

    Triple-negative breast cancer (TNBC) is a clinically aggressive form of breast cancer that is unresponsive to endocrine agents or trastuzumab. TNBC accounts for ~10-20% of all breast cancer cases and represents the form with the poorest prognosis. Patients with TNBC are at higher risk of early recurrence, mainly in the lungs, brain and soft tissue, therefore, there is an urgent need for new therapies. The present study was carried out in MDA-MB-231 cells, where we assessed the role of caspase-8 (casp-8), a critical effector of death receptors, also involved in non‑apoptotic functions. Analysis of casp-8 mRNA and protein levels indicated that they were up-regulated with respect to the normal human mammalian epithelial cells. We demonstrated that silencing of casp-8 by small interfering-RNA, strongly decreased MDA-MB-231 cell growth by delaying G0/G1- to S-phase transition and increasing p21, p27 and hypo-phosphorylated/active form of pRb levels. Surprisingly, casp-8-knockdown, also potently increased both the migratory and metastatic capacity of MDA-MB‑231 cells, as shown by both wound healing and Matrigel assay, and by the expression of a number of related-genes and/or proteins such as VEGFA, C-MYC, CTNNB1, HMGA2, CXCR4, KLF4, VERSICAN V1 and MMP2. Among these, KLF4, a transcriptional factor with a dual role (activator and repressor), seemed to play critical roles. We suggest that in MDA-MB‑231 cells, the endogenous expression of casp-8 might keep the cells perpetually cycling through downregulation of KLF4, the subsequent lowering of p21 and p27, and the inactivation by hyperphosphorylation of pRb. Simultaneously, by lowering the expression of some migratory and invasive genes, casp-8 might restrain the metastatic ability of the cells. Overall, our findings showed that, in MDA-MB-231 cells, casp-8 might play some unusual roles which should be better explored, in order to understand whether it might be identified as a molecular therapeutic target. PMID

  16. Reducing VDAC1 expression induces a non-apoptotic role for pro-apoptotic proteins in cancer cell differentiation.

    Science.gov (United States)

    Arif, Tasleem; Krelin, Yakov; Shoshan-Barmatz, Varda

    2016-08-01

    Proteins initially identified as essential for apoptosis also mediate a wide range of non-apoptotic functions that include cell cycle progression, differentiation and metabolism. As this phenomenon was mostly reported with non-cancer cells, we considered non-conventional roles for the apoptotic machinery in the cancer setting. We found that treating glioblastoma (GBM) tumors with siRNA against VDAC1, a mitochondrial protein found at the crossroads of metabolic and survival pathways and involved in apoptosis, inhibited tumor growth while leading to differentiation of tumor cells into neuronal-like cells, as reflected in the expression of specific markers. Although VDAC1 depletion did not induce apoptosis, the expression levels of several pro-apoptotic regulatory proteins were changed. Specifically, VDAC1 deletion led to up-regulation of caspases, p53, cytochrome c, and down-regulation of SMAC/Diablo, AIF and TSPO. The down-regulated group was highly expressed in U-87MG xenografts, as well as in GBMs from human patients. We also showed that the rewired cancer-cell metabolism resulting from VDAC1 depletion reinforced cell growth arrest and differentiation via alterations in the transcription factors p53, c-Myc, HIF-1α and NF-κB. The decrease in c-Myc, HIF-1α and NF-κB levels was in accord with reduced cell proliferation, whereas increased p53 expression promoted differentiation. Thus, upon metabolic re-programing induced by VDAC1 depletion, the levels of pro-apoptotic proteins associated with cell growth decreased, while those connected to cell differentiation increased, converting GBM cells into astrocyte- and neuron-like cells. The results reveal that in tumors, pro-apoptotic proteins can perform non-apoptotic functions, acting as regulators of cell growth and differentiation, making these molecules potential new targets for cancer therapy. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy

  17. ROLE OF PI3K-AKT-mTOR AND Wnt SIGNALING PATHWAYS IN G1-S TRANSITION OF CELL CYCLE IN CANCER CELLS

    Directory of Open Access Journals (Sweden)

    LAKSHMIPATHI eVADLAKONDA

    2013-04-01

    Full Text Available The PI3K–Akt pathway together with one of its downstream targets, the mechanistic target of rapamycin (mTOR is a highly deregulated pathway in cancers. There is a reciprocal relation between the Akt phosphorylation and mTOR complexes. Akt phosphorylated at T308 activates mTORC1 by inhibition of the tuberous sclerosis complex (TSC1/2, where as mTORC2 is recognized as the kinase that phosphorylates Akt at S473. Recent developments in the research on regulatory mechanisms of autophagy places mTORC1 mediated inhibition of autophagy at the central position in activation of proliferation and survival pathways in cells. Autophagy is a negative regulator of Wnt signaling pathway and the downstream effectors of Wnt signaling pathway, cyclin D1 and the c-Myc, are the key players in initiation of cell cycle and regulation of the G1-S transition in cancer cells. Production of reaction oxygen species (ROS, a common feature of a cancer cell metabolism, activates several downstream targets like the transcription factors FoxO, which play key roles in promoting the progression of cell cycle. A model is presented on the role of PI3K -Akt - mTOR and Wnt pathways in regulation of the progression of cell cycle through Go-G1-and S phases.

  18. Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis; the role of p53 and p21

    OpenAIRE

    Escandell, José M.; Kaler, Pawan; Recio, M. Carmen; Sasazuki, Takehiko; Shirasawa, Senji; Augenlicht, Leonard; Ríos, José-Luis; Klampfer, Lidija

    2008-01-01

    Cucurbitacins have been shown to inhibit proliferation in a variety of cancer cell lines. The aim of this study was to determine their biological activity in colon cancer cell lines that do not harbor activated STAT3, the key target of cucurbitacin. In order to establish the role of activated kRas in the responsiveness of cells to cucurbitacins, we performed experiments in isogenic colon cancer cell lines, HCT116 and Hke-3, which differ only by the presence of an activated kRas allele. We com...

  19. Role of erlotinib in first-line and maintenance treatment of advanced non-small-cell lung cancer

    International Nuclear Information System (INIS)

    Erlotinib hydrochloride (Tarceva®) is a member of a class of small molecule inhibitors that targets the tyrosine kinase domain of the epidermal growth factor receptor (EGFR), with anti-tumor activity in preclinical models. Erlotinib represents a new-generation of agents known as “targeted therapies” designed to act upon cancer cells by interfering with aberrant specific activated pathways needed for tumor growth, angiogenesis and cell survival. Since its approval in November 2004 for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) after the failure of at least one prior chemotherapy regimen and with a view to improving patients’ outcomes and prevent symptoms, the scientific community has evaluated the potential role of erlotinib in other scenarios such as in maintenance therapy and, in first-line setting for a selected population based on biological markers of response such as mutations of the EGFR. The convenient once-a-day pill administration and the good toxicity profile of erlotinib make it a reasonable candidate for testing in this context. This report provides a review of the role of erlotinib therapy in advanced NSCLC. It summarizes current data and perspectives of erlotinib in upfront treatment and maintenance for advanced NSCLC as well as looking at candidate biomarkers of response to these new targeted-agents

  20. TNF{alpha} induced FOXP3-NF{kappa}B interaction dampens the tumor suppressor role of FOXP3 in gastric cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Hao, Qiang; Li, Weina; Zhang, Cun; Qin, Xin; Xue, Xiaochang; Li, Meng; Shu, Zhen; Xu, Tianjiao; Xu, Yujin; Wang, Weihua [The State Key Laboratory of Cancer Biology, School of Pharmacy, Department of Biopharmaceutics, Fourth Military Medical University, Xi' an 710032 (China); Zhang, Wei, E-mail: Zhangw90@fmmu.edu.cn [The State Key Laboratory of Cancer Biology, School of Pharmacy, Department of Biopharmaceutics, Fourth Military Medical University, Xi' an 710032 (China); Zhang, Yingqi, E-mail: Zhangyqh@fmmu.edu.cn [The State Key Laboratory of Cancer Biology, School of Pharmacy, Department of Biopharmaceutics, Fourth Military Medical University, Xi' an 710032 (China)

    2013-01-04

    Highlights: Black-Right-Pointing-Pointer FOXP3 inhibition of cell proliferation is p21-dependent under basal conditions. Black-Right-Pointing-Pointer Inflammation induced by TNF{alpha} inhibits the tumor suppressor role of FOXP3. Black-Right-Pointing-Pointer Interaction between p65 and FOXP3 inhibits p21 transcription activation. -- Abstract: Controversial roles of FOXP3 in different cancers have been reported previously, while its role in gastric cancer is largely unknown. Here we found that FOXP3 is unexpectedly upregulated in some gastric cancer cells. To test whether increased FOXP3 remains the tumor suppressor role in gastric cancer as seen in other cancers, we test its function in cell proliferation both at basal and TNF{alpha} mimicked inflammatory condition. Compared with the proliferation inhibitory role observed in basal condition, FOXP3 is insufficient to inhibit the cell proliferation under TNF{alpha} treatment. Molecularly, we found that TNF{alpha} induced an interaction between FOXP3 and p65, which in turn drive the FOXP3 away from the promoter of the well known target p21. Our data here suggest that although FOXP3 is upregulated in gastric cancer, its tumor suppressor role has been dampened due to the inflammation environment.

  1. TNFα induced FOXP3–NFκB interaction dampens the tumor suppressor role of FOXP3 in gastric cancer cells

    International Nuclear Information System (INIS)

    Highlights: ► FOXP3 inhibition of cell proliferation is p21-dependent under basal conditions. ► Inflammation induced by TNFα inhibits the tumor suppressor role of FOXP3. ► Interaction between p65 and FOXP3 inhibits p21 transcription activation. -- Abstract: Controversial roles of FOXP3 in different cancers have been reported previously, while its role in gastric cancer is largely unknown. Here we found that FOXP3 is unexpectedly upregulated in some gastric cancer cells. To test whether increased FOXP3 remains the tumor suppressor role in gastric cancer as seen in other cancers, we test its function in cell proliferation both at basal and TNFα mimicked inflammatory condition. Compared with the proliferation inhibitory role observed in basal condition, FOXP3 is insufficient to inhibit the cell proliferation under TNFα treatment. Molecularly, we found that TNFα induced an interaction between FOXP3 and p65, which in turn drive the FOXP3 away from the promoter of the well known target p21. Our data here suggest that although FOXP3 is upregulated in gastric cancer, its tumor suppressor role has been dampened due to the inflammation environment.

  2. Role of erlotinib in first-line and maintenance treatment of advanced non-small-cell lung cancer

    Directory of Open Access Journals (Sweden)

    Noemí Reguart

    2010-06-01

    Full Text Available Noemí Reguart1, Andrés Felipe Cardona2, Rafael Rosell31Medical Oncology Service, ICMHO, Hospital Clinic Barcelona, Barcelona, Spain; 2Clinical and Translational Oncology Group, Institute of Oncology, Fundación Santa Fe de Bogotá, Bogotá, D.C., Colombia; 3Medical Oncology Service, Catalan Institute of Oncology, ICO, Hospital Germans Trias i Pujol, Badalona, Barcelona, SpainAbstract: Erlotinib hydrochloride (Tarceva® is a member of a class of small molecule inhibitors that targets the tyrosine kinase domain of the epidermal growth factor receptor (EGFR, with anti-tumor activity in preclinical models. Erlotinib represents a new-generation of agents known as “targeted therapies” designed to act upon cancer cells by interfering with aberrant specific activated pathways needed for tumor growth, angiogenesis and cell survival. Since its approval in November 2004 for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC after the failure of at least one prior chemotherapy regimen and with a view to improving patients’ outcomes and prevent symptoms, the scientific community has evaluated the potential role of erlotinib in other scenarios such as in maintenance therapy and, in first-line setting for a selected population based on biological markers of response such as mutations of the EGFR. The convenient once-a-day pill administration and the good toxicity profile of erlotinib make it a reasonable candidate for testing in this context. This report provides a review of the role of erlotinib therapy in advanced NSCLC. It summarizes current data and perspectives of erlotinib in upfront treatment and maintenance for advanced NSCLC as well as looking at candidate biomarkers of response to these new targeted-agents.Keywords: erlotinib, tyrosine kinase inhibitors, first line, maintenance, non-small-cell lung cancer

  3. Cross-species functional analysis of cancer-associated fibroblasts identifies a critical role for CLCF1 and IL6 in non-small cell lung cancer in vivo

    OpenAIRE

    Vicent, Silvestre; Sayles, Leanne C.; Vaka, Dedeepya; Khatri, Purvesh; Gevaert, Olivier; Chen, Ron; Zheng, Yanyan; Anna K Gillespie; Clarke, Nicole; Xu, Yue; Shrager, Joseph; Hoang, Chuong D.; Plevritis, Sylvia; Butte, Atul J; Sweet-Cordero, E. Alejandro

    2012-01-01

    Cancer-associated fibroblasts (CAFs) have been reported to support tumor progression by a variety of mechanisms. However, their role in the progression of non-small cell lung cancer (NSCLC) remains poorly defined. In addition, the extent to which specific proteins secreted by CAFs contribute directly to tumor growth is unclear. To study the role of CAFs in NSCLC, a cross-species functional characterization of mouse and human lung CAFs was performed. CAFs supported the growth of lung cancer ce...

  4. The evolving role of cancer cell line-based screens to define the impact of cancer genomes on drug response ?

    OpenAIRE

    Garnett, Mathew J.; McDermott, Ultan

    2014-01-01

    Over the last decade we have witnessed the convergence of two powerful experimental designs toward a common goal of defining the molecular subtypes that underpin the likelihood of a cancer patient responding to treatment in the clinic. The first of these ‘experiments’ has been the systematic sequencing of large numbers of cancer genomes through the International Cancer Genome Consortium and The Cancer Genome Atlas. This endeavour is beginning to yield a complete catalogue of the cancer genes ...

  5. The role of the bi-compartmental stem cell niche in delaying cancer

    Science.gov (United States)

    Shahriyari, Leili; Komarova, Natalia L.

    2015-10-01

    In recent years, by using modern imaging techniques, scientists have found evidence of collaboration between different types of stem cells (SCs), and proposed a bi-compartmental organization of the SC niche. Here we create a class of stochastic models to simulate the dynamics of such a heterogeneous SC niche. We consider two SC groups: the border compartment, S1, is in direct contact with transit-amplifying (TA) cells, and the central compartment, S2, is hierarchically upstream from S1. The S1 SCs differentiate or divide asymmetrically when the tissue needs TA cells. Both groups proliferate when the tissue requires SCs (thus maintaining homeostasis). There is an influx of S2 cells into the border compartment, either by migration, or by proliferation. We examine this model in the context of double-hit mutant generation, which is a rate-limiting step in the development of many cancers. We discover that this type of a cooperative pattern in the stem niche with two compartments leads to a significantly smaller rate of double-hit mutant production compared with a homogeneous, one-compartmental SC niche. Furthermore, the minimum probability of double-hit mutant generation corresponds to purely symmetric division of SCs, consistent with the literature. Finally, the optimal architecture (which minimizes the rate of double-hit mutant production) requires a large proliferation rate of S1 cells along with a small, but non-zero, proliferation rate of S2 cells. This result is remarkably similar to the niche structure described recently by several authors, where one of the two SC compartments was found more actively engaged in tissue homeostasis and turnover, while the other was characterized by higher levels of quiescence (but contributed strongly to injury recovery). Both numerical and analytical results are presented.

  6. Role of YAP and TAZ in pancreatic ductal adenocarcinoma and in stellate cells associated with cancer and chronic pancreatitis.

    Science.gov (United States)

    Morvaridi, Susan; Dhall, Deepti; Greene, Mark I; Pandol, Stephen J; Wang, Qiang

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibrotic and inflammatory microenvironment that is formed primarily by activated, myofibroblast-like, stellate cells. Although the stellate cells are thought to contribute to tumorigenesis, metastasis and drug resistance of PDAC, the signaling events involved in activation of the stellate cells are not well defined. Functioning as transcription co-factors, Yes-associated protein (YAP) and its homolog transcriptional co-activator with PDZ-binding motif (TAZ) modulate the expression of genes involved in various aspects of cellular functions, such as proliferation and mobility. Using human tissues we show that YAP and TAZ expression is restricted to the centroacinar and ductal cells of normal pancreas, but is elevated in cancer cells. In particular, YAP and TAZ are expressed at high levels in the activated stellate cells of both chronic pancreatitis and PDAC patients as well as in the islets of Langerhans in chronic pancreatitis tissues. Of note, YAP is up regulated in both acinar and ductal cells following induction of acute and chronic pancreatitis in mice. These findings indicate that YAP and TAZ may play a critical role in modulating pancreatic tissue regeneration, neoplastic transformation, and stellate cell functions in both PDAC and pancreatitis. PMID:26567630

  7. Roles of Krüppel-like factor 4 in normal homeostasis, cancer and stem cells

    Institute of Scientific and Technical Information of China (English)

    Paul M Evans; Chunming Liu

    2008-01-01

    Krüppel-like factor 4 (KLF4) is a zinc finger-type trans cription factor expressed in a variety of tissues,including the epithelium of the intestine and the skin,and it plays an important role in differentiation and cell cycle arrest.Depending on the gene targeted,KLF4 can both activate and repress transcription.Moreover,in certain cellular contexts,KLF4 can function as a tumor suppressor or an oncogene.Finally,KLF4 is important in reprogramming differentiated fibroblasts into inducible pluripotent stem cells,which highly resemble embryonic stem cells.This review summarizes what is known about the diverse functions of KLF4 as well as their molecular mechanisms.

  8. The role of surface modification for TiO2 nanoparticles in cancer cells.

    Science.gov (United States)

    Xie, Jin; Pan, Xiaobo; Wang, Mengyan; Ma, Jiong; Fei, Yiyan; Wang, Pei-Nan; Mi, Lan

    2016-07-01

    Titanium dioxide nanoparticles (TiO2 NPs) have a potential in the field of biological application. However, its poor dispersibility in water hampered its applications. In this study, 3-phosphonopropionic acid and 3-aminopropyl-triethoxysilane were respectively used for surface modification on TiO2 NPs with negative and positive surface charges (denoted as TiO2-COOH and TiO2-NH2). Zeta potentials of the prepared samples with high absolute value demonstrate the great improvement in their dispersibility. In terms of viability experiment, both TiO2-COOH and TiO2-NH2 showed low cytotoxicity. The cellular uptake efficiency and the uptake pathways of TiO2-COOH and TiO2-NH2 for cancer cells were studied. The exocytosis of TiO2-NH2 was also observed in the experiment. PMID:27003465

  9. Lung Cancer Stem Cells

    Directory of Open Access Journals (Sweden)

    Sharon R. Pine

    2008-01-01

    Full Text Available Lung cancer remains a major cause of cancer-related lethality because of high incidence and recurrence in spite of significant advances in staging and therapies. Recent data indicates that stem cells situated throughout the airways may initiate cancer formation. These putative stem cells maintain protumorigenic characteristics including high proliferative capacity, multipotent differentiation, drug resistance and long lifespan relative to other cells. Stem cell signaling and differentiation pathways are maintained within distinct cancer types, and destabilization of this machinery may participate in maintenance of cancer stem cells. Characterization of lung cancer stem cells is an area of active research and is critical for developing novel therapies. This review summarizes the current knowledge on stem cell signaling pathways and cell markers used to identify the lung cancer stem cells.

  10. Cell phones and cancer

    Science.gov (United States)

    Cancer and cell phones; Do cell phones cause cancer? ... Several major studies show no link between cell phones and cancer at this time. However, since the information available is based on short-term studies, the impact of many years of ...

  11. Chrysin enhances doxorubicin-induced cytotoxicity in human lung epithelial cancer cell lines: The role of glutathione

    Energy Technology Data Exchange (ETDEWEB)

    Brechbuhl, Heather M. [Pediatrics, National Jewish Health, Denver, Colorado (United States); Kachadourian, Remy; Min, Elysia [Department of Medicine, National Jewish Health, Denver, Colorado (United States); Chan, Daniel [Medical Oncology, University of Colorado Denver Health Sciences Center (United States); Day, Brian J., E-mail: dayb@njhealth.org [Department of Medicine, University of Colorado Denver Health Sciences Center (United States); Immunology, University of Colorado Denver Health Sciences Center (United States); Pharmaceutical Sciences, University of Colorado Denver Health Sciences Center (United States); Department of Medicine, National Jewish Health, Denver, Colorado (United States)

    2012-01-01

    We hypothesized that flavonoid-induced glutathione (GSH) efflux through multi-drug resistance proteins (MRPs) and subsequent intracellular GSH depletion is a viable mechanism to sensitize cancer cells to chemotherapies. This concept was demonstrated using chrysin (5–25 μM) induced GSH efflux in human non-small cell lung cancer lines exposed to the chemotherapeutic agent, doxorubicin (DOX). Treatment with chrysin resulted in significant and sustained intracellular GSH depletion and the GSH enzyme network in the four cancer cell types was predictive of the severity of chrysin induced intracellular GSH depletion. Gene expression data indicated a positive correlation between basal MRP1, MRP3 and MRP5 expression and total GSH efflux before and after chrysin exposure. Co-treating the cells for 72 h with chrysin (5–30 μM) and DOX (0.025–3.0 μM) significantly enhanced the sensitivity of the cells to DOX as compared to 72-hour DOX alone treatment in all four cell lines. The maximum decrease in the IC{sub 50} values of cells treated with DOX alone compared to co-treatment with chrysin and DOX was 43% in A549 cells, 47% in H157 and H1975 cells and 78% in H460 cells. Chrysin worked synergistically with DOX to induce cancer cell death. This approach could allow for use of lower concentrations and/or sensitize cancer cells to drugs that are typically resistant to therapy. -- Graphical abstract: Possible mechanisms by which chrysin enhances doxorubicin-induced toxicity in cancer cells. Highlights: ► Chyrsin sustains a significant depletion of GSH levels in lung cancer cells. ► Chyrsin synergistically potentiates doxorubicin-induced cancer cell cytotoxicity. ► Cancer cell sensitivity correlated with GSH and MRP gene network expression. ► This approach could allow for lower side effects and targeting resistant tumors.

  12. Role of ornithine decarboxylase in regulation of estrogen receptor alpha expression and growth in human breast cancer cells.

    Science.gov (United States)

    Zhu, Qingsong; Jin, Lihua; Casero, Robert A; Davidson, Nancy E; Huang, Yi

    2012-11-01

    Our previous studies demonstrated that specific polyamine analogues, oligoamines, down-regulated the activity of a key polyamine biosynthesis enzyme, ornithine decarboxylase (ODC), and suppressed expression of estrogen receptor alpha (ERα) in human breast cancer cells. However, the mechanism underlying the potential regulation of ERα expression by polyamine metabolism has not been explored. Here, we demonstrated that RNAi-mediated knockdown of ODC (ODC KD) down-regulated the polyamine pool, and hindered growth in ERα-positive MCF7 and T47D and ERα-negative MDA-MB-231 breast cancer cells. ODC KD significantly induced the expression and activity of the key polyamine catabolism enzymes, spermine oxidase (SMO) and spermidine/spermine N (1)-acetyltransferase (SSAT). However, ODC KD-induced growth inhibition could not be reversed by exogenous spermidine or overexpression of antizyme inhibitor (AZI), suggesting that regulation of ODC on cell proliferation may involve the signaling pathways independent of polyamine metabolism. In MCF7 and T47D cells, ODC KD, but not DFMO treatment, diminished the mRNA and protein expression of ERα. Overexpression of antizyme (AZ), an ODC inhibitory protein, suppressed ERα expression, suggesting that ODC plays an important role in regulation of ERα expression. Decrease of ERα expression by ODC siRNA altered the mRNA expression of a subset of ERα response genes. Our previous analysis showed that oligoamines disrupt the binding of Sp1 family members to an ERα minimal promoter element containing GC/CA-rich boxes. By using DNA affinity precipitation and mass spectrometry analysis, we identified ZBTB7A, MeCP2, PARP-1, AP2, and MAZ as co-factors of Sp1 family members that are associated with the ERα minimal promoter element. Taken together, these data provide insight into a novel antiestrogenic mechanism for polyamine biosynthesis enzymes in breast cancer. PMID:22976807

  13. A critical role for FBXW8 and MAPK in cyclin D1 degradation and cancer cell proliferation.

    Directory of Open Access Journals (Sweden)

    Hiroshi Okabe

    Full Text Available Cyclin D1 regulates G1 progression. Its transcriptional regulation is well understood. However, the mechanism underlying cyclin D1 ubiquitination and its subsequent degradation is not yet clear. We report that cyclin D1 undergoes increased degradation in the cytoplasm during S phase in a variety of cancer cells. This is mediated by phosphorylation at Thr286 through the activity of the Ras/Raf/MEK/ERK cascade and the F-box protein FBXW8, which is an E3 ligase. The majority of FBXW8 is expressed in the cytoplasm during G1 and S phase. In contrast, cyclin D1 accumulates in the nucleus during G1 phase and exits into the cytoplasm in S phase. Increased cyclin D1 degradation is linked to association with FBXW8 in the cytoplasm, and enhanced phosphorylation of cyclin D1 through sustained ERK1/2 signaling. Depletion of FBXW8 caused a significant accumulation of cyclin D1, as well as sequestration of CDK1 in the cytoplasm. This resulted in a severe reduction of cell proliferation. These effects could be rescued by constitutive nuclear expression of cyclin D1-T286A. Thus, FBXW8 plays an essential role in cancer cell proliferation through proteolysis of cyclin D1. It may present new opportunities to develop therapies targeting destruction of cyclin D1 or its regulator E3 ligase selectively.

  14. The role of maintenance proteins in the preservation of epithelial cell identity during mammary gland remodeling and breast cancer initiation

    Directory of Open Access Journals (Sweden)

    Danila Coradini

    2014-02-01

    Full Text Available During normal postnatal mammary gland development and adult remodeling related to the menstrual cycle, pregnancy, and lactation, ovarian hormones and peptide growth factors contribute to the delineation of a definite epithelial cell identity. This identity is maintained during cell replication in a heritable but DNA-independent manner. The preservation of cell identity is fundamental, especially when cells must undergo changes in response to intrinsic and extrinsic signals. The maintenance proteins, which are required for cell identity preservation, act epigenetically by regulating gene expression through DNA methylation, histone modification, and chromatin remodeling. Among the maintenance proteins, the Trithorax (TrxG and Polycomb (PcG group proteins are the best characterized. In this review, we summarize the structures and activities of the TrxG and PcG complexes and describe their pivotal roles in nuclear estrogen receptor activity. In addition, we provide evidence that perturbations in these epigenetic regulators are involved in disrupting epithelial cell identity, mammary gland remodeling, and breast cancer initiation.

  15. Cancer Stem Cells

    OpenAIRE

    Katarzyna Wieczorek; Jolanta Niewiarowska

    2008-01-01

    Cancer stem cell theory gains increasingly greater significance in the world of medicine. Numerous findings of scientific research in vivo and in vitro indicate that it is the population of undifferentiated, self-renewing cells which is responsible for recurrence of cancer and metastasis. Similarly to normal stem cells, cancer stem cells (CSC) function in the environment of the other cells of the organism, called the niche, where they receive signals for differentiation and proliferation proc...

  16. Role of oxidative stress and intracellular glutathione in the sensitivity to apoptosis induced by proteasome inhibitor in thyroid cancer cells

    International Nuclear Information System (INIS)

    The proteasome inhibitor bortezomib has shown impressive clinical activity alone and in combination with conventional and other novel agents for the treatment of multiple myeloma (MM) and some solid cancers. Although bortezomib is known to be a selective proteasome inhibitor, the downstream mechanisms of cytotoxicity and drug resistance are poorly understood. Proteasome activity, intracellular glutathione (GSH) and ROS levels, as well as activities of GSH synthesis enzymes were measured using spectrophotometric methods. Cell death was analyzed using flow cytometry and caspase activity assay. The expression level of GSH synthesis enzymes were measured using real-time RT-PCR. At concentrations that effectively inhibited proteasome activity, bortezomib induced apoptosis in FRO cells, but not in ARO cells. Bortezomib elevated the amount of glutathione (GSH) and the treatment with bortezomib increased the level of mRNA for GCL, a rate-limiting enzyme in glutathione synthesis. Furthermore, depletion of GSH increases apoptosis induced by bortezomib, in contrast, repletion of GSH decreases bortezomib-mediated cell death. GSH protects cells from proteasome inhibition-induced oxidative stress and glutathione-dependent redox system might play an important role in the sensitivity to proteasome inhibition-induced apoptosis

  17. Role of oxidative stress and intracellular glutathione in the sensitivity to apoptosis induced by proteasome inhibitor in thyroid cancer cells

    Directory of Open Access Journals (Sweden)

    Guan Yifu

    2009-02-01

    Full Text Available Abstract Background The proteasome inhibitor bortezomib has shown impressive clinical activity alone and in combination with conventional and other novel agents for the treatment of multiple myeloma (MM and some solid cancers. Although bortezomib is known to be a selective proteasome inhibitor, the downstream mechanisms of cytotoxicity and drug resistance are poorly understood. Methods Proteasome activity, intracellular glutathione (GSH and ROS levels, as well as activities of GSH synthesis enzymes were measured using spectrophotometric methods. Cell death was analyzed using flow cytometry and caspase activity assay. The expression level of GSH synthesis enzymes were measured using real-time RT-PCR. Results At concentrations that effectively inhibited proteasome activity, bortezomib induced apoptosis in FRO cells, but not in ARO cells. Bortezomib elevated the amount of glutathione (GSH and the treatment with bortezomib increased the level of mRNA for GCL, a rate-limiting enzyme in glutathione synthesis. Furthermore, depletion of GSH increases apoptosis induced by bortezomib, in contrast, repletion of GSH decreases bortezomib-mediated cell death. Conclusion GSH protects cells from proteasome inhibition-induced oxidative stress and glutathione-dependent redox system might play an important role in the sensitivity to proteasome inhibition-induced apoptosis.

  18. The role of Gefitinib in patients with non-small-cell lung cancer in India

    Directory of Open Access Journals (Sweden)

    Asmita Anilkumar Mehta

    2013-01-01

    Full Text Available Background: Gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor, represents a new treatment option for patients with advanced non-small-cell lung cancer (NSCLC. We analyzed the data of patients who received Gefitinib for NSCLC in a tertiary care center in South India. Materials and Methods: Sixty-three patients with advanced NSCLC who had received Gefitinib either after failure of conventional chemotherapy or were previously not treated as they were unfit or unwilling for conventional treatment were included in the analysis. Results: The median follow-up for the cohort was 311 days (range 11-1544 days. Median time to progression was 161 (range 9-883 days. Complete and partial remission was seen in 1 (2% and 6 (9% patients, respectively, with overall response rate of 11%. Twenty-four (38% patients had stable disease. Gefitinib was well tolerated with no significant side effects. Conclusion: Gefitinib shows anti-tumor activity in pretreated or previously untreated patients with advanced NSCLC. It has a favorable toxicity profile and is well tolerated. Gefitinib should be considered as a viable therapy in patients with NSCLC.

  19. Increased fucosylation has a pivotal role in invasive and metastatic properties of head and neck cancer stem cells

    Science.gov (United States)

    Zheng, Li; Matossian, Margarite; Prince, Mark E.; Paino, Francesca; Mele, Luigi; Papaccio, Federica; Montella, Roberta; Papaccio, Gianpaolo; Papagerakis, Silvana

    2015-01-01

    Oral squamous cell carcinoma (OSCC) is an aggressive malignancy with high mortality rates. Major challenges for OSCC management include development of resistance to therapy and early formation of distant metastases. Cancer stem cells (CSCs) have emerged as important players in both pathologic mechanisms. Increased fucosylation activity and increased expression of fucosylated polysaccharides, such as Sialyl Lewis X (SLex), are associated with invasion and metastasis. However, the role of fucosylation in CSCs has not been elucidated yet. We used the spheroid culture technique to obtain a CSC-enriched population and compared orospheres with adherent cells. We found that orospheres expressed markers of CSCs and metastasis at higher levels, were more invasive and tumorigenic, and were more resistant to cisplatin/radiation than adherent counterparts. We found fucosyltransferases FUT3 and FUT6 highly up-regulated, increased SLex expression and increased adhesion by shear flow assays in orospheres. Inhibition of fucosylation negatively affected orospheres formation and invasion of oral CSCs. These results confirm that orospheres are enriched in CSCs and that fucosylation is of paramount importance for CSC invasion. In addition, SLex may play a key role in CSC metastasis. Thus, inhibition of fucosylation may be used to block CSCs and metastatic spread. PMID:25428916

  20. Autophagy inhibition plays the synergetic killing roles with radiation in the multi-drug resistant SKVCR ovarian cancer cells

    International Nuclear Information System (INIS)

    Autophagy has attracted attentions as a novel mechanism for tumor development. In this study Human ovarian carcinoma cell line SKOV3 and multidrug-resistant phenotype SKVCR cells were used and the roles of autophagy in radiation-induced cell death were analyzed. Cell viability was examined by colony formation and cell counting kit-8 (CCK-8) assay, 3MA and ZVAD were used to block autophagy and apoptosis, respectively. Quantitative real-time PCR was used to detect mRNA level and Western blot was used to detect protein expression, monodansylcadaverine (MDC) staining and flow cytometery were used for autophagy, apoptosis and cell cycle dynamics, respectively. (1) The radiosensitivity exhibited differently in SKOV3 and SKVCR cells (SKOV3: D0=3.37, SKVCR: D0= 4.18); compared with SKOV3 the constitutive expression of MAPLC3 in SKVCR was higher, but no change of Caspase-3 and cleaved Caspase-3. (2) The ionizing radiation (IR)- induced apoptosis and autophagy were significant in both cells (P<0.05); inhibition of apoptosis with ZVAD showed no impact on survival of SKOV3 and SKVCR cells after radiation, while inhibition of autophagy significantly decreased viability in SKVCR cells, for SKVO3 cells only low level of radiation (2 Gy and 4 Gy) could decrease the viability(P<0.05). (3) ZVAD inhibited apoptosis and autophagy in both cells, 3MA inhibit apoptosis in SKOV3, and promote apoptosis in SKVCR, together with inhibition of autophagy. (4) G2/M arrest was induced by radiation in both cells; the accumulation of G2/M was more significant in SKOV3, 3MA attenuated the radiation-induced S phase delay in SKVCR. IR-induced autophagy provides a self-protective mechanism against radiotherapy in SKVCR cells, the use of autophagy inhibitor, 3MA, increases the killing effects of radiation by inhibiting autophagy and radiation- induced S phase delay, also by the increase of apoptosis, which suggests a better therapeutic strategy in drug- resistant SKVCR ovarian cancer cells

  1. Cancer Stem Cells and Side Population Cells in Breast Cancer and Metastasis

    OpenAIRE

    Lennard, Thomas W.J.; Meeson, Annette P; Britton, Kelly M.; Kirby, John A.

    2011-01-01

    In breast cancer it is never the primary tumour that is fatal; instead it is the development of metastatic disease which is the major cause of cancer related mortality. There is accumulating evidence that suggests that Cancer Stem Cells (CSC) may play a role in breast cancer development and progression. Breast cancer stem cell populations, including side population cells (SP), have been shown to be primitive stem cell-like populations, being long-lived, self-renewing and highly proliferative....

  2. Role of liver stem cells in hepatocarcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Lei-Bo; Xu; Chao; Liu

    2014-01-01

    Liver cancer is an aggressive disease with a high mortality rate. Management of liver cancer is strongly dependent on the tumor stage and underlying liver disease. Unfortunately, most cases are discovered when the cancer is already advanced, missing the opportunity for surgical resection. Thus, an improved understanding of the mechanisms responsible for liver cancer initiation and progression will facilitate the detection of more reliable tumor markers and the development of new small molecules for targeted therapy of liver cancer. Recently, there is increasing evidence for the "cancer stem cell hypothesis", which postulates that liver cancer originates from the malignant transformation of liver stem/progenitor cells(liver cancer stem cells). This cancer stem cell model has important significance for understanding the basic biology of liver cancer and has profound importance for the development of new strategies for cancer prevention and treatment. In this review, we highlight recent advances in the role of liver stem cells in hepatocarcinogenesis. Our review of the literature shows that identification of the cellular origin and the signaling pathways involved is challenging issues in liver cancer with pivotal implications in therapeutic perspectives. Although the dedifferentiation of mature hepatocytes/cholangiocytes in hepatocarcinogenesis cannot be excluded, neoplastic transformation of a stem cell subpopulation more easily explains hepatocarcinogenesis. Elimination of liver cancer stem cells in liver cancer could result in the degeneration of downstream cells, which makes them potential targets for liver cancer therapies. Therefore, liver stem cells could represent a new target for therapeutic approaches to liver cancer in the near future.

  3. Ovarian Cancer Stroma: Pathophysiology and the Roles in Cancer Development

    International Nuclear Information System (INIS)

    Ovarian cancer represents one of the cancers with the worst prognostic in adult women. More than half of the patients who present with clinical signs such as abdominal bloating and a feeling of fullness already show advanced stages. The majority of ovarian cancers grow as cystic masses, and cancer cells easily spread into the pelvic cavity once the cysts rupture or leak. When the ovarian cancer cells disseminate into the peritoneal cavity, metastatic nests may grow in the cul-de-sac, and in more advanced stages, the peritoneal surfaces of the upper abdomen become the next largest soil for cancer progression. Ascites is also produced frequently in ovarian cancers, which facilitates distant metastasis. Clinicopathologic, epidemiologic and molecular studies on ovarian cancers have improved our understanding and therapeutic approaches, but still further efforts are required to reduce the risks in the patients who are predisposed to this lethal disease and the mortality of the patients in advanced stages. Among various molecules involved in ovarian carcinogenesis, special genes such as TP53, BRCA1 and BRCA2 have been well investigated. These genes are widely accepted as the predisposing factors that trigger malignant transformation of the epithelial cells of the ovary. In addition, adnexal inflammatory conditions such as chronic salpingitis and ovarian endometriosis have been great research interests in the context of carcinogenic background of ovarian cancers. In this review, I discuss the roles of stromal cells and inflammatory factors in the carcinogenesis and progression of ovarian cancers

  4. Ovarian Cancer Stroma: Pathophysiology and the Roles in Cancer Development

    Energy Technology Data Exchange (ETDEWEB)

    Furuya, Mitsuko [Department of Pathology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004 (Japan)

    2012-07-18

    Ovarian cancer represents one of the cancers with the worst prognostic in adult women. More than half of the patients who present with clinical signs such as abdominal bloating and a feeling of fullness already show advanced stages. The majority of ovarian cancers grow as cystic masses, and cancer cells easily spread into the pelvic cavity once the cysts rupture or leak. When the ovarian cancer cells disseminate into the peritoneal cavity, metastatic nests may grow in the cul-de-sac, and in more advanced stages, the peritoneal surfaces of the upper abdomen become the next largest soil for cancer progression. Ascites is also produced frequently in ovarian cancers, which facilitates distant metastasis. Clinicopathologic, epidemiologic and molecular studies on ovarian cancers have improved our understanding and therapeutic approaches, but still further efforts are required to reduce the risks in the patients who are predisposed to this lethal disease and the mortality of the patients in advanced stages. Among various molecules involved in ovarian carcinogenesis, special genes such as TP53, BRCA1 and BRCA2 have been well investigated. These genes are widely accepted as the predisposing factors that trigger malignant transformation of the epithelial cells of the ovary. In addition, adnexal inflammatory conditions such as chronic salpingitis and ovarian endometriosis have been great research interests in the context of carcinogenic background of ovarian cancers. In this review, I discuss the roles of stromal cells and inflammatory factors in the carcinogenesis and progression of ovarian cancers.

  5. Lung Cancer Stem Cells

    OpenAIRE

    Pine, Sharon R.; Blair Marshall; Lyuba Varticovski

    2008-01-01

    Lung cancer remains a major cause of cancer-related lethality because of high incidence and recurrence in spite of significant advances in staging and therapies. Recent data indicates that stem cells situated throughout the airways may initiate cancer formation. These putative stem cells maintain protumorigenic characteristics including high proliferative capacity, multipotent differentiation, drug resistance and long lifespan relative to other cells. Stem cell signaling and differentiation p...

  6. Breast and ovarian cancers: a survey and possible roles for the cell surface heparan sulfate proteoglycans

    DEFF Research Database (Denmark)

    Yoneda, Atsuko; Lendorf, Maria E; Couchman, John R;

    2012-01-01

    . Occurrence of breast and ovarian cancer is high in older women. Common known risk factors of developing these cancers in addition to age are not having children or having children at a later age, the use of hormone replacement therapy, and mutations in certain genes. In addition, women with a history of...

  7. Preliminary Evidence on the Diagnostic and Molecular Role of Circulating Soluble EGFR in Non-Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Filippo Lococo

    2015-08-01

    Full Text Available Assessment of biological diagnostic factors providing clinically-relevant information to guide physician decision-making are still needed for diseases with poor outcomes, such as non-small cell lung cancer (NSCLC. Epidermal growth factor receptor (EGFR is a promising molecule in the clinical management of NSCLC. While the EGFR transmembrane form has been extensively investigated in large clinical trials, the soluble, circulating EGFR isoform (sEGFR, which may have a potential clinical use, has rarely been considered. This study investigates the use of sEGFR as a potential diagnostic biomarker for NSCLC and also characterizes the biological function of sEGFR to clarify the molecular mechanisms involved in the course of action of this protein. Plasma sEGFR levels from a heterogeneous cohort of 37 non-advanced NSCLC patients and 54 healthy subjects were analyzed by using an enzyme-linked immunosorbent assay. The biological function of sEGFR was analyzed in vitro using NSCLC cell lines, investigating effects on cell proliferation and migration. We found that plasma sEGFR was significantly decreased in the NSCLC patient group as compared to the control group (median value: 48.6 vs. 55.6 ng/mL respectively; p = 0.0002. Moreover, we demonstrated that sEGFR inhibits growth and migration of NSCLC cells in vitro through molecular mechanisms that included perturbation of EGF/EGFR cell signaling and holoreceptor internalization. These data show that sEGFR is a potential circulating biomarker with a physiological protective role, providing a first approach to the functional role of the soluble isoform of EGFR. However, the impact of these data on daily clinical practice needs to be further investigated in larger prospective studies.

  8. The role of prophylactic cranial irradiation in small cell lung cancer

    International Nuclear Information System (INIS)

    To analyse if prophylactic cranial irradiation is small cell lung cancer for improved survival is indicated; if adjuvant irradiation could cure the microscopic disease; if and how late effects could be minimized. Data from randomized trials and retrospective studies are critically analysed related to the incidence of central nervous system (CNS) metastases in limited disease patients in complete remission with or without prophylactic cranial irradiation. The mechanisms of late effects on CNS of prophylactic cranial irradiation and combined treatment are presented. Prophylactic cranial irradiation could decrease the incidence of CNS metastases but could not improve survival. A subgroup of patients (9 to 14%) most likely to benefit from prophylactic cranial irradiation includes patients who are likely to have an isolated CNS failure. The actual used total dose in the range 30 to 40 Gy could only conditionally decrease the CNS failure. Higher total and/or daily doses and combined treatment are related with potentially devastating neurologic and intellectual disabilities. No prospective randomized trial has demonstrated a significant survival advantage for patients treated with prophylactic cranial irradiation. Prophylactic cranial irradiation is capable of reducing the incidence of cerebral metastases and delays CNS failure. A subgroup of patients most likely to benefit from prophylactic cranial irradiation (9 to 14%) includes patients who are likely to have an isolated CNS failure, but this had yet to be demonstrated. The toxicity of treatment is difficult to be influenced. Prophylactic cranial irradiation should not be given concurrently with chemotherapy, a larger interval after chemotherapy is indicated. The total dose should be in the range 30 to 36 Gy and the daily fraction size not larger than 2 Gy. (orig.)

  9. Roles of SHARP1 in thyroid cancer.

    Science.gov (United States)

    Zhou, Zun-Hai; Wang, Bo; Cheng, Xiao-Bing; Zhang, Xuan-E; Tang, Jian; Tang, Wen-Jia; Gu, Lei

    2016-06-01

    SHARP1 is a basic helix‑loop‑helix transcription factor involved in various cellular processes, including proliferation and differentiation. The present study assessed the role of SHARP1 in the progression and invasion of thyroid cancer. PCR and western blot analysis demonstrated that in thyroid cancer tissues, SHARP1 was significantly downregulated at the mRNA and protein level compared with that in normal tissues. Furthermore, SHARP1 was downregulated in the TT and TPC‑1 thyroid cancer cell lines compared with a normal thyroid cell line, while it was upregulated in other thyroid cancer cell lines. Overexpression of SHARP1 in TT and TPC‑1 cells significantly inhibited the cell viability, migration and invasion in vitro. Furthermore, the protein and mRNA levels of HIF‑1α were found to be decreased in TT and TPC‑1 cells following forced overexpression of SHARP1. In addition, silencing of HIF‑1α reduced the viability, migration and invasion of TT and TPC-1 cells. In conclusion, the present study indicated that SHARP1 acts as a tumor suppressor in thyroid cancer and that its downregulation may contribute to the proliferation, migration and invasion of thyroid cancer cells through mechanisms possibly involving HIF‑1α, suggesting that SHARP1 may be an important therapeutic target for the treatment of thyroid cancer. PMID:27121679

  10. Breast cancer stem cells

    OpenAIRE

    Owens, Thomas W.; Naylor, Matthew J.

    2013-01-01

    Cancer metastasis, resistance to therapies and disease recurrence are significant hurdles to successful treatment of breast cancer. Identifying mechanisms by which cancer spreads, survives treatment regimes and regenerates more aggressive tumors are critical to improving patient survival. Substantial evidence gathered over the last 10 years suggests that breast cancer progression and recurrence is supported by cancer stem cells (CSCs). Understanding how CSCs form and how they contribute to th...

  11. Non-small cell lung cancer. The role of chemoimmunoradiotherapy after surgery

    International Nuclear Information System (INIS)

    The aim of this study was to determine expediency of adjuvant chemoimmunoradiotherapy for radically operated non-small cell lung cancer patients (LCP) with pathologic stage II-III (T1-4N0-2M0G1-3). In retrospective trial (1985-1998) a 5-year survival of 54 consecutive radically operated LCP after radical procedures (group C) and with therapy (group A) was compared with 5-year survival of 264 LCP, after radical procedures (group C) and with 5-year survival of 86 radically operated LCP after postoperative radiotherapy (group B) (45-50 Gy). 1 cycle of chemoimmunotherapy was given on day 10-14 after complete resections. Radiotherapy (45-50 Gy) was administered since day 7 after 1 cycle. After irradiation 3-4 courses of CAVT were repeated every 21-28 day. Variables selected for 5-year survival and life span study were sex, age, TNMG, cell type, tumor size. Survival curves were estimated by the Kaplan-Meier method. Differences in curves between groups of LCP were evaluated using a logrank test. Multivariate proportional hazard Cox regression, multi-factor clustering, structural equation modeling and Monte Carlo simulation were used to determine any significant overall regularity. 5-year survival was superior in group A (64.8%: 35 out of 54 LCP with N0-2: life span=1998.2±156.9 days) compared with group B (45.3%: 39 out of 86 LCP with N0-2; life span=1296.4±109.5 days) (P0.05 for group A and P<0.001 for group B). For LCP with N1-2 5-year survival was significantly superior for group A (63.6%: 21 from 33; life span=1934.0±189.9 days) compared with group C (28.1%: 25 out of 89; life span=1056.9±91.1 days) (P<0.001) and with group B (35.6%: 21 out of 59; life span=1051.7±119.6 days) (P<0.001). Structural equation modeling and Monte Carlo simulation confirmed significant overall differences between 5-year survival (P<0.05) and life span (P<0.001) of LCP with N1-2 in group A with respect to group C or B; however, 5-year survival of LCP for N0 in groups A, B and C were not

  12. Stages of Renal Cell Cancer

    Science.gov (United States)

    ... cell cancer is a disease in which malignant (cancer) cells form in tubules of the kidney. Renal cell ... diagnosed, tests are done to find out if cancer cells have spread within the kidney or to other ...

  13. Notch and Wnt/β-catenin signaling pathway play important roles in activating liver cancer stem cells.

    Science.gov (United States)

    Wang, Ronghua; Sun, Qian; Wang, Peng; Liu, Man; Xiong, Si; Luo, Jing; Huang, Hai; Du, Qiang; Geller, David A; Cheng, Bin

    2016-02-01

    Human hepatocellular carcinoma (HCC) is driven and maintained by liver cancer stem cells (LCSCs) that display stem cell properties. These LCSCs are promoted by the intersecting of Notch and Wnt/β-Catenin signaling pathways. In this study, we demonstrate that LCSCs with markers CD90, CD24, CD13, and CD133 possess stem properties of self-renewal and tumorigenicity in NOD/SCID mice. The increased expression of these markers was correlated with advanced disease stage, larger tumors, and worse overall survival in 61 HCC cases. We also found that both Notch and Wnt/β-catenin signaling pathways played important roles in increasing the stem-ness characteristics of LCSCs. Our data suggested that Notch1 was downstream of Wnt/β-catenin. The active form of Notch1 intracellular domain (NICD) expression depended on Wnt/β-catenin pathway activation. Moreover, Notch1 negatively contributed to Wnt/β-catenin signaling modulation. Knock down of Notch1 with lentivirus N1ShRNA up-regulated the active form of β-catenin. Ectopic expression of NICD with LV-Notch1 in LCSCs attenuated β-catenin/TCF dependent luciferase activity significantly. In addition, there was a non-proteasome mediated feedback loop between Notch1 and Wnt/β-catenin signaling in LCSCs. The central role of Notch and the Wnt/β-catenin signaling pathway in LCSCs may provide an attractive therapeutic strategy against HCC. PMID:26735577

  14. Extraction and identification of exosomes from drug-resistant breast cancer cells and their potential role in cell-to-cell drug-resistance transfer

    Institute of Scientific and Technical Information of China (English)

    许金金

    2014-01-01

    Objective To explore whether docetaxel-resistant cells(MCF-7/Doc)and doxorubicin-resistant cells(MCF-7/ADM)can secrete Exosomes and their potential role in cell-cell drug-resistance transfer.Methods Exosomes were extracted from the cell culture supernatants of MCF-7/Doc and MCF-7/ADM cells by fractionation ultracentrifugation,and were identified by transmission

  15. The relationship of cancer stem cells in urological cancers

    OpenAIRE

    Marta Pokrywczyńska; Jan Adamowicz; Jakub Tworkiewicz; Zbigniew Wolski; Tomasz Drewa

    2013-01-01

    Numerous studies are ongoing to identify and isolate cancer stem cells from cancers of genito-urinary tracts. Better understanding of their role in prostate, urothelial and kidney cancer origin, growth and progression opens new pathways in development of more effective treatment methods. However there are still many issues before advances in this field can be introduced for clinical application. This review addresses current achievements in cancer stem cells research in uro-oncology.

  16. The relationship of cancer stem cells in urological cancers

    Directory of Open Access Journals (Sweden)

    Marta Pokrywczyńska

    2013-08-01

    Full Text Available Numerous studies are ongoing to identify and isolate cancer stem cells from cancers of genito-urinary tracts. Better understanding of their role in prostate, urothelial and kidney cancer origin, growth and progression opens new pathways in development of more effective treatment methods. However there are still many issues before advances in this field can be introduced for clinical application. This review addresses current achievements in cancer stem cells research in uro-oncology.

  17. Breast cancer stem cell-like cells are more sensitive to ionizing radiation than non-stem cells: role of ATM.

    Directory of Open Access Journals (Sweden)

    Seog-Young Kim

    Full Text Available There are contradictory observations about the different radiosensitivities of cancer stem cells and cancer non-stem cells. To resolve these contradictory observations, we studied radiosensitivities by employing breast cancer stem cell (CSC-like MDA-MB231 and MDA-MB453 cells as well as their corresponding non-stem cells. CSC-like cells proliferate without differentiating and have characteristics of tumor-initiating cells [1]. These cells were exposed to γ-rays (1.25-8.75 Gy and survival curves were determined by colony formation. A final slope, D(0, of the survival curve for each cell line was determined to measure radiosensitivity. The D(0 of CSC-like and non-stem MDA-MB-453 cells were 1.16 Gy and 1.55 Gy, respectively. Similar results were observed in MDA-MB-231 cells (0.94 Gy vs. 1.56 Gy. After determination of radiosensitivity, we investigated intrinsic cellular determinants which influence radiosensitivity including cell cycle distribution, free-radical scavengers and DNA repair. We observed that even though cell cycle status and antioxidant content may contribute to differential radiosensitivity, differential DNA repair capacity may be a greater determinant of radiosensitivity. Unlike non-stem cells, CSC-like cells have little/no sublethal damage repair, a low intracellular level of ataxia telangiectasia mutated (ATM and delay of γ-H2AX foci removal (DNA strand break repair. These results suggest that low DNA repair capacity is responsible for the high radiosensitivity of these CSC-like cells.

  18. Bioinformatics Analyses of the Role of Vascular Endothelial Growth Factor in Patients with Non-Small Cell Lung Cancer.

    Directory of Open Access Journals (Sweden)

    Ying Wang

    Full Text Available This study was aimed to identify the expression pattern of vascular endothelial growth factor (VEGF in non-small cell lung cancer (NSCLC and to explore its potential correlation with the progression of NSCLC.Gene expression profile GSE39345 was downloaded from the Gene Expression Omnibus database. Twenty healthy controls and 32 NSCLC samples before chemotherapy were analyzed to identify the differentially expressed genes (DEGs. Then pathway enrichment analysis of the DEGs was performed and protein-protein interaction networks were constructed. Particularly, VEGF genes and the VEGF signaling pathway were analyzed. The sub-network was constructed followed by functional enrichment analysis.Total 1666 up-regulated and 1542 down-regulated DEGs were identified. The down-regulated DEGs were mainly enriched in the pathways associated with cancer. VEGFA and VEGFB were found to be the initiating factor of VEGF signaling pathway. In addition, in the epidermal growth factor receptor (EGFR, VEGFA and VEGFB associated sub-network, kinase insert domain receptor (KDR, fibronectin 1 (FN1, transforming growth factor beta induced (TGFBI and proliferating cell nuclear antigen (PCNA were found to interact with at least two of the three hub genes. The DEGs in this sub-network were mainly enriched in Gene Ontology terms related to cell proliferation.EGFR, KDR, FN1, TGFBI and PCNA may interact with VEGFA to play important roles in NSCLC tumorigenesis. These genes and corresponding proteins may have the potential to be used as the targets for either diagnosis or treatment of patients with NSCLC.

  19. Role of Radiation Therapy in the Management of Renal Cell Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Blanco, Angel I.; Teh, Bin S. [Department of Radiation Oncology, The Methodist Hospital, The Methodist Hospital Research Institute, Houston, TX 77030 (United States); Department of Radiation Oncology, The Methodist Hospital, Houston, TX 77030 (United States); Amato, Robert J., E-mail: Robert.amato@uth.tmc.edu [Division of Oncology, University of Texas Health Science Center at Houston, Memorial Hermann Cancer Center, Houston, TX 77030 (United States)

    2011-10-26

    Renal cell carcinoma (RCC) is traditionally considered to be radioresistant; therefore, conventional radiotherapy (RT) fraction sizes of 1.8 to 2 Gy are thought to have little role in the management of primary RCC, especially for curative disease. In the setting of metastatic RCC, conventionally fractionated RT has been an effective palliative treatment in 50% of patients. Recent technological advances in radiation oncology have led to the clinical implementation of image-guided radiotherapy, allowing biologically potent doses to the tumors intra- and extra-cranially. As predicted by radiobiologic modeling, favorable outcomes have been observed with highly hypofractionated schemes modeled after the experience with intracranial stereotactic radiosurgery (SRS) for RCC brain metastases with reported local control rates averaging 85%. At present, both primary and metastatic RCC tumors may be successfully treated using stereotactic approaches, which utilize steep dose gradients to maximally preserve function and avoid toxicity of adjacent organs including liver, uninvolved kidney, bowel, and spinal cord regions. Future endeavors will combine stereotactic body radiation therapy (SBRT) with novel targeted therapies, such as tyrosine kinase inhibitors and targeted rapamycin (mTOR) inhibitors, to maximize both local and systemic control.

  20. Role of Radiation Therapy in the Management of Renal Cell Cancer

    International Nuclear Information System (INIS)

    Renal cell carcinoma (RCC) is traditionally considered to be radioresistant; therefore, conventional radiotherapy (RT) fraction sizes of 1.8 to 2 Gy are thought to have little role in the management of primary RCC, especially for curative disease. In the setting of metastatic RCC, conventionally fractionated RT has been an effective palliative treatment in 50% of patients. Recent technological advances in radiation oncology have led to the clinical implementation of image-guided radiotherapy, allowing biologically potent doses to the tumors intra- and extra-cranially. As predicted by radiobiologic modeling, favorable outcomes have been observed with highly hypofractionated schemes modeled after the experience with intracranial stereotactic radiosurgery (SRS) for RCC brain metastases with reported local control rates averaging 85%. At present, both primary and metastatic RCC tumors may be successfully treated using stereotactic approaches, which utilize steep dose gradients to maximally preserve function and avoid toxicity of adjacent organs including liver, uninvolved kidney, bowel, and spinal cord regions. Future endeavors will combine stereotactic body radiation therapy (SBRT) with novel targeted therapies, such as tyrosine kinase inhibitors and targeted rapamycin (mTOR) inhibitors, to maximize both local and systemic control

  1. Gastric Cancer Stem Cells

    OpenAIRE

    Takaishi, Shigeo; Okumura, Tomoyuki; Timothy C Wang

    2008-01-01

    Cancer stem cells are defined as the unique subpopulation in the tumors that possess the ability to initiate tumor growth and sustain self-renewal as well as metastatic potential. Accumulating evidence in recent years strongly indicate the existence of cancer stem cells in solid tumors of a wide variety of organs. In this review, we will discuss the possible existence of a gastric cancer stem cell. Our recent data suggest that a subpopulation with a defined marker shows spheroid colony format...

  2. Cancer stem cell metabolism

    OpenAIRE

    Peiris-Pagès, Maria; Martinez-Outschoorn, Ubaldo E.; Pestell, Richard G.; Sotgia, Federica; Lisanti, Michael P

    2016-01-01

    Cancer is now viewed as a stem cell disease. There is still no consensus on the metabolic characteristics of cancer stem cells, with several studies indicating that they are mainly glycolytic and others pointing instead to mitochondrial metabolism as their principal source of energy. Cancer stem cells also seem to adapt their metabolism to microenvironmental changes by conveniently shifting energy production from one pathway to another, or by acquiring intermediate metabolic phenotypes. Deter...

  3. Liver Cancer Stem Cells

    OpenAIRE

    Sameh Mikhail; Aiwu Ruth He

    2011-01-01

    Hepatocellular carcinoma is the most common primary malignancy of the liver in adults. It is also the fifth most common solid cancer worldwide and the third leading cause of cancer-related death. Recent research supports that liver cancer is a disease of adult stem cells. From the models of experimental hepatocarcinogenesis, there may be at least three distinct cell lineages with progenitor properties susceptible to neoplastic transformation. Identification of specific cell surface markers fo...

  4. Tanshinone I induces human colorectal cancer cell apoptosis: The potential roles of Aurora A-p53 and survivin-mediated signaling pathways.

    Science.gov (United States)

    Lu, Mingjie; Wang, Chen; Wang, Jian

    2016-08-01

    Colorectal cancer (CRC) is one of the most common malignancies worldwide and a leading cause of cancer death. Despite decades of intensive investigations, effective interventional options are still limited and patient prognosis remains poor. Tanshinone I, an active compound from traditional Chinese herbal medicine Salvia miltiorrhiza Bunge, has been shown to inhibit cell growth of leukemia, lung, and breast cancers. However, whether and how Tanshinone I exerts similar effects on CRC needs to be elucidated. Tanshinone I induced CRC cell apoptosis was characterized and the roles of Aurora A-p53 and survivin-mediated pathways were analyzed in different CRC cell lines. Tanshinone I markedly inhibited CRC cell growth and induced apoptosis in CRC cells with functional p53 protein. Interestingly, Tanshinone I did not exert as much inhibitory effect on normal colon epithelial cells or CRC cells with mutant p53, indicating relative selectivity toward colorectal cancer cells with full presence of p53. In tse cells with wild-type p53, data showed that Tanshinone I mediated Aurora A inhibition results in p53 upregulation, which is required for cell apoptosis. In CRC cells with mutant p53 protein (not able to localize to the nucleus), however, Aurora A knockdown failed to induce CRC cell apoptosis. Instead, data showed that protein level of survivin decreased following Tanshinone I treatment. These observations were further substantiated by the pivotal role of survivin in Tanshinone I mediated apoptosis in CRC cells with p53 mutant. Tanshinone I, a novel natural compound, exerts significant inhibitory effect on CRC cell growth via a mechanism involving either Aurora A-p53 axis or survivin-involving mechanism depending on different intrinsic characteristics of tumor cells. PMID:27279458

  5. Tumor suppressor p53 plays a key role in induction of both tristetraprolin and let-7 in human cancer cells

    OpenAIRE

    Lee, Ji Young; Kim, Hyo Jeong; Yoon, Nal Ae; Lee, Won Hyeok; Min, Young Joo; Ko, Byung Kyun; Lee, Byung Ju; Lee, Aran; Cha, Hee Jeong; Cho, Wha Ja; Park, Jeong Woo

    2013-01-01

    Tristetraprolin (TTP) and let-7 microRNA exhibit suppressive effects on cell growth through down-regulation of oncogenes. Both TTP and let-7 are often repressed in human cancers, thereby promoting oncogenesis by derepressing their target genes. However, the precise mechanism of this repression is unknown. We here demonstrate that p53 stimulated by the DNA-damaging agent doxorubicin (DOX) induced the expression of TTP in cancer cells. TTP in turn increased let-7 levels through down-regulation ...

  6. Tumor Initiating Cells and FZD8 play a major role in drug resistance in Triple-Negative Breast Cancer

    OpenAIRE

    Yin, Shuping; Xu, Liping; Bonfil, R. Daniel; Banerjee, Sanjeev; Sarkar, Fazlul H; Sethi, Seema; Reddy, Kaladhar B.

    2013-01-01

    Triple-negative breast cancer (TNBC) studies have shown that neoadjuvant chemotherapy before surgery was effective in the minority of women, whereas the majority who had residual tumor had a relatively poor outcome. To identify the mechanism by which residual cancer cells survive chemotherapy, we initially performed gene expression profiling using the CRL2335 TNBC cell line derived from a squamous breast carcinoma before and after treatment with cisplatin plus TRAIL. We found a significant in...

  7. The Roles of 4β-Hydroxywithanolide E from Physalis peruviana on the Nrf2-Anti-Oxidant System and the Cell Cycle in Breast Cancer Cells.

    Science.gov (United States)

    Peng, Chieh Yu; You, Bang Jau; Lee, Chia Lin; Wu, Yang Chang; Lin, Wen Hsin; Lu, Te Ling; Chang, Fei-Ching; Lee, Hong Zin

    2016-01-01

    4[Formula: see text]-Hydroxywithanolide E is an active component of the extract of Physalis peruviana that has been reported to exhibit antitumor effects. Although the involvement of reactive oxygen species (ROS) production and the ataxia-telangiectasia mutated protein (ATM)-dependent DNA damage signaling pathway in 4[Formula: see text]-hydroxywithanolide E-induced apoptosis of breast cancer MCF-7 cells was demonstrated in our previous study, the relationship between ROS production and the cellular defense system response in 4[Formula: see text]-hydroxywithanolide E-induced cell death requires further verification. The present study suggests that ROS play an important role in 4[Formula: see text]-hydroxywithanolide E-induced MCF-7 cell death in which anti-oxidants, such as glutathione or N-acetylcysteine, can resist the 4[Formula: see text]-hydroxywithanolide E-induced accumulation of ROS and cell death. Furthermore, N-acetylcysteine or glutathione can reverse the 4[Formula: see text]-hydroxywithanolide E-induced changes in the cell cycle distribution and the expression of cell cycle regulators. We found that the 4[Formula: see text]-hydroxywithanolide E-induced ROS accumulation was correlated with the upregulation of Nrf2 and Nrf2-downstream genes, such as antioxidative defense enzymes. In general, the activity of Nrf2 is regulated by the Ras signalling pathway. However, we demonstrated that Nrf2 was activated during 4[Formula: see text]-hydroxywithanolide E-induced MCF-7 cell death in spite of the 4[Formula: see text]-hydroxywithanolide E-induced inhibition of the Ras/Raf/ERK pathway. The activity and protein expression of superoxide dismutase and catalase were involved in the 4[Formula: see text]-hydroxywithanolide E-induced ROS production in MCF-7 cells. Furthermore, 4[Formula: see text]-hydroxywithanolide E was demonstrated to significantly reduce the sizes of the tumor nodules in the human breast cancer MDA-MB231 xenograft tumor model. PMID:27109152

  8. Methylselenol, a selenium metabolite, plays common and different roles in cancerous colon HCT116 cell and noncancerous NCM460 colon cell proliferation

    Science.gov (United States)

    Methylselenol has been hypothesized to be a critical selenium (Se) metabolite for anticancer activity in vivo. To determine differential chemopreventive effects of methylselenol on colon cancer cells versus colon noncancerous cells, colon-cancer-derived HCT-116 cells and noncancerous colonic NCM460 ...

  9. Role for DNA methylation in the regulation of miR-200c and miR-141 expression in normal and cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Vrba, Lukas; Jensen, Taylor J.; Garbe, James C.; Heimark, Ronald L.; Cress, Anne E.; Dickinson, Sally; Stampfer, Martha R.; Futscher, Bernard W.

    2009-12-23

    BACKGROUND: The microRNA-200 family participates in the maintenance of an epithelial phenotype and loss of its expression can result in epithelial to mesenchymal transition (EMT). Furthermore, the loss of expression of miR-200 family members is linked to an aggressive cancer phenotype. Regulation of the miR-200 family expression in normal and cancer cells is not fully understood. METHODOLOGY/ PRINCIPAL FINDINGS: Epigenetic mechanisms participate in the control of miR-200c and miR-141 expression in both normal and cancer cells. A CpG island near the predicted mir-200c/mir-141 transcription start site shows a striking correlation between miR-200c and miR-141 expression and DNA methylation in both normal and cancer cells, as determined by MassARRAY technology. The CpG island is unmethylated in human miR-200/miR-141 expressing epithelial cells and in miR-200c/miR-141 positive tumor cells. The CpG island is heavily methylated in human miR-200c/miR-141 negative fibroblasts and miR-200c/miR-141 negative tumor cells. Mouse cells show a similar inverse correlation between DNA methylation and miR-200c expression. Enrichment of permissive histone modifications, H3 acetylation and H3K4 trimethylation, is seen in normal miR-200c/miR-141-positive epithelial cells, as determined by chromatin immunoprecipitation coupled to real-time PCR. In contrast, repressive H3K9 dimethylation marks are present in normal miR-200c/miR-141-negative fibroblasts and miR-200c/miR-141 negative cancer cells and the permissive histone modifications are absent. The epigenetic modifier drug, 5-aza-2'-deoxycytidine, reactivates miR-200c/miR-141 expression showing that epigenetic mechanisms play a functional role in their transcriptional control. CONCLUSIONS/ SIGNIFICANCE: We report that DNA methylation plays a role in the normal cell type-specific expression of miR-200c and miR-141 and this role appears evolutionarily conserved, since similar results were obtained in mouse. Aberrant DNA methylation

  10. The Role of Treg Cells in the Cancer Immunological Response

    OpenAIRE

    Ansell, Stephen M.; Zhi-Zhang Yang

    2009-01-01

    Problem statement: T cell-mediated immunosuppression has been observed for decades without clarification as to which factor was responsible for this observation. The identification of CD4+CD25+ regulatory T (Treg) cells represents a milestone in the filed of immunology and provides an explanation for T-cell-mediated immunosuppression. Although Treg cells were originally identified for their ability to prevent organ-specific autoimmune disease in mice, emerging &#...

  11. Cancer stem cells and brain tumors

    OpenAIRE

    Pérez Castillo, Ana; Aguilar Morante, Diana; Morales-García, José A.; Dorado, Jorge

    2008-01-01

    Besides the role of normal stem cells in organogenesis, cancer stem cells are thought to be crucial for tumorigenesis. Most current research on human tumors is focused on molecular and cellular analysis of the bulk tumor mass. However, evidence in leukemia and, more recently, in solid tumors suggests that the tumor cell population is heterogeneous. In recent years, several groups have described the existence of a cancer stem cell population in different brain tumors. These neural cancer stem ...

  12. Small cell lung cancer transformation and T790M mutation: complimentary roles in acquired resistance to kinase inhibitors in lung cancer

    OpenAIRE

    Kenichi Suda; Isao Murakami; Kazuko Sakai; Hiroshi Mizuuchi; Shigeki Shimizu; Katsuaki Sato; Kenji Tomizawa; Shuta Tomida; Yasushi Yatabe; Kazuto Nishio; Tetsuya Mitsudomi

    2015-01-01

    Lung cancers often harbour a mutation in the epidermal growth factor receptor (EGFR) gene. Because proliferation and survival of lung cancers with EGFR mutation solely depend on aberrant signalling from the mutated EGFR, these tumours often show dramatic responses to EGFR tyrosine kinase inhibitors (TKIs). However, acquiring resistance to these drugs is almost inevitable, thus a better understanding of the underlying resistance mechanisms is critical. Small cell lung cancer (SCLC) transformat...

  13. The Role of Cancer Stem Cells in the Organ Tropism of Breast Cancer Metastasis: A Mechanistic Balance between the Seed and the Soil?

    International Nuclear Information System (INIS)

    Breast cancer is a prevalent disease worldwide, and the majority of deaths occur due to metastatic disease. Clinical studies have identified a specific pattern for the metastatic spread of breast cancer, termed organ tropism; where preferential secondary sites include lymph node, bone, brain, lung, and liver. A rare subpopulation of tumor cells, the cancer stem cells (CSCs), has been hypothesized to be responsible for metastatic disease and therapy resistance. Current treatments are highly ineffective against metastatic breast cancer, likely due to the innate therapy resistance of CSCs and the complex interactions that occur between cancer cells and their metastatic micro environments. A better understanding of these interactions is essential for the development of novel therapeutic targets for metastatic disease. This paper summarizes the characteristics of breast CSCs and their potential metastatic micro environments. Furthermore, it raises the question of the existence of a CSC niche and highlights areas for future investigation.

  14. Expression of Peroxisome Proferator-Activated Receptor γ (PPARγ in Human Transitional Bladder Cancer and its Role in Inducing Cell Death

    Directory of Open Access Journals (Sweden)

    You-Fei Guan

    1999-10-01

    Full Text Available The present study examined the expression and role of the thiazolidinedione (TZD-activated transcription factor, peroxisome proliferator-activated receptor γ (PPARγ, in human bladder cancers. In situ hybridization shows that PPARγ mRNA is highly expressed in all human transitional epithelial cell cancers (TCCa's studied (n=11. PPARγ was also expressed in five TCCa cell lines as determined by RNase protection assays and immunoblot. Retinoid X receptor α (RXRα, a 9-cis-retinoic acid stimulated (9-cis-RA heterodimeric partner of PPARγ, was also co-expressed in all TCCa tissues and cell lines. Treatment of the T24 bladder cancer cells with the TZD PPARγ agonist troglitazone, dramatically inhibited 3H-thymidine incorporation and induced cell death. Addition of the RXRα ligands, 9-cis-RA or LG100268, sensitized T24 bladder cancer cells to the lethal effect of troglitazone and two other PPARγ activators, ciglitazone and 15-deoxy-Δ12,14-PGJ2 (15dPGJ2. Troglitazone treatment increased expression of two cyclin-dependent kinase inhibitors, p21wAF1/CIP1 and p16INK4, reduced cyclin D1 expression, consistent with G1 arrest. Troglitazone also induced an endogenous PPARγ target gene in T24 cells, adipocyte-type fatty acid binding protein (A-FABP, the expression of which correlates with bladder cancer differentiation. In situ hybridization shows that A-FABP expression is localized to normal uroepithelial cells as well as some TCCa's. Taken together, these results demonstrate that PPARγ is expressed in human TCCa where it may play a role in regulating TCCa differentiation and survival, thereby providing a potential target for therapy of uroepithelial cancers.

  15. The evolving roles of canonical WNT signaling in stem cells and tumorigenesis: implications in targeted cancer therapies.

    Science.gov (United States)

    Yang, Ke; Wang, Xin; Zhang, Hongmei; Wang, Zhongliang; Nan, Guoxin; Li, Yasha; Zhang, Fugui; Mohammed, Maryam K; Haydon, Rex C; Luu, Hue H; Bi, Yang; He, Tong-Chuan

    2016-02-01

    The canonical WNT/β-catenin signaling pathway governs a myriad of biological processes underlying the development and maintenance of adult tissue homeostasis, including regulation of stem cell self-renewal, cell proliferation, differentiation, and apoptosis. WNTs are secreted lipid-modified glycoproteins that act as short-range ligands to activate receptor-mediated signaling pathways. The hallmark of the canonical pathway is the activation of β-catenin-mediated transcriptional activity. Canonical WNTs control the β-catenin dynamics as the cytoplasmic level of β-catenin is tightly regulated via phosphorylation by the 'destruction complex', consisting of glycogen synthase kinase 3β (GSK3β), casein kinase 1α (CK1α), the scaffold protein AXIN, and the tumor suppressor adenomatous polyposis coli (APC). Aberrant regulation of this signaling cascade is associated with varieties of human diseases, especially cancers. Over the past decade, significant progress has been made in understanding the mechanisms of canonical WNT signaling. In this review, we focus on the current understanding of WNT signaling at the extracellular, cytoplasmic membrane, and intracellular/nuclear levels, including the emerging knowledge of cross-talk with other pathways. Recent progresses in developing novel WNT pathway-targeted therapies will also be reviewed. Thus, this review is intended to serve as a refresher of the current understanding about the physiologic and pathogenic roles of WNT/β-catenin signaling pathway, and to outline potential therapeutic opportunities by targeting the canonical WNT pathway. PMID:26618721

  16. A novel role for peptidylarginine deiminases in microvesicle release reveals therapeutic potential of PAD inhibition in sensitizing prostate cancer cells to chemotherapy

    Directory of Open Access Journals (Sweden)

    Sharad Kholia

    2015-06-01

    Full Text Available Introduction: Protein deimination, defined as the post-translational conversion of protein-bound arginine to citrulline, is carried out by a family of 5 calcium-dependent enzymes, the peptidylarginine deiminases (PADs and has been linked to various cancers. Cellular microvesicle (MV release, which is involved in cancer progression, and deimination have not been associated before. We hypothesize that elevated PAD expression, observed in cancers, causes increased MV release in cancer cells and contributes to cancer progression. Background: We have previously reported that inhibition of MV release sensitizes cancer cells to chemotherapeutic drugs. PAD2 and PAD4, the isozymes expressed in patients with malignant tumours, can be inhibited with the pan-PAD-inhibitor chloramidine (Cl-am. We sought to investigate whether Cl-am can inhibit MV release and whether this pathway could be utilized to further increase the sensitivity of cancer cells to drug-directed treatment. Methods: Prostate cancer cells (PC3 were induced to release high levels of MVs upon BzATP stimulation of P2X7 receptors. Western blotting with the pan-protein deimination antibody F95 was used to detect a range of deiminated proteins in cells stimulated to microvesiculate. Changes in deiminated proteins during microvesiculation were revealed by immunoprecipitation and immunoblotting, and mass spectrometry identified deiminated target proteins with putative roles in microvesiculation. Conclusion: We report for the first time a novel function of PADs in the biogenesis of MVs in cancer cells. Our results reveal that during the stimulation of prostate cancer cells (PC3 to microvesiculate, PAD2 and PAD4 expression levels and the deimination of cytoskeletal actin are increased. Pharmacological inhibition of PAD enzyme activity using Cl-am significantly reduced MV release and abrogated the deimination of cytoskeletal actin. We demonstrated that combined Cl-am and methotrexate (MTX treatment of

  17. Tumour-derived exosomes and their role in cancer-associated T-cell signalling defects

    OpenAIRE

    Taylor, D D; Gerçel-Taylor, C

    2005-01-01

    Dendritic and lymphoid ‘exosomes' regulate immune activation. Tumours release membranous material mimicking these ‘exosomes,' resulting in deletion of reactive lymphocytes. Tumour-derived ‘exosomes' have recently been explored as vaccines, without analysis of their immunologic consequences. This investigation examines the composition of tumour-derived ‘exosomes' and their effects on T lymphocytes. Membranous materials were isolated from ascites of ovarian cancer patients (n=6) and Western imm...

  18. Novel role of microRNAs in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    YU Jun-jie; XIA Shu-jie

    2013-01-01

    Objective To discuss the novel biomarkers of microRNAs in prostate cancer.Data sources The literatures about microRNAs and prostate cancer cited in this review were obtained mainly from Pubmed published in English from 2004 to 2012.Study selection Original articles regarding the novel role of microRNAs in prostate cancer were selected.Results MicroRNAs play an important role in prostate cancer such as cell differentiation,proliferation,apoptosis,and invasion.Especially microRNAs correlate with prostate cancer cell epithelial-mesenchymal transition (EMT),cancer stem cells (CSCs),drug sensitivity,cancer microenvironment,energy metabolism,androgen independence transformation,and diagnosis prediction.Conclusions MicroRNAs are involved in various aspects of prostate cancer biology.The role of microRNA in the initiation and development of prostate cancer deserves further study.

  19. Methionine enkephalin, its role in immunoregulation and cancer therapy.

    Science.gov (United States)

    Zhao, Dingliang; Plotnikoff, Nicolas; Griffin, Noreen; Song, Tao; Shan, Fengping

    2016-08-01

    Methionine enkephalin (MENK), an endogenous neuropeptide has a crucial role in both neuroendocrine and immune systems. MENK is believed to have an immunoregulatory activity to have cancer biotherapy activity by binding to the opioid receptors on immune and cancer cells. Clinical trial studies in cancer patients have shown that MENK activates immune cells directly and by inhibiting regulatory T-cells (Tregs). MENK may also change the tumor microenvironment by binding to opioid receptor on or in cancer cells. All of these mechanisms of action have biologic significance and potential for use in cancer immunotherapy. Furthermore, they reveal a relationship between the endocrine and immune systems. Due to the apparent role of MENK in cancer therapy we reviewed herein, the research undertaken with MENK in recent years; which has advanced our understanding of the role MENK has in cancer progression and its relationship to immunity, supporting MENK as a new strategy for cancer immunotherapy. PMID:26927200

  20. Methylselenol, a selenium metabolite, plays a critical role in inhibiting colon cancer cell growth in vitro and in vivo

    Science.gov (United States)

    Methylselenol is hypothesized to be a critical selenium (Se) metabolite for anticancer activity. In this study, submicromolar methylselenol was generated by incubating methionase with seleno-L methionine, and both colon-cancer-derived HCT-116 cells and noncancerous colon NCM460 cells were exposed to...

  1. The role of Crk/Dock180/Rac1 pathway in the malignant behavior of human ovarian cancer cell SKOV3.

    Science.gov (United States)

    Wang, Hui; Linghu, Hua; Wang, Jin; Che, Ya-ling; Xiang, Ting-xiu; Tang, Wei-xue; Yao, Zhen-wei

    2010-01-01

    Small GTPases, particularly the Rho family, are key regulators of cell motility and migration. Dock180 was well known for the main target of signal adaptor protein Crk and acted as a guanine-nucleotide exchange factor for small GTPase Rac1. In the present study, Dock180 was found to combine primarily with CrkI other than CrkII, and its association with Elmo1 was also demonstrated in ovarian cancer cell SKOV3. To evaluate the role of Dock180 in human ovarian cancer cell, we performed RNAi-mediated knockdown of Dock180 in SKOV3 cells using small interfering RNA expression vector. In Dock180 knockdown cells, we found that Elmo1 expression and Rac1 activity were decreased simultaneously. By contrast, the expressions of both another Crk-combining molecule C3G and Rap1 activity were observed to increase obviously. Accordingly, all Dock180 knockdown cells present with evident change in cell morphology, reduced cell proliferation, and attenuated cell migration. Taken together, these results suggest that signal transfer of Crk/Dock180/Rac1 is implicated in actin cytoskeleton reorganization and thus in the cell proliferation, motility, invasion, and of human ovarian cancer cell line SKOV3. PMID:20237902

  2. The role of autophagy induced by tumor microenvironment in different cells and stages of cancer

    OpenAIRE

    Yang, Xue; Yu, Dan-Dan; Yan, Fei; Jing, Ying-Ying; Han, Zhi-Peng; Sun, Kai; Liang, Lei; Hou, Jing; Li-xin WEI

    2015-01-01

    Development of a tumor is a very complex process, and invasion and metastasis of malignant tumors are hallmarks and are difficult problems to overcome. The tumor microenvironment plays an important role in controlling tumor fate and autophagy induced by the tumor microenvironment is attracting more and more attention. Autophagy can be induced by several stressors in the tumor microenvironment and autophagy modifies the tumor microenvironment, too. Autophagy has dual roles in tumor growth. In ...

  3. Role of Insulin-Like Growth Factor-1 Signaling Pathway in Cisplatin-Resistant Lung Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Sun Yunguang [Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN (United States); Zheng Siyuan [Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN (United States); Torossian, Artour; Speirs, Christina K.; Schleicher, Stephen; Giacalone, Nicholas J. [Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN (United States); Carbone, David P. [Department of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN (United States); Zhao Zhongming, E-mail: zhongming.zhao@vanderbilt.edu [Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN (United States); Lu Bo, E-mail: bo.lu@vanderbilt.edu [Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN (United States)

    2012-03-01

    Purpose: The development of drug-resistant phenotypes has been a major obstacle to cisplatin use in non-small-cell lung cancer. We aimed to identify some of the molecular mechanisms that underlie cisplatin resistance using microarray expression analysis. Methods and Materials: H460 cells were treated with cisplatin. The differences between cisplatin-resistant lung cancer cells and parental H460 cells were studied using Western blot, MTS, and clonogenic assays, in vivo tumor implantation, and microarray analysis. The cisplatin-R cells were treated with human recombinant insulin-like growth factor (IGF) binding protein-3 and siRNA targeting IGF-1 receptor. Results: Cisplatin-R cells illustrated greater expression of the markers CD133 and aldehyde dehydrogenase, more rapid in vivo tumor growth, more resistance to cisplatin- and etoposide-induced apoptosis, and greater survival after treatment with cisplatin or radiation than the parental H460 cells. Also, cisplatin-R demonstrated decreased expression of insulin-like growth factor binding protein-3 and increased activation of IGF-1 receptor signaling compared with parental H460 cells in the presence of IGF-1. Human recombinant IGF binding protein-3 reversed cisplatin resistance in cisplatin-R cells and targeting of IGF-1 receptor using siRNA resulted in sensitization of cisplatin-R-cells to cisplatin and radiation. Conclusions: The IGF-1 signaling pathway contributes to cisplatin-R to cisplatin and radiation. Thus, this pathway represents a potential target for improved lung cancer response to treatment.

  4. Role of Insulin-Like Growth Factor-1 Signaling Pathway in Cisplatin-Resistant Lung Cancer Cells

    International Nuclear Information System (INIS)

    Purpose: The development of drug-resistant phenotypes has been a major obstacle to cisplatin use in non–small-cell lung cancer. We aimed to identify some of the molecular mechanisms that underlie cisplatin resistance using microarray expression analysis. Methods and Materials: H460 cells were treated with cisplatin. The differences between cisplatin-resistant lung cancer cells and parental H460 cells were studied using Western blot, MTS, and clonogenic assays, in vivo tumor implantation, and microarray analysis. The cisplatin-R cells were treated with human recombinant insulin-like growth factor (IGF) binding protein-3 and siRNA targeting IGF-1 receptor. Results: Cisplatin-R cells illustrated greater expression of the markers CD133 and aldehyde dehydrogenase, more rapid in vivo tumor growth, more resistance to cisplatin- and etoposide-induced apoptosis, and greater survival after treatment with cisplatin or radiation than the parental H460 cells. Also, cisplatin-R demonstrated decreased expression of insulin-like growth factor binding protein-3 and increased activation of IGF-1 receptor signaling compared with parental H460 cells in the presence of IGF-1. Human recombinant IGF binding protein-3 reversed cisplatin resistance in cisplatin-R cells and targeting of IGF-1 receptor using siRNA resulted in sensitization of cisplatin-R-cells to cisplatin and radiation. Conclusions: The IGF-1 signaling pathway contributes to cisplatin-R to cisplatin and radiation. Thus, this pathway represents a potential target for improved lung cancer response to treatment.

  5. Role of ornithine decarboxylase in breast cancer

    Institute of Scientific and Technical Information of China (English)

    Wensheng Deng; Xian Jiang; Yu Mei; Jingzhong Sun; Rong Ma; Xianxi Liu; Hui Sun; Hui Tian; Xueying Sun

    2008-01-01

    Ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis that decarboxylates ornithine to putrescine, has become a promising target for cancer research. The aim of this study is to investigate the role of ODC in breast cancer. We detected expression of ODC in breast cancer tissues and four breast cancer cell lines, and transfected breast cancer cells with an adenoviral vector carrying antisense ODC (rAd-ODC/Ex3as) and examined their growth and migration.ODC was overexpressed in breast cancer tissues and cell lines compared with non-tumor tissues and normal breast epithelial celis,and there was a positive correlation between the level of ODC mRNA and the staging of tumors.The expression of ODC correlated with cyclin D1,a cell cycle protein,in synchronized breast cancer MDA-MB-231 cells.Gene transfection of rAd-ODC/Ex3as markedly down-regulated expression Of ODC and cyclin D1,resulting in suppression of proliferation and cell cycle arrest at G0-G1 phase,and the inhibifion of colony formation,an anchorage-independent growth pattern,and the migratory ability of MDA-MB-231 cells.rAd-ODC/Ex3as also markedly reduced the concentration of putrescine,but not spermidine or spermine,in MDA-MB-231 cells.The results suggested that the ODC gene might act as aprognostic factor for breast cancer and it could be a promising therapeutic target.

  6. Mechanism of 2',3'-dimethoxyflavanone-induced apoptosis in breast cancer stem cells: role of ubiquitination of caspase-8 and LC3.

    Science.gov (United States)

    Tran, Thao Anh; Ahn, Kwang Seok; Song, Yeon Woo; Moon, Jeong Yong; Cho, Moonjae; Lim, Yoongho; Cho, Somi Kim

    2014-11-15

    Accumulating evidence has displayed that targeting cancer stem cells (CSCs) is a very promising way for anti-cancer therapies. 2',3'-Dimethoxyflavanone (2',3'-DMF) showed the most potent toxicity of a group of 42 flavonoids tested in MCF-7-SC breast cancer stem cells. 2',3'-DMF triggered intrinsic and extrinsic apoptosis by stimulating the cleavage of PARP and the activation of caspase-9, -8, and -3. Interestingly, 2',3'-DMF induces a dramatic increase in the conversion of LC3, a well-known marker for autophagy. However, acidic vesicular organelles (AVOs), one of the autophagic flux markers were not detected. Co-treatment with chloroquine, the lysosomal inhibitor that blocks autophagic degradation did not show any change in the degree of LC3 conversion, implying that LC3 could play a role in the non-autophagic cell death of MCF-7-SC. We found that 2',3'-DMF induces the ubiquitination of caspase-8, this resulted in an interaction between caspase-8 and LC3, which led to the aggregation and activation of caspase-8. Co-treating cells with 2',3'-DMF and 3-methyladenine, an inhibitor of LC3 lipidation, reduced the activation of caspase-8. These findings provide novel insights into the anti-cancer effects of 2',3'-DMF in breast cancer stem cells by revealing that it induced apoptosis in accompany with the activation of caspase-8 mediated by LC3 conversion. PMID:25132643

  7. Active Roles of Tumor Stroma in Breast Cancer Metastasis

    Directory of Open Access Journals (Sweden)

    Zahraa I. Khamis

    2012-01-01

    Full Text Available Metastasis is the major cause of death for breast cancer patients. Tumors are heterogenous cellular entities composed of cancer cells and cells of the microenvironment in which they reside. A reciprocal dynamic interaction occurs between the tumor cells and their surrounding stroma under physiological and pathological conditions. This tumor-host communication interface mediates the escape of tumor cells at the primary site, survival of circulating cancer cells in the vasculature, and growth of metastatic cancer at secondary site. Each step of the metastatic process is accompanied by recruitment of stromal cells from the microenvironment and production of unique array of growth factors and chemokines. Stromal microenvironment may play active roles in breast cancer metastasis. Elucidating the types of cells recruited and signal pathways involved in the crosstalk between tumor cells and stromal cells will help identify novel strategies for cotargeting cancer cells and tumor stromal cells to suppress metastasis and improve patient outcome.

  8. The roles of beta-adrenergic receptors in tumorigenesis and the possible use of beta-adrenergic blockers for cancer treatment: possible genetic and cell-signaling mechanisms

    International Nuclear Information System (INIS)

    Cancer is the leading cause of death in the USA, and the incidence of cancer increases dramatically with age. Beta-adrenergic blockers appear to have a beneficial clinical effect in cancer patients. In this paper, we review the evidence of an association between β-adrenergic blockade and cancer. Genetic studies have provided the opportunity to determine which proteins link β-adrenergic blockade to cancer pathology. In particular, this link involves the major histocompatibility complex class II molecules, the renin–angiotensin system, transcription factor nuclear factor-kappa-light-chain-enhancer of activated B cells, poly(ADP-ribose) polymerase-1, vascular endothelial growth factor, and the reduced form of nicotinamide adenine dinucleotide phosphate oxidase. Beta-adrenergic blockers also exert anticancer effects through non-genomic factors, including matrix metalloproteinase, mitogen-activated protein kinase pathways, prostaglandins, cyclooxygenase-2, oxidative stress, and nitric oxide synthase. In conclusion, β-adrenergic blockade may play a beneficial role in cancer treatment. Additional investigations that examine β-adrenergic blockers as cancer therapeutics are required to further elucidate this role

  9. Roles of StearoylCoA Desaturase-1 in the Regulation of Cancer Cell Growth, Survival and Tumorigenesis

    International Nuclear Information System (INIS)

    The development and maintenance of defining features of cancer, such as unremitting cell proliferation, evasion of programmed cell death, and the capacity for colonizing local tissues and distant organs, demand a massive production of structural, signaling and energy-storing lipid biomolecules of appropriate fatty acid composition. Due to constitutive activation of fatty acid biosynthesis, cancer cell lipids are enriched with saturated (SFA) and, in particular, monounsaturated fatty acids (MUFA), which are generated by StearoylCoA desaturase-1, the main enzyme that transforms SFA into MUFA. An increasing number of experimental and epidemiological studies suggest that high levels of SCD1 activity is a major factor in establishing the biochemical and metabolic perturbations that favors the oncogenic process. This review examines evidence that suggests the critical implication of SCD1 in the modulation of multiple biological mechanisms, specifically lipid biosynthesis and proliferation and survival signaling pathways that contribute to the development and progression of cancer

  10. Breathless cancer cells get fat on glutamine

    Institute of Scientific and Technical Information of China (English)

    Dimitrios Anastasiou; Lewis C Cantley

    2012-01-01

    Many cancer cells depend on glutamine as a fuel for proliferation,yet the mechanisms by which glutamine supports cancer metabolism are not fully understood.Two recent studies highlight an important role for glutamine in the synthesis of lipids and provide novel insights into how glutamine metabolism could be targeted for cancer therapy.

  11. CARBON MONOXIDE: ITS ROLE IN MITOCHONDRIAL PATHWAY OF APOPTOSIS INDUCTION IN JURKAT CANCER CELLS

    Directory of Open Access Journals (Sweden)

    E. G. Starikova

    2014-07-01

    Full Text Available  Abstract. This study demonstrates ability of carbon monoxide to trigger mitochondrial pathway of apoptosis induction of Jurcat cells. We have shown that proapoptotic action of carbon monoxide is coupled to permeabilization of cellular mitochondrial membranes. Imbalance in Bcl-2 family of regulatory proteins may be considered among possible reasons of the membrane pore formation. We have shown downregulated cl-2 and Bcl-xl mRNA expression and decreased levels of antiapoptotic proteins, along wih decreased mRNA expression and increase of Bad proapototic protein level in Jurkat cells following incubation with 50 μm of CORM-2, a carbon monoxide donor.

  12. The role of the tissue microenvironment in the regulation of cancer cell motility and invasion

    Czech Academy of Sciences Publication Activity Database

    Brabek, J.; Mierke, C.T.; Rosel, D.; Veselý, Pavel; Fabry, B.

    2010-01-01

    Roč. 8, č. 22 (2010), 22e-22e. ISSN 1478-811X R&D Projects: GA MŠk(CZ) LC06061 Institutional research plan: CEZ:AV0Z50520514 Keywords : endothelial barrier function * pericellular proteolysis * melanoma cells Subject RIV: EB - Genetics ; Molecular Biology

  13. Cancer Stem Cells, Cancer Cell Plasticity and Radiation Therapy

    OpenAIRE

    Vlashi, Erina; Pajonk, Frank

    2014-01-01

    Since the first prospective identification of cancer stem cells in solid cancers the cancer stem cell hypothesis has reemerged as a research topic of increasing interest. It postulates that solid cancers are organized hierarchically with a small number of cancer stem cells driving tumor growth, repopulation after injury and metastasis. They give rise to differentiated progeny, which lack these features. The model predicts that for any therapy to provide cure, all cancer stem cells have to be ...

  14. A neomorphic cancer cell-specific role of MAGE-A4 in trans-lesion synthesis

    OpenAIRE

    Gao, Yanzhe; Mutter-Rottmayer, Elizabeth; Greenwalt, Alicia M.; Goldfarb, Dennis; Yan, Feng; Yang, Yang; Martinez-Chacin, Raquel C.; Pearce, Kenneth H.; Tateishi, Satoshi; Major, Michael B.; Vaziri, Cyrus

    2016-01-01

    Trans-lesion synthesis (TLS) is an important DNA-damage tolerance mechanism that permits ongoing DNA synthesis in cells harbouring damaged genomes. The E3 ubiquitin ligase RAD18 activates TLS by promoting recruitment of Y-family DNA polymerases to sites of DNA-damage-induced replication fork stalling. Here we identify the cancer/testes antigen melanoma antigen-A4 (MAGE-A4) as a tumour cell-specific RAD18-binding partner and an activator of TLS. MAGE-A4 depletion from MAGE-A4-expressing cancer...

  15. Alteration of pancreatic cancer cell functions by tumor-stromal cell interaction

    OpenAIRE

    Shin eHamada; Atsushi eMasamune; Tooru eShimosegawa

    2013-01-01

    Pancreatic cancer shows a characteristic tissue structure called desmoplasia, which consists of dense fibrotic stroma surrounding cancer cells. Interactions between pancreatic cancer cells and stromal cells promote invasive growth of cancer cells and establish a specific microenvironment such as hypoxia which further aggravates the malignant behavior of cancer cells. Pancreatic stellate cells (PSCs) play pivotal role in the development of fibrosis within the pancreatic cancer tissue, and also...

  16. Alteration of pancreatic cancer cell functions by tumor-stromal cell interaction

    OpenAIRE

    Hamada, Shin; Masamune, Atsushi; Shimosegawa, Tooru

    2013-01-01

    Pancreatic cancer shows a characteristic tissue structure called desmoplasia, which consists of dense fibrotic stroma surrounding cancer cells. Interactions between pancreatic cancer cells and stromal cells promote invasive growth of cancer cells and establish a specific microenvironment such as hypoxia which further aggravates the malignant behavior of cancer cells. Pancreatic stellate cells (PSCs) play a pivotal role in the development of fibrosis within the pancreatic cancer tissue, and al...

  17. Autophagy/Xenophagy as a survival strategy of cancer cells. The role of Cathepsins

    International Nuclear Information System (INIS)

    Macroautophagy, often referred as to autophagy (self-cannibalism), designates the genetically determined process by which portions of the cytoplasm, organelles and long-lived proteins are engulfed in double-membraned vacuoles (autophagosomes) and sent for lysosomal degradation. Basal levels of autophagy contribute to the maintenance of intracellular homoeostasis by ensuring the turnover of supernumerary, aged and/or damaged components. Under conditions of starvation, the autophagic pathway operates to supply cells with metabolic substrates, and thus represents an important pro-survival mechanism. In cultured cells, the withdrawal of growth factors, known to represent an experimental condition triggering autophagy, can also enhance xeno-cannibalism (xenophagy; xeno is from ancient greek=foreign)

  18. Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis; the role of p53 and p21

    Science.gov (United States)

    Escandell, José M.; Kaler, Pawan; Recio, M. Carmen; Sasazuki, Takehiko; Shirasawa, Senji; Augenlicht, Leonard; Ríos, José-Luis; Klampfer, Lidija

    2008-01-01

    Cucurbitacins have been shown to inhibit proliferation in a variety of cancer cell lines. The aim of this study was to determine their biological activity in colon cancer cell lines that do not harbor activated STAT3, the key target of cucurbitacin. In order to establish the role of activated kRas in the responsiveness of cells to cucurbitacins, we performed experiments in isogenic colon cancer cell lines, HCT116 and Hke-3, which differ only by the presence of an activated kRas allele. We compared the activity of 23, 24-dihydrocucurbitacin B (DHCB) and cucurbitacin R (CCR), two cucurbitacins that we recently isolated, with cucurbitacin I (CCI), a cucurbitacin with established antitumorigenic activity. We showed that cucurbitacins induced dramatic changes in the cytoskeleton (collapse of actin and bundling of tubulin microfilaments), inhibited proliferation and finally induced apoptosis of both HCT116 and Hke3 cells. However, the presence of oncogenic k-Ras significantly decreased the sensitivity of cells to the three cucurbitacins tested, CCR, DHCB and CCI. We confirmed that mutational activation of kRas protects cells from cucurbitacin-induced apoptosis using nontransfromed intestinal epithelial cells with inducible expression of k-RasV12. Cucurbitacins induced the expression of p53 and p21 predominantly in HCT116 cells that harbor mutant Ras. Using HCT116 cells with targeted deletion of p53 or p21 we confirmed that p53 and p21 protect cells from apoptosis induced by cucurbitacins. These results demonstrated that sensitivity of human colon cancer cell lines to cucurbitacins depends on the kRas and p53/p21 status, and established that cucurbitacins can exert antitumorigenic activity in the absence of activated STAT3. PMID:18561895

  19. Focus on the potential role of ficlatuzumab in the treatment of non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    D'Arcangelo M

    2013-03-01

    Full Text Available Manolo D’Arcangelo,1,2 Federico Cappuzzo2 1Cancer Center, University of Colorado, Aurora (CO, USA; 2Department of Oncology, Istituto Toscano Tumori, Ospedale Civile, Livorno, Italy Abstract: Lung cancer treatment has rapidly changed in the last few years thanks to novel insights into cancer biology. Several biomarkers and signaling pathways have been recognized as conceivable targets for treatment, and among them is the mesenchymal–epithelial transition/hepatocyte growth factor (c-MET/HGF axis. Alterations in the c-MET gene and aberrations of MET and HGF expression impact on lung cancer prognosis and are involved in resistance to epidermal growth factor receptor (EGFR inhibitors in non-small cell lung cancer (NSCLC patients harboring activating EGFR mutations. Several anti-MET and anti-HGF strategies are currently under investigation, including monoclonal antibodies. Ficlatuzumab is a monoclonal antibody directed against HGF that is currently under investigation in NSCLC. The aim of the present review is to critically review available data on HGF and ficlatuzumab in NSCLC. Keywords: non-small cell lung cancer, MET, hepatocyte growth factor, ficlatuzumab, AV-299

  20. Dr. Josef Steiner Cancer Research Prize Lecture: the role of physiological cell death in neoplastic transformation and in anti-cancer therapy.

    Science.gov (United States)

    Strasser, A

    1999-05-17

    Cell death is a physiological process which is required for normal development and existence of multi-cellular organisms. Physiological cell death, or apoptosis, is controlled by an evolutionarily conserved mechanism. Abnormalities in this process are implicated as a cause or contributing factor in a variety of diseases. Inhibition of apoptosis can promote neoplastic transformation, particularly in combination with dysregulated cell-cycle control, and can influence the response of tumour cells to anti-cancer therapy. Molecular biological and biochemical approaches are used to find missing cell-death regulators and to define signalling cascades, while experiments in genetically modified mice will identify the essential function of these molecules. Discoveries from cell death research should provide clues for designing therapies for a variety of diseases, including degenerative disorders, auto-immunity and cancer. PMID:10225436

  1. CD133: A cancer stem cells marker, is used in colorectal cancers

    OpenAIRE

    Fei Ren; Wei-Qi Sheng; Xiang Du

    2013-01-01

    Colorectal cancer is one of the most common malignant tumors worldwide. A model of cancer development involving cancer stem cells has been put forward because it provides a possible explanation of tumor hierarchy. Cancer stem cells are characterized by their proliferation, tumorigenesis, differentiation, and self-renewal capacities, and chemoradiotherapy resistance. Due to the role of cancer stem cells in tumor initiation and treatment failure, studies of cancer stem cell markers, such as CD1...

  2. CD24 negative lung cancer cells, possessing partial cancer stem cell properties, cannot be considered as cancer stem cells

    OpenAIRE

    Xu, Haineng; Mu, Jiasheng; Xiao, Jing; Wu, Xiangsong; Li, Maolan; Liu, Tianrun; Liu, Xinyuan

    2015-01-01

    Cancer stem cells (CSCs) play vital role in lung cancer progression, resistance, metastasis and relapse. Identifying lung CSCs makers for lung CSCs targeting researches are critical for lung cancer therapy. In this study, utilizing previous identified lung CSCs as model, we compared the expression of CD24, CD133 and CD44 between CSCs and non-stem cancer cells. Increased ratio of CD24- cells were found in CSCs. CD24- cells were then sorted by flow cytometry and their proliferative ability, che...

  3. Role of lymphangiogenesis in lung cancer.

    Directory of Open Access Journals (Sweden)

    Renata Jankowska

    2010-02-01

    Full Text Available Lung cancer represents one of the most frequent causes of death due to neoplastic disease in Poland and around the world. The high mortality which accompany neoplastic diseases used to be ascribed mainly to dissemination of cancerous cells. Studies on animal models suggest that tumour lymphangiogenesis represents the principal factor in the process of metastases formation. Lymphangiogenesis involves a process of formation of new lymphatic vessels from already existing lymphatic capillaries. Lymphangiogenesis is stimulated by vascular endothelial growth factors (VEGF and other, recently reported factors, such as, e.g., cyclooxygenase 2, fibroblast growth factor 2, angiopoetin-1 and the insulin-resembling growth factor. In lymphangiogenesis a key role is played by neutropilin 2 or podoplanin and this promoted development of studies on lymphangiogenesis. Activation of VEGF-C/VEGF-D/VEGFR-3 axis increases motility and invasiveness of neoplastic cells, promotes development of metastases in several types of tumours such as, e.g., lung cancer, mammary carcinoma, cancers of the neck, prostate and large intestine. In recent years lymphangiogenesis provided topic of many studies. A positive correlation was detected between expressions of VEGF-C/D and VEGFR-3 in non-small cell lung cancer. In patients with lung cancer with high expression of VEGF-C a markedly abbreviated survival was noted. Positive correlation was detected between expression of VEGF-C and VEGF-D on one hand and expression of LYVE-1 on the other in sentinel lymph nodes with metastases of neoplastic cells in patients with non-small cell lung cancer. Also, high density of lymphatic vessels and high density of intraneoplastic microvessels proved to be independent poor prognostic indices in patients with non-small cell lung cancer. Extensive hope is linked to studies on inhibitors of lymphangiogenesis, which may improve results of treatment also in tumour patients.

  4. Role of TGF-β-induced Claudin-4 expression through c-Jun signaling in non-small cell lung cancer.

    Science.gov (United States)

    Rachakonda, Girish; Vu, Trung; Jin, Lin; Samanta, Debangshu; Datta, Pran K

    2016-10-01

    Claudin-4 has been identified as an integral member of tight junctions and has been found to be upregulated in various types of cancers especially in metastatic cancers. However, the molecular mechanism of the upregulation of Claudin-4 and its role in lung tumorigenesis are unknown. The aim of the present study is to investigate the role of Claudin-4 on migration and tumorigenicity of lung cancer cells and to examine the regulatory effects of TGF-β on Claudin-4 expression. We have observed that TGF-β induces the expression of Claudin-4 dramatically in lung cell lines in a time dependent manner. TGF-β-induced Smad signaling is important for enhancing Claudin-4 mRNA level through inducing its promoter activity. Treatment with curcumin, a c-Jun inhibitor, or stable knockdown of c-Jun abrogates TGF-β-induced Claudin-4 expression suggesting an involvement of the c-Jun pathway. Notably, TGF-β-induced Claudin-4 expression through c-Jun pathway plays a role in TGF-β-mediated motility and tumorigenicity of these cells. In support of these observations, we have uncovered that Claudin-4 is upregulated in 14 of 24 (58%) lung tumors when compared with normal lung tissue. This is the first study to show how TGF-β regulates the expression of Claudin-4 through c-Jun signaling and how this pathway contributes to the migratory and tumorigenic phenotype of lung tumor cells. PMID:27424491

  5. Aspirin and salicylic acid decrease c-Myc expression in cancer cells: a potential role in chemoprevention.

    Science.gov (United States)

    Ai, Guoqiang; Dachineni, Rakesh; Muley, Pratik; Tummala, Hemachand; Bhat, G Jayarama

    2016-02-01

    Epidemiological studies have demonstrated a significant correlation between regular aspirin use and reduced colon cancer incidence and mortality; however, the pathways by which it exerts its anti-cancer effects are still not fully explored. We hypothesized that aspirin's anti-cancer effect may occur through downregulation of c-Myc gene expression. Here, we demonstrate that aspirin and its primary metabolite, salicylic acid, decrease the c-Myc protein levels in human HCT-116 colon and in few other cancer cell lines. In total cell lysates, both drugs decreased the levels of c-Myc in a concentration-dependent fashion. Greater inhibition was observed in the nucleus than the cytoplasm, and immunofluorescence studies confirmed these observations. Pretreatment of cells with lactacystin, a proteasome inhibitor, partially prevented the downregulatory effect of both aspirin and salicylic acid, suggesting that 26S proteasomal pathway is involved. Both drugs failed to decrease exogenously expressed DDK-tagged c-Myc protein levels; however, under the same conditions, the endogenous c-Myc protein levels were downregulated. Northern blot analysis showed that both drugs caused a decrease in c-Myc mRNA levels in a concentration-dependent fashion. High-performance liquid chromatography (HPLC) analysis showed that aspirin taken up by cells was rapidly metabolized to salicylic acid, suggesting that aspirin's inhibitory effect on c-Myc may occur through formation of salicylic acid. Our result suggests that salicylic acid regulates c-Myc level at both transcriptional and post-transcription levels. Inhibition of c-Myc may represent an important pathway by which aspirin exerts its anti-cancer effect and decrease the occurrence of cancer in epithelial tissues. PMID:26314861

  6. Prognostic role of syncytin expression in breast cancer

    DEFF Research Database (Denmark)

    Larsson, Lars-Inge; Holck, Susanne; Christensen, Ib Jarle

    2007-01-01

    prognostic indicator for recurrence-free survival. In addition, we examined a second series of 54 consecutively operated breast cancer patients of all categories and the results supported the conclusions made from the first study. Thus, syncytin expression constitutes a positive prognostic factor in breast......Breast cancer cells were recently found to produce syncytin, an endogenous retroviral protein implicated in cell fusion, immune regulation, and nitric oxide synthase expression. To determine whether syncytin has a prognostic role in breast cancer, we investigated a series of 165 premenopausal lymph...... cancer - a phenomenon that may be related to the involvement of syncytin in mediating fusions between breast cancer cells and entodhelial cells....

  7. Role of Caveolin 1, E-Cadherin, Enolase 2 and PKCalpha on resistance to methotrexate in human HT29 colon cancer cells

    DEFF Research Database (Denmark)

    Selga, Elisabet; Morales Torres, Christina; Noé, Véronique;

    2008-01-01

    ABSTRACT: BACKGROUND: Methotrexate is one of the earliest cytotoxic drugs used in cancer therapy, and despite the isolation of multiple other folate antagonists, methotrexate maintains its significant role as a treatment for different types of cancer and other disorders. The usefulness of treatment...... with methotrexate is limited by the development of drug resistance, which may be acquired through different ways. To get insights into the mechanisms associated with drug resistance and sensitization we performed a functional analysis of genes deregulated in methotrexate resistant cells, either due to...

  8. The Role of Histone Deacetylases in Prostate Cancer

    OpenAIRE

    Abbas, Ata; Gupta, Sanjay

    2008-01-01

    Epigenetic modifications play a key role in the patho-physiology of prostate cancer. Histone deacetylases (HDACs) play major roles in prostate cancer progression. HDACs are part of a transcriptional co-repressor complex that influences various tumor suppressor genes. Because of the significant roles played by HDACs in various human cancers, HDAC inhibitors are emerging as a new class of chemotherapeutic agents. HDAC inhibitors have been shown to induce cell growth arrest, differentiation and/...

  9. Fingerprints in cancer cells

    International Nuclear Information System (INIS)

    Gene research has shown that factors causing cancer, or carcinogens, may leave marks typical of each particular carcinogen (fingerprints) in the genotype of the cell. Radiation, for instance, may leave such fingerprints in a cancer cell. In particular, the discovery of a gene called p53 has yielded much new information on fingerprints. It has been discovered, for example, that toxic fungus and UV-radiation each leave fingerprints in the p53 gene. Based on the detection of fingerprints, it may be possible in the future to tell a cancer patient what factor had trigged the maglinancy

  10. Phosphoproteome analysis demonstrates the potential role of THRAP3 phosphorylation in androgen-independent prostate cancer cell growth.

    Science.gov (United States)

    Ino, Yoko; Arakawa, Noriaki; Ishiguro, Hitoshi; Uemura, Hiroji; Kubota, Yoshinobu; Hirano, Hisashi; Toda, Tosifusa

    2016-04-01

    Elucidating the androgen-independent growth mechanism is critical for developing effective treatment strategies to combat androgen-independent prostate cancer. We performed a comparative phosphoproteome analysis using a prostate cancer cell line, LNCaP, and an LNCaP-derived androgen-independent cell line, LNCaP-AI, to identify phosphoproteins involved in this mechanism. We performed quantitative comparisons of the phosphopeptide levels in tryptic digests of protein extracts from these cell lines using MS. We found that the levels of 69 phosphopeptides in 66 proteins significantly differed between LNCaP and LNCaP-AI. In particular, we focused on thyroid hormone receptor associated protein 3 (THRAP3), which is a known transcriptional coactivator of the androgen receptor. The phosphorylation level of THRAP3 was significantly lower at S248 and S253 in LNCaP-AI cells. Furthermore, pull-down assays showed that 32 proteins uniquely bound to the nonphosphorylatable mutant form of THRAP3, whereas 31 other proteins uniquely bound to the phosphorylation-mimic form. Many of the differentially interacting proteins were identified as being involved with RNA splicing and processing. These results suggest that the phosphorylation state of THRAP3 at S248 and S253 might be involved in the mechanism of androgen-independent prostate cancer cell growth by changing the interaction partners. PMID:26841317

  11. EGFR-Ras-Raf Signaling in Epidermal Stem Cells: Roles in Hair Follicle Development, Regeneration, Tissue Remodeling and Epidermal Cancers

    OpenAIRE

    Manuela Baccarini; Christian Rupp; Eszter Doma

    2013-01-01

    The mammalian skin is the largest organ of the body and its outermost layer, the epidermis, undergoes dynamic lifetime renewal through the activity of somatic stem cell populations. The EGFR-Ras-Raf pathway has a well-described role in skin development and tumor formation. While research mainly focuses on its role in cutaneous tumor initiation and maintenance, much less is known about Ras signaling in the epidermal stem cells, which are the main targets of skin carcinogenesis. In this review,...

  12. Head and neck cancer stem cells.

    Science.gov (United States)

    Krishnamurthy, S; Nör, J E

    2012-04-01

    Most cancers contain a small sub-population of cells that are endowed with self-renewal, multipotency, and a unique potential for tumor initiation. These properties are considered hallmarks of cancer stem cells. Here, we provide an overview of the field of cancer stem cells with a focus on head and neck cancers. Cancer stem cells are located in the invasive fronts of head and neck squamous cell carcinomas (HNSCC) close to blood vessels (perivascular niche). Endothelial cell-initiated signaling events are critical for the survival and self-renewal of these stem cells. Markers such as aldehyde dehydrogenase (ALDH), CD133, and CD44 have been successfully used to identify highly tumorigenic cancer stem cells in HNSCC. This review briefly describes the orosphere assay, a method for in vitro culture of undifferentiated head and neck cancer stem cells under low attachment conditions. Notably, recent evidence suggests that cancer stem cells are exquisitely resistant to conventional therapy and are the "drivers" of local recurrence and metastatic spread. The emerging understanding of the role of cancer stem cells in the pathobiology of head and neck squamous cell carcinomas might have a profound impact on the treatment paradigms for this malignancy. PMID:21933937

  13. Prostate cancer stem cells

    OpenAIRE

    Tu, Shi-Ming; Lin, Sue-Hwa

    2011-01-01

    Stem cells have long been implicated in prostate glandular formation. The prostate undergoes regression after androgen deprivation and regeneration after testosterone replacement. Regenerative studies suggest that these cells are found in the proximal ducts and basal layer of the prostate. Many characteristics of prostate cancer indicate that it originates from stem cells. For example, the putative AR− status of prostate stem cells renders them inherently insensitive to androgen blockade ther...

  14. BDNF is associated with SFRP1 expression in luminal and basal-like breast cancer cell lines and primary breast cancer tissues: a novel role in tumor suppression?

    Directory of Open Access Journals (Sweden)

    Laura Huth

    Full Text Available Secreted frizzled related protein 1 (SFRP1 functions as an important inhibitor of the Wnt pathway and is a known tumor suppressor gene, which is epigenetically silenced in a variety of tumors e.g. in breast cancer. However, it is still unclear how SFRP1 exactly affects the Wnt pathway. Our aim was to decipher SFRP1 involvement in biochemical signaling in dependency of different breast cancer subtypes and to identify novel SFRP1-regulated genes. We generated SFRP1 over-expressing in vitro breast cancer models, reflecting the two major subtypes by using basal-like BT20 and luminal-like HER2-positive SKBR3 cells. DNA microarray expression profiling of these models revealed that SFRP1 expression potentially modulates Bone morphogenetic protein- and Smoothened signaling (p<0.01, in addition to the known impact on Wnt signaling. Importantly, further statistical analysis revealed that in dependency of the cancer subtype model SFRP1 may affect the canonical and non-canonical Wnt pathway (p<0.01, respectively. While SFRP1 re-expression generally mediated distinct patterns of transcriptionally induced or repressed genes in BT20 and SKBR3 cells, brain derived neurotrophic factor (BDNF was identified as a SFRP1 induced gene in both cell lines. Although BDNF has been postulated as a putative oncogene, the co-regulation with SFRP1 indicates a potential suppressive function in breast cancer. Indeed, a positive correlation between SFRP1 and BDNF protein expression could be shown (p<0.001 in primary breast cancer samples. Moreover, TCGA dataset based analysis clearly underscores that BDNF mRNA is down-regulated in primary breast cancer samples predicting a poor prognosis of these patients. In line, we functionally provide evidence that stable BDNF re-expression in basal-like BT20 breast cancer cells blocks tumor cell proliferation. Hence, our results suggest that BDNF might rather mediate suppressive than promoting function in human breast cancer whose mode of

  15. The Essential Role of Radiotherapy in the Treatment of Merkel Cell Carcinoma: A Study From the Rare Cancer Network

    International Nuclear Information System (INIS)

    Purpose: To evaluate the role of postoperative radiotherapy (RT) in Merkel cell carcinoma (MCC). Methods and Materials: A retrospective multicenter study was performed in 180 patients with MCC treated between February 1988 and September 2009. Patients who had had surgery alone were compared with patients who received surgery and postoperative RT or radical RT. Local relapse-free survival (LRFS), regional relapse-free survival (RRFS), and distant metastasis-free survival (DMFS) rates were assessed together with disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) rates. Results: Seventy-nine patients were male and 101 patients were female, and the median age was 73 years old (range, 38–93 years). The majority of patients had localized disease (n = 146), and the remaining patients had regional lymph node metastasis (n = 34). Forty-nine patients underwent surgery for the primary tumor without postoperative RT to the primary site; the other 131 patients received surgery for the primary tumor, followed by postoperative RT (n = 118) or a biopsy of the primary tumor followed by radical RT (n = 13). Median follow-up was 5 years (range, 0.2–16.5 years). Patients in the RT group had improved LRFS (93% vs. 64%; p < 0.001), RRFS (76% vs. 27%; p < 0.001), DMFS (70% vs. 42%; p = 0.01), DFS (59% vs. 4%; p < 0.001), and CSS (65% vs. 49%; p = 0.03) rates compared to patients who underwent surgery for the primary tumor alone; LRFS, RRFS, DMFS, and DFS rates remained significant with multivariable Cox regression analysis. However OS was not significantly improved by postoperative RT (56% vs. 46%; p = 0.2). Conclusions: After multivariable analysis, postoperative RT was associated with improved outcome and seems to be an important component in the multimodality treatment of MCC.

  16. The Essential Role of Radiotherapy in the Treatment of Merkel Cell Carcinoma: A Study From the Rare Cancer Network

    Energy Technology Data Exchange (ETDEWEB)

    Ghadjar, Pirus, E-mail: pirus.ghadjar@insel.ch [Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern (Switzerland); Kaanders, Johannes H. [Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Institute of Oncology (Netherlands); Poortmans, Philipp [Department of Radiation Oncology, Institute Verbeeten, Tilburg (Netherlands); Zaucha, Renata [Department of Oncology and Radiotherapy, Medical University, Gdansk (Poland); Krengli, Marco [Department of Radiotherapy, University Hospital Maggiore della Carita, Novara (Italy); Lagrange, Jean L. [Service de Radiotherapie, Hopital Henri-Mondor, Creteil (France); Oezsoy, Orhan [Department of Radiation Oncology, CHCVs-RSV, Sion (Switzerland); Nguyen, Tan D. [Department of Radiation Oncology, Institut Jean Godinot, Reims (France); Miralbell, Raymond [Department of Radiation Oncology, Hopitaux Universitaires de Geneve, Geneva (Switzerland); Baize, Adele [Department de Radio-Oncologie, Institut Jules Bordet, Bruxelles (Belgium); Boujelbene, Noureddine [Department of Radiation Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne (Switzerland); Collen, Timothy [Department of Radiation Oncology, Kantonsspital St. Gallen (Switzerland); Scandolaro, Luciano [Radioterapia, Azienda Ospedale Sant' Anna, Como (Italy); Untereiner, Michel [Centre Francois Baclesse, Luxembourg (Luxembourg); Goldberg, Hadassah [Oncology Departement, Rambam Medical Center, Haifa (Israel); Pesce, Gianfranco A. [Department of Radiation Oncology, Oncology Institute of Southern Switzerland, Opedale San Giovanni, Bellinzona (Switzerland); Anacak, Yavuz [Department of Radiation Oncology, EGE University, Izmir (Turkey); Friedrich, Esther E.; Aebersold, Daniel M. [Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern (Switzerland); Beer, Karl T. [Radio Onkologiezentrum Biel (Switzerland)

    2011-11-15

    Purpose: To evaluate the role of postoperative radiotherapy (RT) in Merkel cell carcinoma (MCC). Methods and Materials: A retrospective multicenter study was performed in 180 patients with MCC treated between February 1988 and September 2009. Patients who had had surgery alone were compared with patients who received surgery and postoperative RT or radical RT. Local relapse-free survival (LRFS), regional relapse-free survival (RRFS), and distant metastasis-free survival (DMFS) rates were assessed together with disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) rates. Results: Seventy-nine patients were male and 101 patients were female, and the median age was 73 years old (range, 38-93 years). The majority of patients had localized disease (n = 146), and the remaining patients had regional lymph node metastasis (n = 34). Forty-nine patients underwent surgery for the primary tumor without postoperative RT to the primary site; the other 131 patients received surgery for the primary tumor, followed by postoperative RT (n = 118) or a biopsy of the primary tumor followed by radical RT (n = 13). Median follow-up was 5 years (range, 0.2-16.5 years). Patients in the RT group had improved LRFS (93% vs. 64%; p < 0.001), RRFS (76% vs. 27%; p < 0.001), DMFS (70% vs. 42%; p = 0.01), DFS (59% vs. 4%; p < 0.001), and CSS (65% vs. 49%; p = 0.03) rates compared to patients who underwent surgery for the primary tumor alone; LRFS, RRFS, DMFS, and DFS rates remained significant with multivariable Cox regression analysis. However OS was not significantly improved by postoperative RT (56% vs. 46%; p = 0.2). Conclusions: After multivariable analysis, postoperative RT was associated with improved outcome and seems to be an important component in the multimodality treatment of MCC.

  17. Role of IGF-1/IGF-1R in regulation of invasion in DU145 prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Setya Hemani

    2008-07-01

    Full Text Available Abstract Background Prostate cancer progression to androgen independence is the primary cause of mortality by this tumor type. The IGF-1/IGF-1R axis is well known to contribute to prostate cancer initiation, but its contribution to invasiveness and the downstream signalling mechanisms that are involved are unclear at present. Results We examined the invasive response of androgen independent DU145 prostate carcinoma cells to IGF-1 stimulation using Matrigel assays. We then examined the signaling mechanisms and protease activities that are associated with this response. IGF-1 significantly increased the invasive capacity of DU145 cells in vitro, and this increase was inhibited by blocking IGF-1R. We further demonstrated that specific inhibitors of the MAPK and PI3-K pathways decrease IGF-1-mediated invasion. To determine potential molecular mechanisms for this change in invasive capacity, we examined changes in expression and activity of matrix metalloproteinases. We observed that IGF-1 increases the enzymatic activity of MMP-2 and MMP-9 in DU145 cells. These changes in activity are due to differences in expression in the case of MMP-9 but not in the case of MMP-2. This observation is corroborated by the fact that correlated changes of expression in a regulator of MMP-2, TIMP-2, were also seen. Conclusion This work identifies a specific effect of IGF-1 on the invasive capacity of DU145 prostate cancer cells, and furthermore delineates mechanisms that contribute to this effect.

  18. Mitochondria, cholesterol and cancer cell metabolism.

    Science.gov (United States)

    Ribas, Vicent; García-Ruiz, Carmen; Fernández-Checa, José C

    2016-12-01

    Given the role of mitochondria in oxygen consumption, metabolism and cell death regulation, alterations in mitochondrial function or dysregulation of cell death pathways contribute to the genesis and progression of cancer. Cancer cells exhibit an array of metabolic transformations induced by mutations leading to gain-of-function of oncogenes and loss-of-function of tumor suppressor genes that include increased glucose consumption, reduced mitochondrial respiration, increased reactive oxygen species generation and cell death resistance, all of which ensure cancer progression. Cholesterol metabolism is disturbed in cancer cells and supports uncontrolled cell growth. In particular, the accumulation of cholesterol in mitochondria emerges as a molecular component that orchestrates some of these metabolic alterations in cancer cells by impairing mitochondrial function. As a consequence, mitochondrial cholesterol loading in cancer cells may contribute, in part, to the Warburg effect stimulating aerobic glycolysis to meet the energetic demand of proliferating cells, while protecting cancer cells against mitochondrial apoptosis due to changes in mitochondrial membrane dynamics. Further understanding the complexity in the metabolic alterations of cancer cells, mediated largely through alterations in mitochondrial function, may pave the way to identify more efficient strategies for cancer treatment involving the use of small molecules targeting mitochondria, cholesterol homeostasis/trafficking and specific metabolic pathways. PMID:27455839

  19. Cell of origin of lung cancer

    Directory of Open Access Journals (Sweden)

    Jennifer M Hanna

    2013-01-01

    Full Text Available Lung cancer is the leading cause of cancer deaths worldwide, and current therapies are disappointing. Elucidation of the cell(s of origin of lung cancer may lead to new therapeutics. In addition, the discovery of putative cancer-initiating cells with stem cell properties in solid tumors has emerged as an important area of cancer research that may explain the resistance of these tumors to currently available therapeutics. Progress in our understanding of normal tissue stem cells, tumor cell of origin, and cancer stem cells has been hampered by the heterogeneity of the disease, the lack of good in vivo transplantation models to assess stem cell behavior, and an overall incomplete understanding of the epithelial stem cell hierarchy. As such, a systematic computerized literature search of the MEDLINE database was used to identify articles discussing current knowledge about normal lung and lung cancer stem cells or progenitor cells. In this review, we discuss what is currently known about the role of cancer-initiating cells and normal stem cells in the development of lung tumors.

  20. Characterization of adult α- and β-globin elevated by hydrogen peroxide in cervical cancer cells that play a cytoprotective role against oxidative insults.

    Directory of Open Access Journals (Sweden)

    Xiaolei Li

    Full Text Available OBJECTIVES: Hemoglobin (Hgb is the main oxygen and carbon dioxide carrier in cells of erythroid lineage and is responsible for oxygen delivery to the respiring tissues of the body. However, Hgb is also expressed in nonerythroid cells. In the present study, the expression of Hgb in human uterine cervix carcinoma cells and its role in cervical cancer were investigated. METHODOLOGY: The expression level of Hgb in cervical cancer tissues was assessed by quantitative reverse transcriptase-PCR (qRT-PCR. We applied multiple methods, such as RT-PCR, immunoblotting, and immunohistochemical analysis, to confirm Hgb expression in cervical cancer cells. The effects of ectopic expression of Hgb and Hgb mutants on oxidative stress and cell viability were investigated by cellular reactive oxygen species (ROS analysis and lactate dehydrogenase (LDH array, respectively. Both Annexin V staining assay by flow cytometry and caspase-3 activity assay were used, respectively, to evaluate cell apoptosis. RESULTS: qRT-PCR analysis showed that Hgb-α- (HBA1 and Hgb-β-globin (HBB gene expression was significantly higher in cervical carcinoma than in normal cervical tissues, whereas the expression of hematopoietic transcription factors and erythrocyte specific marker genes was not increased. Immunostaining experiments confirmed the expression of Hgb in cancer cells of the uterine cervix. Hgb mRNA and protein were also detected in the human cervical carcinoma cell lines SiHa and CaSki, and Hgb expression was up-regulated by hydrogen peroxide-induced oxidative stress. Importantly, ectopic expression of wild type HBA1/HBB or HBA1, rather than mutants HBA1(H88R/HBB(H93R unable to bind hemo, suppressed oxidative stress and improved cell viability. CONCLUSIONS: The present findings show for the first time that Hgb is expressed in cervical carcinoma cells and may act as an antioxidant, attenuating oxidative stress-induced damage in cervical cancer cells. These data provide a

  1. The regulatory role of nickel on H3K27 demethylase JMJD3 in kidney cancer cells.

    Science.gov (United States)

    Guo, Xiaoqiang; Zhang, Yanmin; Zhang, Qiang; Fa, Pingping; Gui, Yaoting; Gao, Guoquan; Cai, Zhiming

    2014-11-26

    Nickel compounds are an important class of environmental pollutants and carcinogens. Chronic exposure to nickel compounds has been connected with increased risks of numerous cancers, including lung and kidney cancers. But the precise mechanism by which nickel compounds exert their carcinogenic properties is not completely understood. In this study, kidney cancer cells namely human embryonic kidney 293-containing SV40 large T-antigen (HEK293T) and 786-0 were incubated with various concentrations of nickel chloride for 24 h before analysing the expression of three histone H3K27 methylation-modifying enzymes and H3K27me3 using quantitative real-time polymerase chain reaction, Western blot and immunofluorescence analyses. Our results showed that incubation of nickel chloride upregulated the expression of H3K27me3 demethylase jumonji domain-containing protein 3 (JMJD3) in kidney cancer cells, which was accompanied by the reduction in the protein level of H3K27me3. Enhanced demethylation of H3K27me3 may represent a novel mechanism underlying the carcinogenicity of nickel compounds. PMID:25427687

  2. The role of vascular endothelial growth factor in the tissue specific in vivo growth of prostate cancer cells.

    Science.gov (United States)

    Krupski, T; Harding, M A; Herce, M E; Gulding, K M; Stoler, M H; Theodorescu, D

    2001-01-01

    Despite the fact that cancer cells can be found in many vascular beds, continued growth of the metastatic tumor focus exhibits a significant degree of 'organ tropism', with only certain organs exhibiting the ravages of metastatic disease. Since a limiting factor to the growth of metastases beyond 2 mm in diameter, may be a lack of angiogenesis, we sought to determine whether tumor overexpression of vascular endothelial growth factor (VEGF), a potent angiogenic factor related to prostate cancer metastasis, is causally related to organ specific tumor growth in a prostate cancer xenograft model. LnCaP-C4-2 is a subline of the human prostate cancer cell line LnCaP which unlike its parent, has a predilection for growth in bone, a common site for human prostate cancer metastasis. LnCaP-C4-2, is tumorigenic when injected intrafemorally in mice but requires co-injection of stromal components (Matrigel) to be tumorigenic in the subcutaneous site. Because of this site-specific tumorigenicity profile and relatively low VEGF mRNA and protein expression, this line was transfected with a full length cDNA encoding the 165 isoform of VEGF. Cells either overexpressing or not expressing the transfected gene were selected for study in vivo and in vitro. Overexpression of VEGF did not seem to affect in vitro cell growth. Such overexpression did affect tumorigenicity and in vivo tumor growth rates when cells were inoculated in the subcutaneus site. Interestingly, the dependency of subcutaneous tumorigenicity on Matrigel co-inoculation was still observed in cells overexpressing VEGF. In contrast to the impact that VEGF overexpression has on subcutaneous tumorigenicity, no such effect was observed when cells were inoculated in orthotopic/prostate (primary) or intrafemoral (metastatic) sites. In view of the importance of tumor-stromal interactions in growth of xenografts, we sought to determine if the host strain is important to the observed tumorigenicity effects of VEGF overexpression

  3. Cancer Stem Cells in Pancreatic Cancer

    International Nuclear Information System (INIS)

    Pancreatic cancer is an aggressive malignant solid tumor well-known by early metastasis, local invasion, resistance to standard chemo- and radiotherapy and poor prognosis. Increasing evidence indicates that pancreatic cancer is initiated and propagated by cancer stem cells (CSCs). Here we review the current research results regarding CSCs in pancreatic cancer and discuss the different markers identifying pancreatic CSCs. This review will focus on metastasis, microRNA regulation and anti-CSC therapy in pancreatic cancer

  4. EGFR-Ras-Raf Signaling in Epidermal Stem Cells: Roles in Hair Follicle Development, Regeneration, Tissue Remodeling and Epidermal Cancers

    Directory of Open Access Journals (Sweden)

    Manuela Baccarini

    2013-09-01

    Full Text Available The mammalian skin is the largest organ of the body and its outermost layer, the epidermis, undergoes dynamic lifetime renewal through the activity of somatic stem cell populations. The EGFR-Ras-Raf pathway has a well-described role in skin development and tumor formation. While research mainly focuses on its role in cutaneous tumor initiation and maintenance, much less is known about Ras signaling in the epidermal stem cells, which are the main targets of skin carcinogenesis. In this review, we briefly discuss the properties of the epidermal stem cells and review the role of EGFR-Ras-Raf signaling in keratinocyte stem cells during homeostatic and pathological conditions.

  5. Cancer Stem Cells and Side Population Cells in Breast Cancer and Metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Britton, Kelly M. [Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle-upon-Tyne, NE1 3BZ (United Kingdom); Kirby, John A. [Institute of Cellular Medicine, Newcastle University, 3rd Floor William Leech Building, Framlington Place, Newcastle-upon-Tyne, NE2 4HH (United Kingdom); Lennard, Thomas W.J. [Faculty of Medical Sciences, Newcastle University, 3rd Floor William Leech Building, Framlington Place, Newcastle-upon-Tyne, NE2 4HH (United Kingdom); Meeson, Annette P., E-mail: annette.meeson@ncl.ac.uk [Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle-upon-Tyne, NE1 3BZ (United Kingdom); North East England Stem Cell Institute, Bioscience Centre, International Centre for Life, Central Parkway, Newcastle-upon-Tyne, NE1 3BZ (United Kingdom)

    2011-04-19

    In breast cancer it is never the primary tumour that is fatal; instead it is the development of metastatic disease which is the major cause of cancer related mortality. There is accumulating evidence that suggests that Cancer Stem Cells (CSC) may play a role in breast cancer development and progression. Breast cancer stem cell populations, including side population cells (SP), have been shown to be primitive stem cell-like populations, being long-lived, self-renewing and highly proliferative. SP cells are identified using dual wavelength flow cytometry combined with Hoechst 33342 dye efflux, this ability is due to expression of one or more members of the ABC transporter family. They have increased resistance to chemotherapeutic agents and apoptotic stimuli and have increased migratory potential above that of the bulk tumour cells making them strong candidates for the metastatic spread of breast cancer. Treatment of nearly all cancers usually involves one first-line agent known to be a substrate of an ABC transporter thereby increasing the risk of developing drug resistant tumours. At present there is no marker available to identify SP cells using immunohistochemistry on breast cancer patient samples. If SP cells do play a role in breast cancer progression/Metastatic Breast Cancer (MBC), combining chemotherapy with ABC inhibitors may be able to destroy both the cells making up the bulk tumour and the cancer stem cell population thus preventing the risk of drug resistant disease, recurrence or metastasis.

  6. Cancer Stem Cells and Side Population Cells in Breast Cancer and Metastasis

    International Nuclear Information System (INIS)

    In breast cancer it is never the primary tumour that is fatal; instead it is the development of metastatic disease which is the major cause of cancer related mortality. There is accumulating evidence that suggests that Cancer Stem Cells (CSC) may play a role in breast cancer development and progression. Breast cancer stem cell populations, including side population cells (SP), have been shown to be primitive stem cell-like populations, being long-lived, self-renewing and highly proliferative. SP cells are identified using dual wavelength flow cytometry combined with Hoechst 33342 dye efflux, this ability is due to expression of one or more members of the ABC transporter family. They have increased resistance to chemotherapeutic agents and apoptotic stimuli and have increased migratory potential above that of the bulk tumour cells making them strong candidates for the metastatic spread of breast cancer. Treatment of nearly all cancers usually involves one first-line agent known to be a substrate of an ABC transporter thereby increasing the risk of developing drug resistant tumours. At present there is no marker available to identify SP cells using immunohistochemistry on breast cancer patient samples. If SP cells do play a role in breast cancer progression/Metastatic Breast Cancer (MBC), combining chemotherapy with ABC inhibitors may be able to destroy both the cells making up the bulk tumour and the cancer stem cell population thus preventing the risk of drug resistant disease, recurrence or metastasis

  7. Pregnancy and its role in breast cancer

    Directory of Open Access Journals (Sweden)

    Filipe Correia Martins

    2011-12-01

    Full Text Available Early full-term pregnancy is the only recognized factor able to prevent breast cancer. There are several hypotheses to explain the mechanisms of this protection, namely an altered hormonal milieu, a differentiation process or a switch in stem cell properties. To explore them, authors have been using animal models, mainly in rodents. Hormonal administration with estrogen and progesterone was the most widely used process to mimic the mammary changes during pregnancy. We have recently proposed that this enigmatic protective role of a full-term birth in breast cancer is carried out by tumor inhibition mediated by differentiated mammary epithelial cells. This explanation may give a new perspective of breast cancer prevention and treatment.

  8. Role of ornithine decarboxylase in regulation of estrogen receptor alpha expression and growth in human breast cancer cells

    OpenAIRE

    Zhu, Qingsong; Jin, Lihua; CASERO, ROBERT A.; Davidson, Nancy E.; Huang, Yi

    2012-01-01

    Our previous studies demonstrated that specific polyamine analogues, oligoamines, down-regulated the activity of a key polyamine biosynthesis enzyme, ornithine decarboxylase (ODC), and suppressed expression of estrogen receptor alpha (ERα) in human breast cancer cells. However, the mechanism underlying the potential regulation of ERα expression by polyamine metabolism has not been explored. Here, we demonstrated that RNAi-mediated knockdown of ODC (ODC KD) down-regulated the polyamine pool, a...

  9. Proteomic analysis of media from lung cancer cells reveals role of 14-3-3 proteins in cachexia

    OpenAIRE

    Julie B. McLean; Moylan, Jennifer S.; Horrell, Erin M. W.; Andrade, Francisco H.

    2015-01-01

    Aims: At the time of diagnosis, 60% of lung cancer patients present with cachexia, a severe wasting syndrome that increases morbidity and mortality. Tumors secrete multiple factors that contribute to cachectic muscle wasting, and not all of these factors have been identified. We used Orbitrap electrospray ionization mass spectrometry to identify novel cachexia-inducing candidates in media conditioned with Lewis lung carcinoma cells (LCM). Results: One-hundred and 58 proteins were confirmed in...

  10. Roles of WIP and WICH/WIRE proteins in formation and maturation of invasive protrusions in human breast cancer cells

    OpenAIRE

    García González, Esther

    2014-01-01

    Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 14-03-2014 Metastasis is a multistep process wherein cancer cells separate from the primary tumour, cross the surrounding extracellular matrix (ECM), and disperse throughout the body to reach distant tissues where they proliferate and establish themselves as a secondary tumour. Metastasis involves several intracellular processes including s...

  11. Glucose restriction decreases telomerase activity and enhances its inhibitor response on breast cancer cells: possible extra-telomerase role of BIBR 1532

    OpenAIRE

    Wardi, Layal; Alaaeddine, Nada; Raad, Issam; Sarkis, Riad; Serhal, Rim; Khalil, Charbel; Hilal, George

    2014-01-01

    Background Considerable progress has been made to understand the association between lifestyle and diet in cancer initiation and promotion. Because excessive glucose consumption is a key metabolic hallmark of cancer cells, glucose restriction (GR) decreases the proliferation, and promotes the differentiation and transformation of cancer cells to quiescent cells. The immortality of cancerous cells is largely assured by telomerase, which is an interesting target for inhibition by BIBR 1532. In ...

  12. Targeting prostate cancer stem cells for cancer therapy

    OpenAIRE

    Wang, Guocan; Wang, Zhiwei; Sarkar, Fazlul H; Wei, Wenyi

    2012-01-01

    Prostate cancer (PCa) is the most common malignant neoplasm in men and the second most frequent cause of cancer death for males in the United States. Recently, emerging evidence suggests that prostate cancer stem cells (CSCs) may play a critical role in the development and progression of PCa. Therefore, targeting prostate CSCs for the prevention of tumor progression and treatment of PCa could become a novel strategy for better treatment of patients diagnosed with PCa. In this review article, ...

  13. Cancer Stem Cells

    OpenAIRE

    Aurelio Lorico; Eric Deutsch; Bo Lu; Shih-Hwa Chiou

    2011-01-01

    Cancer Stem Cells (CSCs) are a small subpopulation of cells within tumors with capabilities of self-renewal, differentiation, and tumorigenicity when transplanted into an animal host. A number of cell surface markers such as CD44, CD24, and CD133 are often used to identify and enrich CSCs. A regulatory network consisting of microRNAs and Wnt/β-catenin, Notch, and Hedgehog signaling pathways controls the CSC properties. The clinical relevance of CSCs has been strengthened by emerging evidence,...

  14. Role of lysosomes in cancer therapy

    Directory of Open Access Journals (Sweden)

    Halaby R

    2015-09-01

    Full Text Available Reginald Halaby Department of Biology, Montclair State University, Montclair, NJ, USA Abstract: Lysosomes are acidic organelles that are involved in cellular digestion by endocytosis, phagocytosis, and autophagy. They contain more than 50 hydrolases that are capable of degrading all macromolecules. There is accumulating evidence that lysosomal enzymes can provoke apoptotic cell death. This has important implications for cancer, where proapoptotic genes are mutated and antiapoptotic genes are often overexpressed leading to chemoresistance. Lysosomes play a dual role in cancer development depending on their subcellular localization. When they are located extracellularly they can promote invasion, angiogenesis, and metastasis. However, when they are located intracellularly they can trigger apoptosis by leaking into the cytosol. In this review, we examine the pathways by which lysosomes can evoke both apoptosis and tumorigenesis. Although cancer cells have defects in their apoptotic machinery, they can still undergo lysosomal cell death. We offer several strategies to explain how targeting lysosomes can serve as a putative model for the development of novel anticancer agents. Furthermore, we propose that lysosomal cell death is an effective treatment against apoptosis-resistant cancer cells and thus holds great potential as a therapeutic strategy for circumventing apoptosis deficiency in tumors. Keywords: cathepsins, lysosomal membrane permeability, apoptosis, chemoresistance 

  15. Personalized treatment strategies for non-small-cell lung cancer in Chinese patients: the role of crizotinib

    Directory of Open Access Journals (Sweden)

    Niu FY

    2015-05-01

    Full Text Available Fei-Yu Niu,1,2 Yi-Long Wu2 1Graduate School, Southern Medical University, Guangzhou, People’s Republic of China; 2Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China Abstract: Anaplastic lymphoma kinase (ALK rearrangement is an oncogene targeted with approved drugs second to epidermal growth factor receptor (EGFR in lung cancer. Crizotinib was developed and introduced into clinical practice rapidly and successfully after the discovery of ALK rearrangement in non-small-cell lung cancer. Chinese and other Asian patients treated with crizotinib seem to have lower toxicity and higher efficacy compared with other ethnicities. Crizotinib showed potent antitumor activity and manageable toxicity in mesenchymal–epithelial transition factor (c-Met/ROS1-positive non-small-cell lung cancer patients, but prospective clinical trials are still needed to confirm its efficacy and safety. Crizotinib appears to be effective against tumors originating from various organs that harbor ALK abnormalities. In the near future, we would classify the tumors by their genetic information beyond organs, such as ALKoma, EGFRoma, and RAFoma, and a single compound could be used for many different types of cancer in different organs. The major challenge of the widespread use of crizotinib in clinical practice is establishing convenient diagnostic techniques for the detection of ALK/c-Met/ROS1. In the present study, we reviewed the application of crizotinib in Chinese patients. Keywords: NSCLC, crizotinib, ALK, c-Met, ROS1

  16. Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Hamada, Shin [Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai (Japan); Masamune, Atsushi, E-mail: amasamune@med.tohoku.ac.jp [Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai (Japan); Takikawa, Tetsuya; Suzuki, Noriaki; Kikuta, Kazuhiro; Hirota, Morihisa [Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai (Japan); Hamada, Hirofumi [Laboratory of Oncology, Department of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji (Japan); Kobune, Masayoshi [Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo (Japan); Satoh, Kennichi [Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori (Japan); Shimosegawa, Tooru [Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai (Japan)

    2012-05-04

    Highlights: Black-Right-Pointing-Pointer Pancreatic stellate cells (PSCs) promote the progression of pancreatic cancer. Black-Right-Pointing-Pointer Pancreatic cancer cells co-cultured with PSCs showed enhanced spheroid formation. Black-Right-Pointing-Pointer Expression of stem cell-related genes ABCG2, Nestin and LIN28 was increased. Black-Right-Pointing-Pointer Co-injection of PSCs enhanced tumorigenicity of pancreatic cancer cells in vivo. Black-Right-Pointing-Pointer This study suggested a novel role of PSCs as a part of the cancer stem cell niche. -- Abstract: The interaction between pancreatic cancer cells and pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, is receiving increasing attention. There is accumulating evidence that PSCs promote the progression of pancreatic cancer by increasing cancer cell proliferation and invasion as well as by protecting them from radiation- and gemcitabine-induced apoptosis. Recent studies have identified that a portion of cancer cells, called 'cancer stem cells', within the entire cancer tissue harbor highly tumorigenic and chemo-resistant phenotypes, which lead to the recurrence after surgery or re-growth of the tumor. The mechanisms that maintain the 'stemness' of these cells remain largely unknown. We hypothesized that PSCs might enhance the cancer stem cell-like phenotypes in pancreatic cancer cells. Indirect co-culture of pancreatic cancer cells with PSCs enhanced the spheroid-forming ability of cancer cells and induced the expression of cancer stem cell-related genes ABCG2, Nestin and LIN28. In addition, co-injection of PSCs enhanced tumorigenicity of pancreatic cancer cells in vivo. These results suggested a novel role of PSCs as a part of the cancer stem cell niche.

  17. Cysteine-rich secretory protein 3 plays a role in prostate cancer cell invasion and affects expression of PSA and ANXA1.

    Science.gov (United States)

    Pathak, Bhakti R; Breed, Ananya A; Apte, Snehal; Acharya, Kshitish; Mahale, Smita D

    2016-01-01

    Cysteine-rich secretory protein 3 (CRISP-3) is upregulated in prostate cancer as compared to the normal prostate tissue. Higher expression of CRISP-3 has been linked to poor prognosis and hence it has been thought to act as a prognostic marker for prostate cancer. It is proposed to have a role in innate immunity but its role in prostate cancer is still unknown. In order to understand its function, its expression was stably knocked down in LNCaP cells. CRISP-3 knockdown did not affect cell viability but resulted in reduced invasiveness. Global gene expression changes upon CRISP-3 knockdown were identified by microarray analysis. Microarray data were quantitatively validated by evaluating the expression of seven candidate genes in three independent stable clones. Functional annotation of the differentially expressed genes identified cell adhesion, cell motility, and ion transport to be affected among other biological processes. Prostate-specific antigen (PSA, also known as Kallikrein 3) was the top most downregulated gene whose expression was also validated at protein level. Interestingly, expression of Annexin A1 (ANXA1), a known anti-inflammatory protein, was upregulated upon CRISP-3 knockdown. Re-introduction of CRISP-3 into the knockdown clone reversed the effect on invasiveness and also led to increased PSA expression. These results suggest that overexpression of CRISP-3 in prostate tumor may maintain higher PSA expression and lower ANXA1 expression. Our data also indicate that poor prognosis associated with higher CRISP-3 expression could be due to its role in cell invasion. PMID:26369530

  18. The role of prophylactic cranial irradiation in regionally advanced non-small cell lung cancer. A Southwest Oncology Group Study

    Energy Technology Data Exchange (ETDEWEB)

    Rusch, V.W.; Griffin, B.R.; Livingston, R.B. (Univ. of Washington, Seattle (USA))

    1989-10-01

    Lung cancer is the most common malignant disease in the United States. Only the few tumors detected very early are curable, but there has been some progress in the management of more advanced non-small cell lung cancer, particularly in regionally inoperable disease. Prevention of central nervous system relapse is an important issue in this group of patients because brain metastases ultimately develop in 20% to 25% of them. Seventy-three patients with regionally advanced non-small cell lung cancer were entered into a Phase II trial of neutron chest radiotherapy sandwiched between four cycles of chemotherapy including cisplatin, vinblastine, and mitomycin C. Prophylactic cranial irradiation was administered concurrently with chest radiotherapy (3000 cGy in 10 fractions in 15 patients; 3600 cGy in 18 fractions in the remaining 50 patients). Patients underwent computed tomographic scan of the brain before treatment and every 3 months after treatment. The initial overall response rate was 79%, but 65 of the 73 patients have subsequently died of recurrent disease. Median follow-up is 9 months for all 73 patients and 26 months for eight long-term survivors. No patient who completed the prophylactic cranial irradiation program had clinical or radiologic brain metastases. Toxic reactions to prophylactic cranial irradiation included reversible alopecia in all patients, progressive dementia in one patient, and possible optic neuritis in one patient. Both of these patients received 300 cGy per fraction of irradiation. The use of prophylactic cranial irradiation has been controversial, but its safety and efficacy in this trial supports its application in a group of patients at high risk for central nervous system relapse. Further evaluation of prophylactic cranial irradiation in clinical trials for regionally advanced non-small cell lung cancer is warranted.

  19. The role of prophylactic cranial irradiation in regionally advanced non-small cell lung cancer. A Southwest Oncology Group Study

    International Nuclear Information System (INIS)

    Lung cancer is the most common malignant disease in the United States. Only the few tumors detected very early are curable, but there has been some progress in the management of more advanced non-small cell lung cancer, particularly in regionally inoperable disease. Prevention of central nervous system relapse is an important issue in this group of patients because brain metastases ultimately develop in 20% to 25% of them. Seventy-three patients with regionally advanced non-small cell lung cancer were entered into a Phase II trial of neutron chest radiotherapy sandwiched between four cycles of chemotherapy including cisplatin, vinblastine, and mitomycin C. Prophylactic cranial irradiation was administered concurrently with chest radiotherapy (3000 cGy in 10 fractions in 15 patients; 3600 cGy in 18 fractions in the remaining 50 patients). Patients underwent computed tomographic scan of the brain before treatment and every 3 months after treatment. The initial overall response rate was 79%, but 65 of the 73 patients have subsequently died of recurrent disease. Median follow-up is 9 months for all 73 patients and 26 months for eight long-term survivors. No patient who completed the prophylactic cranial irradiation program had clinical or radiologic brain metastases. Toxic reactions to prophylactic cranial irradiation included reversible alopecia in all patients, progressive dementia in one patient, and possible optic neuritis in one patient. Both of these patients received 300 cGy per fraction of irradiation. The use of prophylactic cranial irradiation has been controversial, but its safety and efficacy in this trial supports its application in a group of patients at high risk for central nervous system relapse. Further evaluation of prophylactic cranial irradiation in clinical trials for regionally advanced non-small cell lung cancer is warranted

  20. The role of innate immunity in spontaneous regression of cancer

    Directory of Open Access Journals (Sweden)

    J A Thomas

    2011-01-01

    Full Text Available Nature has provided us with infections - acute and chronic - and these infections have both harmful and beneficial effects on the human system. Worldwide, a number of chronic infections are associated with a risk of cancer, but it is also known that cancer regresses when associated with acute infections such as bacterial, viral, fungal, protozoal, etc. Acute infections are known to cure chronic diseases since the time of Hippocrates. The benefits of these fever producing acute infections has been applied in cancer vaccinology such as the Coley′s toxins. Immune cells like the natural killer cells, macrophages and dendritic cells have taken greater precedence in cancer immunity than ever before. This review provides an insight into the benefits of fever and its role in prevention of cancer, the significance of common infections in cancer regression, the dual nature of our immune system and the role of the often overlooked primary innate immunity in tumor immunology and spontaneous regression of cancer.

  1. Essential roles of the interaction between cancer cell-derived chemokine, CCL4, and intra-bone CCR5-expressing fibroblasts in breast cancer bone metastasis.

    Science.gov (United States)

    Sasaki, Soichiro; Baba, Tomohisa; Nishimura, Tatsunori; Hayakawa, Yoshihiro; Hashimoto, Shin-Ichi; Gotoh, Noriko; Mukaida, Naofumi

    2016-08-01

    From a murine breast cancer cell line, 4T1, we established a subclone, 4T1.3, which consistently metastasizes to bone upon its injection into the mammary fat pad. 4T1.3 clone exhibited similar proliferation rate and migration capacity as the parental clone. However, the intra-bone injection of 4T1.3 clone caused larger tumors than that of the parental cells, accompanied with increases in fibroblast, but not osteoclast or osteoblast numbers. 4T1.3 clone displayed an enhanced expression of a chemokine, CCL4, but not its specific receptor, CCR5. CCL4 shRNA-transfection of 4T1.3 clone had few effects on its in vitro properties, but reduced the tumorigenicity arising from the intra-bone injection. Moreover, intra-bone injection of 4T1.3 clone caused smaller tumors in mice deficient in CCR5 or those receiving CCR5 antagonist than in wild-type mice. The reduced tumor formation was associated with attenuated accumulation of CCR5-positive fibroblasts expressing connective tissue growth factor (CTGF)/CCN2. Tumor cell-derived CCL4 could induce fibroblasts to express CTGF/CCN2, which could support 4T1.3 clone proliferation under hypoxic culture conditions. Thus, the CCL4-CCR5 axis can contribute to breast cancer metastasis to bone by mediating the interaction between cancer cells and fibroblasts in bone cavity. PMID:27177471

  2. Cancer Stem Cells in Breast Cancer

    OpenAIRE

    Fumitaka Takeshita; Tomohiro Fujiwara; Takahiro Ochiya; Makiko Ono; Ryou-u Takahashi

    2011-01-01

    The cancer stem cell (CSC) theory is generally acknowledged as an important field of cancer research, not only as an academic matter but also as a crucial aspect of clinical practice. CSCs share a variety of biological properties with normal somatic stem cells in self-renewal, the propagation of differentiated progeny, the expression of specific cell markers and stem cell genes, and the utilization of common signaling pathways and the stem cell niche. However, CSCs differ from normal stem cel...

  3. Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells

    International Nuclear Information System (INIS)

    Highlights: ► Pancreatic stellate cells (PSCs) promote the progression of pancreatic cancer. ► Pancreatic cancer cells co-cultured with PSCs showed enhanced spheroid formation. ► Expression of stem cell-related genes ABCG2, Nestin and LIN28 was increased. ► Co-injection of PSCs enhanced tumorigenicity of pancreatic cancer cells in vivo. ► This study suggested a novel role of PSCs as a part of the cancer stem cell niche. -- Abstract: The interaction between pancreatic cancer cells and pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, is receiving increasing attention. There is accumulating evidence that PSCs promote the progression of pancreatic cancer by increasing cancer cell proliferation and invasion as well as by protecting them from radiation- and gemcitabine-induced apoptosis. Recent studies have identified that a portion of cancer cells, called “cancer stem cells”, within the entire cancer tissue harbor highly tumorigenic and chemo-resistant phenotypes, which lead to the recurrence after surgery or re-growth of the tumor. The mechanisms that maintain the “stemness” of these cells remain largely unknown. We hypothesized that PSCs might enhance the cancer stem cell-like phenotypes in pancreatic cancer cells. Indirect co-culture of pancreatic cancer cells with PSCs enhanced the spheroid-forming ability of cancer cells and induced the expression of cancer stem cell-related genes ABCG2, Nestin and LIN28. In addition, co-injection of PSCs enhanced tumorigenicity of pancreatic cancer cells in vivo. These results suggested a novel role of PSCs as a part of the cancer stem cell niche.

  4. Low immunogenicity in non-small cell lung cancer; do new developments and novel treatments have a role?

    Science.gov (United States)

    Gardiner, R E; Jahangeer, S; Forde, P; Ariffin, A B; Bird, B; Soden, D; Hinchion, J

    2015-03-01

    Approximately 1.6 million new cases of lung cancer are diagnosed annually (Jemal et al. CA: A Cancer Journal for Clinicians, 61, 69-90, 2011) and it remains the leading cause of cancer-related mortality worldwide. Despite decades of bench and clinical research to attempt to improve outcome for locally advanced, good performance status patients, the 5-year survival remains less than 15 % (Molina et al. 2008). Immune checkpoint inhibitor (ICH) therapies have shown a significant promise in preclinical and clinical trails to date in the treatment of non-small cell lung cancer (NSCLC). The idea of combining these systemic immune therapies with local ablative techniques is one that is gaining momentum. Electrochemotherapy (ECT) is a unique atraumatic local therapy that has had very promising objective response rates and a number of advantages including but not limited to its immunostimulatory effects. ECT in combination with ICHs offers a novel approach for dealing with this difficult disease process. PMID:25726003

  5. Structure-activity relationship and role of oxygen in the potential antitumour activity of fluoroquinolones in human epithelial cancer cells.

    Science.gov (United States)

    Perucca, Paola; Savio, Monica; Cazzalini, Ornella; Mocchi, Roberto; Maccario, Cristina; Sommatis, Sabrina; Ferraro, Daniela; Pizzala, Roberto; Pretali, Luca; Fasani, Elisa; Albini, Angelo; Stivala, Lucia Anna

    2014-11-01

    The photobehavior of ciprofloxacin, lomefloxacin and ofloxacin fluoroquinolones was investigated using several in vitro methods to assess their cytotoxic, antiproliferative, and genotoxic potential against two human cancer cell lines. We focused our attention on the possible relationship between their chemical structure, O₂ partial pressure and photobiological activity on cancer cells. The three molecules share the main features of most fluoroquinolones, a fluorine in 6 and a piperazino group in 7, but differ at the key position 8, unsubstituted in ciprofloxacin, a fluorine in lomefloxacin and an alkoxy group in ofloxacin. Studies in solution show that ofloxacin has a low photoreactivity; lomefloxacin reacts via aryl cation, ciprofloxacin reacts but not via the cation. In our experiments, ciprofloxacin and lomefloxacin showed a high and comparable potential for photodamaging cells and DNA. Lomefloxacin appeared the most efficient molecule in hypoxia, acting mainly against tumour cell proliferation and generating DNA plasmid photocleavage. Although our results do not directly provide evidence that a carbocation is involved in photodamage induced by lomefloxacin, our data strongly support this hypothesis. This may lead to new and more efficient anti-tumour drugs involving a cation in their mechanism of action. This latter acting independently of oxygen, can target hypoxic tumour tissue. PMID:25105482

  6. Novel roles for LIX1L in promoting cancer cell proliferation through ROS1-mediated LIX1L phosphorylation.

    Science.gov (United States)

    Nakamura, Satoki; Kahyo, Tomoaki; Tao, Hong; Shibata, Kiyoshi; Kurabe, Nobuya; Yamada, Hidetaka; Shinmura, Kazuya; Ohnishi, Kazunori; Sugimura, Haruhiko

    2015-01-01

    Herein, we report the characterization of Limb expression 1-like, (LIX1L), a putative RNA-binding protein (RBP) containing a double-stranded RNA binding motif, which is highly expressed in various cancer tissues. Analysis of MALDI-TOF/TOF mass spectrometry and RNA immunoprecipitation-sequencing of interacting proteins and the microRNAs (miRNAs) bound to LIX1L revealed that LIX1L interacts with proteins (RIOK1, nucleolin and PABPC4) and miRNAs (has-miRNA-520a-5p, -300, -216b, -326, -190a, -548b-3p, -7-5p and -1296) in HEK-293 cells. Moreover, the reduction of phosphorylated Tyr(136) (pTyr(136)) in LIX1L through the homeodomain peptide, PY136, inhibited LIX1L-induced cell proliferation in vitro, and PY136 inhibited MKN45 cell proliferation in vivo. We also determined the miRNA-targeted genes and showed that was apoptosis induced through the reduction of pTyr(136). Moreover, ROS1, HCK, ABL1, ABL2, JAK3, LCK and TYR03 were identified as candidate kinases responsible for the phosphorylation of Tyr(136) of LIX1L. These data provide novel insights into the biological significance of LIX1L, suggesting that this protein might be an RBP, with implications for therapeutic approaches for targeting LIX1L in LIX1L-expressing cancer cells. PMID:26310847

  7. Multifunctional lactobionic acid-modified dendrimers for targeted drug delivery to liver cancer cells: investigating the role played by PEG spacer.

    Science.gov (United States)

    Fu, Fanfan; Wu, Yilun; Zhu, Jingyi; Wen, Shihui; Shen, Mingwu; Shi, Xiangyang

    2014-09-24

    We report the development of a lactobionic acid (LA)-modified multifunctional dendrimer-based carrier system for targeted therapy of liver cancer cells overexpressing asialoglycoprotein receptors. In this study, generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers were sequentially modified with fluorescein isothiocyanate (FI) and LA (or polyethylene glycol (PEG)-linked LA, PEG-LA), followed by acetylation of the remaining dendrimer terminal amines. The synthesized G5.NHAc-FI-LA or G5.NHAc-FI-PEG-LA conjugates (NHAc denotes acetamide groups) were used to encapsulate a model anticancer drug doxorubicin (DOX). We show that both conjugates are able to encapsulate approximately 5.0 DOX molecules within each dendrimer and the formed dendrimer/DOX complexes are stable under different pH conditions and different aqueous media. The G5.NHAc-FI-PEG-LA conjugate appears to have a better cytocompatibility, enables a slightly faster DOX release rate, and displays better liver cancer cell targeting ability than the G5.NHAc-FI-LA conjugate without PEG under similar experimental conditions. Importantly, the developed G5.NHAc-FI-PEG-LA/DOX complexes are able to specifically inhibit the growth of the target cells with a better efficiency than the G5.NHAc-FI-LA/DOX complexes at a relatively high DOX concentration. Our results suggest a key role played by the PEG spacer that affords the dendrimer platform with enhanced targeting and therapeutic efficacy of cancer cells. The developed LA-modified multifunctional dendrimer conjugate with a PEG spacer may be used as a delivery system for targeted liver cancer therapy and offers new opportunities in the design of multifunctional drug carriers for targeted cancer therapy applications. PMID:25185074

  8. Is there a role for surgery in stage Ⅲ A-N2 non-small cell lung cancer?

    Institute of Scientific and Technical Information of China (English)

    Paul E. VAN SCHIL; Michèle DE WAELE; Jeroen M. HENDRIKS; Patrick R. LAUWERS

    2008-01-01

    The role of surgery in stage Ⅲ A-N2 non-small cell lung cancer (NSCLC) remains controversial.Most important prognostic factors are mediastinal downstaging and complete surgical resection. Different restaging techniques exist to evaluate response after induction therapy and these are subdivided into non-invasive, invasive and alternative or minimally invasive techniques. In contrast to imaging or functional studies, remediastinoscopy provides pathological evidence of response after induction therapy. Although technically more challenging than a first procedure,remediastinoscopy can select patients for subsequent thoracotomy and provides prognostic information. An alternative approach consists of the use of minimally invasive staging procedures as endobronchial or endoscopic esophageal ultrasound to obtain an initial proof of mediastinal nodal involvement. Mediastinoscopy is subsequently performed after induction therapy to evaluate response. In this way, a technically more difficult remediastinoscopy can be avoided. Stage ⅢA-N2 NSCLC represents a heterogenous spectrum of locally advanced disease and different subsets exist. When N2 disease is discovered during thoracotomy after negative, careful preoperative staging a resection should be performed if this can be complete. Postoperative radiotherapy will decrease local recurrence rate but not overall survival. Adjuvant chemotherapy increases survival and is presently recommended in these cases. Most patients with pathologically proven N2 disease detected during preoperative work-up will be treated by induction therapy followed by surgery or radiotherapy.In two large, recently completed, phase Ill trials there was no difference in overall survival between the surgical and radiotherapy arm, but in one trial there was a difference in progression-free survival in favor of the surgical arm. In the surgery ann the rate of local recurrences was also lower in beth trials. Surgical resection may be recommended in those

  9. The Role of HDAC6 in Cancer

    Directory of Open Access Journals (Sweden)

    Grace I. Aldana-Masangkay

    2011-01-01

    Full Text Available Histone deacetylase 6 (HDAC6, a member of the HDAC family whose major substrate is α-tubulin, has become a target for drug development to treat cancer due to its major contribution in oncogenic cell transformation. Overexpression of HDAC6 correlates with tumorigenesis and improved survival; therefore, HDAC6 may be used as a marker for prognosis. Previous work demonstrated that in multiple myeloma cells, inhibition of HDAC6 results in apoptosis. Furthermore, HDAC6 is required for the activation of heat-shock factor 1 (HSF1, an activator of heat-shock protein encoding genes (HSPs and CYLD, a cylindromatosis tumor suppressor gene. HDAC6 contributes to cancer metastasis since its upregulation increases cell motility in breast cancer MCF-7 cells and its interaction with cortactin regulates motility. HDAC6 also affects transcription and translation by regulating the heat-shock protein 90 (Hsp90 and stress granules (SGs, respectively. This review will discuss the role of HDAC6 in the pathogenesis and treatment of cancer.

  10. The role of versican G3 domain in regulating breast cancer cell motility including effects on osteoblast cell growth and differentiation in vitro – evaluation towards understanding breast cancer cell bone metastasis

    Directory of Open Access Journals (Sweden)

    Du William

    2012-08-01

    Full Text Available Abstract Background Versican is detected in the interstitial tissues at the invasive margins of breast carcinoma, is predictive of relapse, and negatively impacts overall survival rates. The versican G3 domain is important in breast cancer cell growth, migration and bone metastasis. However, mechanistic studies evaluating versican G3 enhanced breast cancer bone metastasis are limited. Methods A versican G3 construct was exogenously expressed in the 66c14 and the MC3T3-E1 cell line. Cells were observed through light microscopy and viability analyzed by Coulter Counter or determined with colorimetric proliferation assays. The Annexin V-FITC apoptosis detection kit was used to detect apoptotic activity. Modified Chemotactic Boyden chamber migration invasion assays were applied to observe tumor migration and invasion to bone stromal cells and MC3T3-E1 cells. Alkaline phosphatase (ALP staining and ALP ELISA assays were performed to observe ALP activity in MC3T3-E1 cells. Results In the four mouse breast cancer cell lines 67NR, 66c14, 4T07, and 4T1, 4T1 cells expressed higher levels of versican, and showed higher migration and invasion ability to MC3T3-E1 cells and primary bone stromal cells. 4T1 conditioned medium (CM inhibited MC3T3-E1 cell growth, and even lead to apoptosis. Only 4T1 CM prevented MC3T3-E1 cell differentiation, noted by inhibition of alkaline phosphatase (ALP activity. We exogenously expressed a versican G3 construct in a cell line that expresses low versican levels (66c14, and observed that the G3-expressing 66c14 cells showed enhanced cell migration and invasion to bone stromal and MC3T3-E1 cells. This observation was prevented by selective EGFR inhibitor AG1478, selective MEK inhibitor PD 98059, and selective AKT inhibitor Triciribine, but not by selective JNK inhibitor SP 600125. Versican G3 enhanced breast cancer cell invasion to bone stromal cells or osteoblast cells appears to occur through enhancing EGFR/ERK or AKT signaling

  11. Extragonadal Germ Cell Cancer (EGC)

    Science.gov (United States)

    ... Testicular Cancer Resource Center Extragonadal Germ Cell Cancer (EGC) 95% of all testicular tumors are germ cell ... seen in young adults. Patients with mediastinal nonseminomatous EGC are typically classed as poor risk patients because ...

  12. Epigenetic targeting of ovarian cancer stem cells.

    Science.gov (United States)

    Wang, Yinu; Cardenas, Horacio; Fang, Fang; Condello, Salvatore; Taverna, Pietro; Segar, Matthew; Liu, Yunlong; Nephew, Kenneth P; Matei, Daniela

    2014-09-01

    Emerging results indicate that cancer stem-like cells contribute to chemoresistance and poor clinical outcomes in many cancers, including ovarian cancer. As epigenetic regulators play a major role in the control of normal stem cell differentiation, epigenetics may offer a useful arena to develop strategies to target cancer stem-like cells. Epigenetic aberrations, especially DNA methylation, silence tumor-suppressor and differentiation-associated genes that regulate the survival of ovarian cancer stem-like cells (OCSC). In this study, we tested the hypothesis that DNA-hypomethylating agents may be able to reset OCSC toward a differentiated phenotype by evaluating the effects of the new DNA methytransferase inhibitor SGI-110 on OCSC phenotype, as defined by expression of the cancer stem-like marker aldehyde dehydrogenase (ALDH). We demonstrated that ALDH(+) ovarian cancer cells possess multiple stem cell characteristics, were highly chemoresistant, and were enriched in xenografts residual after platinum therapy. Low-dose SGI-110 reduced the stem-like properties of ALDH(+) cells, including their tumor-initiating capacity, resensitized these OCSCs to platinum, and induced reexpression of differentiation-associated genes. Maintenance treatment with SGI-110 after carboplatin inhibited OCSC growth, causing global tumor hypomethylation and decreased tumor progression. Our work offers preclinical evidence that epigenome-targeting strategies have the potential to delay tumor progression by reprogramming residual cancer stem-like cells. Furthermore, the results suggest that SGI-110 might be administered in combination with platinum to prevent the development of recurrent and chemoresistant ovarian cancer. PMID:25035395

  13. Estrogen induced concentration dependent differential gene expression in human breast cancer (MCF7) cells: Role of transcription factors

    Energy Technology Data Exchange (ETDEWEB)

    Chandrasekharan, Sabarinath, E-mail: csab@bio.psgtech.ac.in [Department of Biotechnology, PSG College of Technology, Coimbatore 641004 (India); Kandasamy, Krishna Kumar [Max Planck Institute for Biology of Ageing, Cologne (Germany); Dayalan, Pavithra; Ramamurthy, Viraragavan [Department of Biotechnology, PSG College of Technology, Coimbatore 641004 (India)

    2013-08-02

    Highlights: •Estradiol (E2) at low dose induced cell proliferation in breast cancer cells. •E2 at high concentration induced cell stress in breast cancer cells. •Estrogen receptor physically interacts only with a few transcription factors. •Differential expression of genes with Oct-1 binding sites increased under stress. •Transcription factor binding sites showed distinct spatial distribution on genes. -- Abstract: Background: Breast cancer cells respond to estrogen in a concentration dependent fashion, resulting in proliferation or apoptosis. The mechanism of this concentration dependent differential outcome is not well understood yet. Methodology: Meta-analysis of the expression data of MCF7 cells treated with low (1 nM) or high (100 nM) dose of estradiol (E2) was performed. We identified genes differentially expressed at the low or the high dose, and examined the nature of regulatory elements in the vicinity of these genes. Specifically, we looked for the difference in the presence, abundance and spatial distribution of binding sites for estrogen receptor (ER) and selected transcription factors (TFs) in the genomic region up to 25 kb upstream and downstream from the transcription start site (TSS) of these genes. Results: It was observed that at high dose E2 induced the expression of stress responsive genes, while at low dose, genes involved in cell cycle were induced. We found that the occurrence of transcription factor binding regions (TFBRs) for certain factors such as Sp1 and SREBP1 were higher on regulatory regions of genes expressed at low dose. At high concentration of E2, genes with a higher frequency of Oct-1 binding regions were predominantly involved. In addition, there were differences in the spatial distribution pattern of the TFBRs in the genomic regions among the two sets of genes. Discussion: E2 induced predominantly proliferative/metabolic response at low concentrations; but at high concentration, stress–rescue responses were induced

  14. Estrogen induced concentration dependent differential gene expression in human breast cancer (MCF7) cells: Role of transcription factors

    International Nuclear Information System (INIS)

    Highlights: •Estradiol (E2) at low dose induced cell proliferation in breast cancer cells. •E2 at high concentration induced cell stress in breast cancer cells. •Estrogen receptor physically interacts only with a few transcription factors. •Differential expression of genes with Oct-1 binding sites increased under stress. •Transcription factor binding sites showed distinct spatial distribution on genes. -- Abstract: Background: Breast cancer cells respond to estrogen in a concentration dependent fashion, resulting in proliferation or apoptosis. The mechanism of this concentration dependent differential outcome is not well understood yet. Methodology: Meta-analysis of the expression data of MCF7 cells treated with low (1 nM) or high (100 nM) dose of estradiol (E2) was performed. We identified genes differentially expressed at the low or the high dose, and examined the nature of regulatory elements in the vicinity of these genes. Specifically, we looked for the difference in the presence, abundance and spatial distribution of binding sites for estrogen receptor (ER) and selected transcription factors (TFs) in the genomic region up to 25 kb upstream and downstream from the transcription start site (TSS) of these genes. Results: It was observed that at high dose E2 induced the expression of stress responsive genes, while at low dose, genes involved in cell cycle were induced. We found that the occurrence of transcription factor binding regions (TFBRs) for certain factors such as Sp1 and SREBP1 were higher on regulatory regions of genes expressed at low dose. At high concentration of E2, genes with a higher frequency of Oct-1 binding regions were predominantly involved. In addition, there were differences in the spatial distribution pattern of the TFBRs in the genomic regions among the two sets of genes. Discussion: E2 induced predominantly proliferative/metabolic response at low concentrations; but at high concentration, stress–rescue responses were induced

  15. The role of TGF-β1–miR-21–ROS pathway in bystander responses induced by irradiated non-small-cell lung cancer cells

    OpenAIRE

    Jiang, Y.; Chen, X.; W. Tian; Yin, X.; Wang, J.; Yang, H.

    2014-01-01

    Background: Many studies have indicated an important implication of radiation-induced bystander effects (RIBEs) in cancer radiotherapy, but the detailed signalling remains unclear. Methods: The roles of tumour growth factor-beta1 (TGF-β1) and miR-21 in medium-mediated RIBEs in H1299 non-small-cell lung cancer cells were investigated using DNA damage, changes in proliferation and levels of reactive oxygen species (ROS) as end points. SB431542, a specific inhibitor of TGF-β type 1 receptor kina...

  16. Essential roles of the interaction between cancer cell-derived chemokine, CCL4, and intra-bone CCR5-expressing fibroblasts in breast cancer bone metastasis

    OpenAIRE

    Sasaki, Soichiro; Baba, Tomohisa; Nishimura, Tatsunori; Hayakawa, Yoshihiro; Hashimoto, Shin-ichi; GOTO, Noriko(Graduate school of Education,Tokyo Gakugei University); Mukaida, Naofumi

    2016-01-01

    From a murine breast cancer cell line, 4T1, we established a subclone, 4T1.3, which consistently metastasizes to bone upon its injection into the mammary fat pad. 4T1.3 clone exhibited similar proliferation rate and migration capacity as the parental clone. However, the intra-bone injection of 4T1.3 clone caused larger tumors than that of the parental cells, accompanied with increases in fibroblast, but not osteoclast or osteoblast numbers. 4T1.3 clone displayed an enhanced expression of a ch...

  17. Cancer stem cells in prostate cancer

    OpenAIRE

    Moltzahn, Felix; Thalmann, George N

    2013-01-01

    Prostate cancer (P-Ca) remains a leading cause of cancer-related death in men. Lately, increasing evidence for a hierarchically organized cancer stem cell (CSC) model emerged for different tumors entities, including P-Ca. CSCs are defined by several characteristics including self-renewal, pluripotency and tumorigenicity and are thought to be responsible for tumor recurrence, metastasis and cancer related death. In this review we discuss the recent research in the field of CSCs, its limitation...

  18. Cancer Stem Cells in Pancreatic Cancer

    OpenAIRE

    Karl-Walter Jauch; Hendrik Seeliger; Hanno Niess; Qi Bao; Andrea Renner; Yue Zhao; Bruns, Christiane J.

    2010-01-01

    Pancreatic cancer is an aggressive malignant solid tumor well-known by early metastasis, local invasion, resistance to standard chemo- and radiotherapy and poor prognosis. Increasing evidence indicates that pancreatic cancer is initiated and propagated by cancer stem cells (CSCs). Here we review the current research results regarding CSCs in pancreatic cancer and discuss the different markers identifying pancreatic CSCs. This review will focus on metastasis, microRNA regulation and anti-CSC t...

  19. Chemokine receptors in cancer metastasis and cancer cell-derived chemokines in host immune response.

    Science.gov (United States)

    Koizumi, Keiichi; Hojo, Shozo; Akashi, Takuya; Yasumoto, Kazuo; Saiki, Ikuo

    2007-11-01

    The chemotactic cytokines called chemokines are a superfamily of small secreted cytokines that were initially characterized through their ability to prompt the migration of leukocytes. Attention has been focused on the chemokine receptors expressed on cancer cells because cancer cell migration and metastasis show similarities to leukocyte trafficking. CXC chemokine receptor 4 (CXCR4) was first investigated as a chemokine receptor that is associated with lung metastasis of breast cancers. Recently, CXCR4 was reported to be a key molecule in the formation of peritoneal carcinomatosis in gastric cancer. In the present review, we highlight current knowledge about the role of CXCR4 in cancer metastases. In contrast to chemokine receptors expressed on cancer cells, little is known about the roles of cancer cell-derived chemokines. Cancer tissue consists of both cancer cells and various stromal cells, and leukocytes that infiltrate into cancer are of particular importance in cancer progression. Although colorectal cancer invasion is regulated by the chemokine CCL9-induced infiltration of immature myeloid cells into cancer, high-level expression of cancer cell-derived chemokine CXCL16 increases infiltrating CD8(+) and CD4(+) T cells into cancer tissues, and correlates with a good prognosis. We discuss the conflicting biological effects of cancer cell-derived chemokines on cancer progression, using CCL9 and CXCL16 as examples. PMID:17894551

  20. Teriflunomide (Leflunomide Promotes Cytostatic, Antioxidant, and Apoptotic Effects in Transformed Prostate Epithelial Cells: Evidence Supporting a Role for Teriflunomide in Prostate Cancer Chemoprevention

    Directory of Open Access Journals (Sweden)

    Numsen Hail, Jr

    2010-06-01

    Full Text Available Teriflunomide (TFN is an inhibitor of de novo pyrimidine synthesis and the active metabolite of leflunomide. Leflunomide is prescribed to patients worldwide as an immunomodulatory and anti-inflammatory disease-modifying prodrug. Leflunomide inhibited the growth of human prostate cancer xenographs in mice, and leflunomide or TFN promoted cytostasis and/or apoptosis in cultured cells. These findings suggest that TFN could be useful in prostate cancer chemoprevention. We investigated the possible mechanistic aspects of this tenet by characterizing the effects of TFN using premalignant PWR-1E and malignant DU-145 human prostate epithelial cells. TFN promoted a dose- and time-dependent cytostasis or apoptosis induction in these cells. The cytostatic effects of TFN, which were reversible but not by the presence of excess uridine in the culture medium, included diminished cellular uridine levels, an inhibition in oxygen consumption, a suppression of reactive oxygen species (ROS generation, S-phase cell cycle arrest, and a conspicuous reduction in the size and number of the nucleoli in the nuclei of these cells. Conversely, TFN's apoptogenic effects were characteristic of catastrophic mitochondrial disruption (i.e., a dissipation of mitochondrial inner transmembrane potential, enhanced ROS production, mitochondrial cytochrome c release, and cytoplasmic vacuolization and followed by DNA fragmentation. The respiration-deficient derivatives of the DU-145 cells, which are also uridine auxotrophs, were markedly resistant to the cytostatic and apoptotic effects of TFN, implicating de novo pyrimidine synthesis and mitochondrial bioenergetics as the primary targets for TFN in the respiration competent cells. These mechanistic findings advocate a role for TFN and mitochondrial bioenergetics in prostate cancer chemoprevention.

  1. Role of MiR-3619-5p in β-Catenin-Mediated Non-Small Cell Lung Cancer Growth and Invasion

    Directory of Open Access Journals (Sweden)

    Xuecai Niu

    2015-10-01

    Full Text Available Background/Aims: The malignancy of non-small cell lung cancer (NSCLC is largely due to its fast growth and invasion. WNT/β-catenin signaling plays a critical role in regulating NSCLC carcinogenesis. Hence, suppression of β-catenin signal transduction in NSCLC cells may improve the therapeutic outcome. Methods: We analyzed the levels of β-catenin and miR-3619-5p in NSCLC specimens, compared to paired non-tumor normal lung tissue (NT. We did Bioinformatics analyses on the binding sites of 3'-UTR of β-catenin mRNA by miR-3619-5p. We modified the levels of miR-3619-5p in NSCLC cells and examined their effects on β-catenin levels, and on the growth and invasion of NSCLC cells in an MTT assay and a transwell cell migration assay, respectively. Results: NSCLC specimens had significant higher levels of β-catenin, and significantly lower levels of miR-3619-5p, compared to NT. The levels of β-catenin and miR-3619-5p were inversely correlated in NSCLC specimens. Bioinformatics analyses showed that miR-3619-5p bound to 3'-UTR of β-catenin mRNA in NSCLC cells to inhibit its translation. Overexpression of miR-3619-5p decreased β-catenin protein, while depletion of miR-3619-5p increased β-catenin protein in NSCLC cells, without altering β-catenin mRNA levels. Overexpression of miR-3619-5p in NSCLC cells inhibited cell growth and invasion, while depletion of miR-3619-5p in NSCLC lines increased cell growth and invasion. Conclusion: Our data demonstrate a previously unappreciated role for miR-3619-5p in suppression of β-catenin-mediated cancer growth and invasion in NSCLC cells, and highlight miR-3619-5p as a novel cancer suppressor in NSCLC.

  2. The role of 14-3-3{beta} in transcriptional activation of estrogen receptor {alpha} and its involvement in proliferation of breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Yoonseo; Kim, Hyungjin; Jang, Sung-Wuk [School of Life Sciences and Biotechnology, Korea University, Seoul 136-701 (Korea, Republic of); Ko, Jesang, E-mail: jesangko@korea.ac.kr [School of Life Sciences and Biotechnology, Korea University, Seoul 136-701 (Korea, Republic of)

    2011-10-14

    Highlights: {yields} 14-3-3{beta} interacts with ER{alpha} and the interaction is Akt-dependent. {yields} 14-3-3{beta} regulates the transcriptional activity of ER{alpha} in a ligand-dependent manner. {yields} 14-3-3{beta} increases expressions of ER{alpha} target genes. {yields} 14-3-3{beta} increases breast cancer cell proliferation. -- Abstract: The estrogen receptor (ER) functions as a transcription factor that mediates the effects of estrogen. ER{alpha}, which plays a crucial role in the development and progression of breast cancer, is activated by estrogen binding, leading to receptor phosphorylation, dimerization, and recruitment of co-activators and chaperons to the estrogen-bound receptor complex. The 14-3-3 proteins bind to target proteins via phosphorylation and influence many cellular events by altering their subcellular localization or acting as a chaperone. However, regulation of ER{alpha} expression and transactivation by the 14-3-3 proteins has not been reported. We demonstrate that 14-3-3{beta} functions as a positive regulator of ER{alpha} through a direct protein-protein interaction in an estrogen-dependent manner. Ectopic expression of 14-3-3{beta} stimulated ER{alpha}-mediated transcriptional activity in MCF-7 breast cancer cells. Enhanced ER{alpha} transcriptional activity due to 14-3-3{beta} increased the expressions of the endogenous ER{alpha} target genes, leading to proliferation of breast cancer cells. We suggest that 14-3-3{beta} has oncogenic potential in breast cancer via binding to ER{alpha} and activation of the transcriptional activity of ER{alpha}.

  3. Adipocyte activation of cancer stem cell signaling in breast cancer

    Institute of Scientific and Technical Information of China (English)

    Benjamin; Wolfson; Gabriel; Eades; Qun; Zhou

    2015-01-01

    Signaling within the tumor microenvironment has a critical role in cancer initiation and progression. Adipocytes, one of the major components of the breast microenvironment,have been shown to provide pro-tumorigenic signals that promote cancer cell proliferation and invasiveness in vitro and tumorigenicity in vivo. Adipocyte secreted factors such as leptin and interleukin-6(IL-6) have a paracrine effect on breast cancer cells. In adipocyte-adjacent breast cancer cells, the leptin and IL-6 signaling pathways activate janus kinase 2/signal transducer and activatorof transcription 5, promoting the epithelial-mesenchymal transition, and upregulating stemness regulators such as Notch, Wnt and the Sex determining region Y-box 2/octamer binding transcription factor 4/Nanog signaling axis. In this review we will summarize the major signaling pathways that regulate cancer stem cells in breast cancer and describe the effects that adipocyte secreted IL-6 and leptin have on breast cancer stem cell signaling. Finally we will introduce a new potential treatment paradigm of inhibiting the adipocyte-breast cancer cell signaling via targeting the IL-6 or leptin pathways.

  4. Response of breast cancer cells and cancer stem cells to metformin and hyperthermia alone or combined.

    Directory of Open Access Journals (Sweden)

    Hyemi Lee

    Full Text Available Metformin, the most widely prescribed drug for treatment of type 2 diabetes, has been shown to exert significant anticancer effects. Hyperthermia has been known to kill cancer cells and enhance the efficacy of various anti-cancer drugs and radiotherapy. We investigated the combined effects of metformin and hyperthermia against MCF-7 and MDA-MB-231 human breast cancer cell, and MIA PaCa-2 human pancreatic cancer cells. Incubation of breast cancer cells with 0.5-10 mM metformin for 48 h caused significant clonogenic cell death. Culturing breast cancer cells with 30 µM metformin, clinically relevant plasma concentration of metformin, significantly reduced the survival of cancer cells. Importantly, metformin was preferentially cytotoxic to CD44(high/CD24(low cells of MCF-7 cells and, CD44(high/CD24(high cells of MIA PaCa-2 cells, which are known to be cancer stem cells (CSCs of MCF-7 cells and MIA PaCa-2 cells, respectively. Heating at 42°C for 1 h was slightly toxic to both cancer cells and CSCs, and it markedly enhanced the efficacy of metformin to kill cancer cells and CSCs. Metformin has been reported to activate AMPK, thereby suppressing mTOR, which plays an important role for protein synthesis, cell cycle progression, and cell survival. For the first time, we show that hyperthermia activates AMPK and inactivates mTOR and its downstream effector S6K. Furthermore, hyperthermia potentiated the effect of metformin to activate AMPK and inactivate mTOR and S6K. Cell proliferation was markedly suppressed by metformin or combination of metformin and hyperthermia, which could be attributed to activation of AMPK leading to inactivation of mTOR. It is conclude that the effects of metformin against cancer cells including CSCs can be markedly enhanced by hyperthermia.

  5. Current Understanding of the Role of PPARγ in Gastrointestinal Cancers

    Directory of Open Access Journals (Sweden)

    Bing Zou

    2009-01-01

    Full Text Available Numerous studies have indicated that PPARγ plays multiple roles such as in inflammation, cell cycle control, cell proliferation, apoptosis, and carcinogenesis, thus PPARγ contributes to the homeostasis. Many in vitro studies have showed that ligand-induced activation of PPARγ possess antitumor effect in many cancers including CRC. However, the role of PPARγ in gastrointestinal cancers, especially in colorectal cancer, is rather controversial. Nevertheless, some recent studies with the positive results on the possible application of PPARγ ligands, such as Bezafibrate or Rosiglitazone in gastrointestinal cancers, have suggested a potential usefulness of PPARγ agonists in cancer prevention and therapy. In this review, the authors discuss the recent developments in the role of PPARγ in gastrointestinal cancers.

  6. Invasive cancer cells and metastasis

    Science.gov (United States)

    Mierke, Claudia Tanja

    2013-12-01

    , vinculin and FAK synergize their functions to regulate the mechanical properties of cells such as stiffness and contractile forces. Finally, the knowledge of the mechanical properties of invasive and non-invasive cells could provide a source for future drug developments to inhibit formation of metastases. This special section also includes two papers from the group of Martin Herrmann, a research paper and a review paper. The research paper by Janko et al deals with the cooperative binding of Annexin A5 to phosphatidylserines on apoptotic cell membranes [6]. This could not alone serve as an 'eat me' signal for macrophages as healthy cells also express Annexin A5 on their cell surface. The authors suggest that the cooperative binding is altered and subsequently the fluidity of Annexin A5 on the membrane. Together this may serve as a signal for phagocytic cells to eat apoptotic cells and leave healthy ones untouched. The paper by Biermann et al reviews the role of biophysical signals in the clearance of apoptotic cells [7]. In addition to the acto-myosin cytoskeleton, the keratin network seems to play a role in cancer research. The paper from the Beil and the Marti group demonstrates that microrheology is a valuable tool to determine the viscoelastic properties of polymer networks such as the keratin network in cells and an arbitrary in vitro network [8]. They describe how the topology of the keratin network affects the overall mechanical behavior of cells. It seems that the field of physical oncology will continue to grow in the future and more research will address the mechanical properties of cancer cells and whole tissues. Biophysical methods will need to be further improved and adapted to the needs of cancer research. References [1] Coughlin M F and Fredberg J J 2013 Phys. Biol. 10 065001 [2] Krause M, te Riet J and Wolf K 2013 Phys. Biol. 10 065002 [3] Munn L L 2013 Phys. Biol. 10 065003 [4] Bordeleau F, Tang L N and Reinhart-King C A 2013 Phys. Biol. 10 065004 [5

  7. The Role of Vaginal Brachytherapy in the Treatment of Surgical Stage I Papillary Serous or Clear Cell Endometrial Cancer

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    Barney, Brandon M., E-mail: barney.brandon@mayo.edu [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Petersen, Ivy A. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Mariani, Andrea; Dowdy, Sean C.; Bakkum-Gamez, Jamie N. [Division of Gynecologic Surgery, Mayo Clinic, Rochester, Minnesota (United States); Haddock, Michael G. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States)

    2013-01-01

    Objectives: The optimal adjuvant therapy for International Federation of Gynecology and Obstetrics (FIGO) stage I papillary serous (UPSC) or clear cell (CC) endometrial cancer is unknown. We report on the largest single-institution experience using adjuvant high-dose-rate vaginal brachytherapy (VBT) for surgically staged women with FIGO stage I UPSC or CC endometrial cancer. Methods and Materials: From 1998-2011, 103 women with FIGO 2009 stage I UPSC (n=74), CC (n=21), or mixed UPSC/CC (n=8) endometrial cancer underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy followed by adjuvant high-dose-rate VBT. Nearly all patients (n=98, 95%) also underwent extended lymph node dissection of pelvic and paraortic lymph nodes. All VBT was performed with a vaginal cylinder, treating to a dose of 2100 cGy in 3 fractions. Thirty-five patients (34%) also received adjuvant chemotherapy. Results: At a median follow-up time of 36 months (range, 1-146 months), 2 patients had experienced vaginal recurrence, and the 5-year Kaplan Meier estimate of vaginal recurrence was 3%. The rates of isolated pelvic recurrence, locoregional recurrence (vaginal + pelvic), and extrapelvic recurrence (including intraabdominal) were similarly low, with 5-year Kaplan-Meier estimates of 4%, 7%, and 10%, respectively. The estimated 5-year overall survival was 84%. On univariate analysis, delivery of chemotherapy did not affect recurrence or survival. Conclusions: VBT is effective at preventing vaginal relapse in women with surgical stage I UPSC or CC endometrial cancer. In this cohort of patients who underwent comprehensive surgical staging, the risk of isolated pelvic or extrapelvic relapse was low, implying that more extensive adjuvant radiation therapy is likely unnecessary.

  8. The Role of Vaginal Brachytherapy in the Treatment of Surgical Stage I Papillary Serous or Clear Cell Endometrial Cancer

    International Nuclear Information System (INIS)

    Objectives: The optimal adjuvant therapy for International Federation of Gynecology and Obstetrics (FIGO) stage I papillary serous (UPSC) or clear cell (CC) endometrial cancer is unknown. We report on the largest single-institution experience using adjuvant high-dose-rate vaginal brachytherapy (VBT) for surgically staged women with FIGO stage I UPSC or CC endometrial cancer. Methods and Materials: From 1998-2011, 103 women with FIGO 2009 stage I UPSC (n=74), CC (n=21), or mixed UPSC/CC (n=8) endometrial cancer underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy followed by adjuvant high-dose-rate VBT. Nearly all patients (n=98, 95%) also underwent extended lymph node dissection of pelvic and paraortic lymph nodes. All VBT was performed with a vaginal cylinder, treating to a dose of 2100 cGy in 3 fractions. Thirty-five patients (34%) also received adjuvant chemotherapy. Results: At a median follow-up time of 36 months (range, 1-146 months), 2 patients had experienced vaginal recurrence, and the 5-year Kaplan Meier estimate of vaginal recurrence was 3%. The rates of isolated pelvic recurrence, locoregional recurrence (vaginal + pelvic), and extrapelvic recurrence (including intraabdominal) were similarly low, with 5-year Kaplan-Meier estimates of 4%, 7%, and 10%, respectively. The estimated 5-year overall survival was 84%. On univariate analysis, delivery of chemotherapy did not affect recurrence or survival. Conclusions: VBT is effective at preventing vaginal relapse in women with surgical stage I UPSC or CC endometrial cancer. In this cohort of patients who underwent comprehensive surgical staging, the risk of isolated pelvic or extrapelvic relapse was low, implying that more extensive adjuvant radiation therapy is likely unnecessary.

  9. Prognostic Role of Circulating Tumor Cells during Induction Chemotherapy Followed by Curative Surgery Combined with Postoperative Radiotherapy in Patients with Locally Advanced Oral and Oropharyngeal Squamous Cell Cancer.

    Directory of Open Access Journals (Sweden)

    Johanna Inhestern

    Full Text Available The prognostic role of circulating tumor cells (CTCs after induction chemotherapy using docetaxel, cisplatin and fluorouracil (TPF prior to surgery and adjuvant (chemoradiation in locally advanced oral squamous cell cancer (OSCC was evaluated.In this prospective study, peripheral blood samples from 40 patients of the phase II study TISOC-1 (NCT01108042 with OSCC before, during, and after treatment were taken. CTCs were quantified using laser scanning cytometry of anti- epithelial cell adhesion molecule-stained epithelial cells. Their detection was correlated with clinical risk factors, recurrence-free (RFS and overall survival (OS.Before starting the treatment CTCs were detected in 32 of 40 patients (80%. The median number at baseline was 3295 CTCs/ml. The median maximal number of CTCs during treatment was 5005 CTCs/ml. There was a significant increase of CTCs before postoperative radiotherapy compared to baseline before 1st cycle of IC (p = 0.011, 2nd cycle of IC (p = 0.001, 3rd cycle of IC (p = 0.004, and before surgery (p = 0.002, but not compared to end of therapy (p = 0.118. CTCs at baseline >median was also associated to risk of recurrence (p = 0.014. Maximal CTCs during therapy >median was more frequently observed in tumors of the oral cavity (p=0.022 and related to higher risk of death during follow-up (p = 0.028. Patients with CTCs at baseline >median value had significant lower RFS than patients with CTCs at baseline median during the complete course of therapy had a significantly lower OS than patients with values

  10. Urothelial Cancer Stem Cells

    Directory of Open Access Journals (Sweden)

    Irena Dimov

    2010-01-01

    Full Text Available There is mounting evidence supporting the idea that tumors, similar to normal adult tissues, arise from a specific stem-like cell population, the cancer stem cells (CSCs, which are considered as the real driving force behind tumor growth, the ability to metastasize, as well as resistance to conventional antitumor therapy. The concept that cancer growth recapitulates normal proliferative and/or regenerative processes, even though in very dysfunctional ways, has tremendous implications for cancer therapy. The rapid development of the CSC field, shoulder to shoulder with powerful genome-wide screening techniques, has provided cause for optimism for the development of more reliable therapies in the future. However, several important issues still lie ahead. Recent identification of a highly tumorigenic stem-like compartment and existence of urothelial differentiation programs in urothelial cell carcinomas (UCCs raised important questions about UCC initiation and development. This review examines the present knowledge on CSCs in UCCs regarding the similarities between CSCs and the adult urothelial stem cells, potential origin of urothelial CSCs, main regulatory pathways, surface markers expression, and the current state of CSC-targeting therapeutic strategies.

  11. White tea extract induces apoptosis in non-small cell lung cancer cells: the role of peroxisome proliferator-activated receptor-{gamma} and 15-lipoxygenases.

    Science.gov (United States)

    Mao, Jenny T; Nie, Wen-Xian; Tsu, I-Hsien; Jin, Yu-Sheng; Rao, Jian Yu; Lu, Qing-Yi; Zhang, Zuo-Feng; Go, Vay Liang W; Serio, Kenneth J

    2010-09-01

    Emerging preclinical data suggests that tea possess anticarcinogenic and antimutagenic properties. We therefore hypothesize that white tea extract (WTE) is capable of favorably modulating apoptosis, a mechanism associated with lung tumorigenesis. We examined the effects of physiologically relevant doses of WTE on the induction of apoptosis in non-small cell lung cancer cell lines A549 (adenocarcinoma) and H520 (squamous cell carcinoma) cells. We further characterized the molecular mechanisms responsible for WTE-induced apoptosis, including the induction of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and the 15-lipoxygenase (15-LOX) signaling pathways. We found that WTE was effective in inducing apoptosis in both A549 and H520 cells, and inhibition of PPAR-gamma with GW9662 partially reversed WTE-induced apoptosis. We further show that WTE increased PPAR-gamma activation and mRNA expression, concomitantly increased 15(S)-hydroxy-eicosatetraenoic acid release, and upregulated 15-LOX-1 and 15-LOX-2 mRNA expression by A549 cells. Inhibition of 15-LOX with nordihydroguaiaretic acid (NGDA), as well as caffeic acid, abrogated WTE-induced PPAR-gamma activation and upregulation of PPAR-gamma mRNA expression in A549 cells. WTE also induced cyclin-dependent kinase inhibitor 1A mRNA expression and activated caspase-3. Inhibition of caspase-3 abrogated WTE-induced apoptosis. Our findings indicate that WTE is capable of inducing apoptosis in non-small cell lung cancer cell lines. The induction of apoptosis seems to be mediated, in part, through the upregulation of the PPAR-gamma and 15-LOX signaling pathways, with enhanced activation of caspase-3. Our findings support the future investigation of WTE as an antineoplastic and chemopreventive agent for lung cancer. PMID:20668019

  12. Physical View on the Interactions Between Cancer Cells and the Endothelial Cell Lining During Cancer Cell Transmigration and Invasion

    Science.gov (United States)

    Mierke, Claudia T.

    current cancer research in a different light from a physical point of view with respect to cancer cell mechanics and the special and unique role of the endothelium on cancer cell invasion. The physical view on cancer disease may lead to novel insights into cancer disease and will help to overcome the classical views on cancer. In addition, in this review it will be discussed how physics of cancer can help to reveal and propose the functional mechanism which cancer cells use to invade connective tissue and transmigrate through the endothelium to finally metastasize. Finally, in this review it will be demonstrated how biophysical measurements can be combined with classical analysis approaches of tumor biology. The insights into physical interactions between cancer cells, the endothelium and the microenvironment may help to answer some "old," but still important questions in cancer disease progression.

  13. Prognostic role of platelet to lymphocyte ratio in non-small cell lung cancers: A meta-analysis including 3,720 patients.

    Science.gov (United States)

    Zhao, Qing-Tao; Yuan, Zheng; Zhang, Hua; Zhang, Xiao-Peng; Wang, Hui-En; Wang, Zhi-Kang; Duan, Guo-Chen

    2016-07-01

    Platelet to lymphocyte ratio (PLR) was recently reported as a useful index in predicting the prognosis of lung cancer. However, the prognostic role of PLR in lung cancer remains controversial. The aim of this study was to evaluate the association between PLR and clinical outcome of lung cancer patients through a meta-analysis. Relevant literatures were retrieved from PubMed, Ovid, the Cochrane Library and Web of Science databases. Meta-analysis was performed using hazard ratio (HR) and 95% confidence intervals (CIs) as effect measures. A total of 5,314 patients from 13 studies were finally enrolled in the meta-analysis. The summary results showed that elevated PLR predicted poorer overall survival (OS) (HR: 1.526, 95%CI: 1.268-1.836, p 160 (HR: 1.842, 95%CI: 1.523-2.228, P  0.05) in patients with small cell lung cancer (SCLC).This meta-analysis result suggested that elevated PLR might be a predicative factor of poor prognosis for NSCLC patients. PMID:26915723

  14. Roles for GP IIb/IIIa and αvβ3 integrins in MDA-MB-231 cell invasion and shear flow-induced cancer cell mechanotransduction.

    Science.gov (United States)

    Zhao, Fenglong; Li, Li; Guan, Liuyuan; Yang, Hong; Wu, Chunhui; Liu, Yiyao

    2014-03-01

    Adhesion of cancer cell to endothelial cells and the subsequent trans-endothelial migration are key steps in hematogenous metastasis. However, the molecular mechanisms of cancer cell/endothelial cell interaction under hemodynamic shear flow and how shear flow-induced cancer cell mechanotransduction are yet to be fully defined. In this study, we identified that the integrins of both platelet glycoprotein IIb/IIIa (GP IIb/IIIa) and αvβ3 were crucial for hematogenous metastasis of human breast carcinoma MDA-MB-231 cells. The cell migration and invasion were studied by using Millicell cell culture insert system. The numbers of invaded MDA-MB-231 cells significantly increased by thrombin-activated platelets and reduced by eptifibatide, a platelet inhibitor. Meanwhile, RGDWE peptides, a specific inhibitor of αvβ3 integrin, also inhibited MDA-MB-231 cell invasion. We further used a parallel-plate flow chamber to investigate MDA-MB-231 cell adhesion under flow conditions. Alike in static condition, the adhesion capability of MDA-MB-231 cells to endothelial monolayer was also significantly affected by GP IIb/IIIa and αvβ3 integrins. The expression of matrix metalloproteinase-2 (MMP-2), MMP-9 and αvβ3 integrin in MDA-MB-231 cells were up-regulated after low shear stress exposure (1.84 dynes/cm(2), 2 h). Moreover, we also demonstrated that low shear stress induced a sustained activation of p85 (a regulatory subunit of PI3K) and Akt. Pre-treating MDA-MB-231 cells with the specific PI3K inhibitor of LY294002 abolished the shear stress induced-Akt activation, and the expression of MMP-2, MMP-9, vascular endothelial growth factor (VEGF) and αvβ3 integrin were also down-regulated. Immunofluorescence assay showed that low shear stress also induced αvβ3 integrin clustering and nuclear factor-κB (NF-κB) activation. Interestingly, shear stress-induced activation of Akt and NF-κB was attenuated by LM609, a specific antibody of αvβ3 integrin. It suggests that αvβ3

  15. Small cell lung cancer transformation and T790M mutation: complimentary roles in acquired resistance to kinase inhibitors in lung cancer.

    Science.gov (United States)

    Suda, Kenichi; Murakami, Isao; Sakai, Kazuko; Mizuuchi, Hiroshi; Shimizu, Shigeki; Sato, Katsuaki; Tomizawa, Kenji; Tomida, Shuta; Yatabe, Yasushi; Nishio, Kazuto; Mitsudomi, Tetsuya

    2015-01-01

    Lung cancers often harbour a mutation in the epidermal growth factor receptor (EGFR) gene. Because proliferation and survival of lung cancers with EGFR mutation solely depend on aberrant signalling from the mutated EGFR, these tumours often show dramatic responses to EGFR tyrosine kinase inhibitors (TKIs). However, acquiring resistance to these drugs is almost inevitable, thus a better understanding of the underlying resistance mechanisms is critical. Small cell lung cancer (SCLC) transformation is a relatively rare acquired resistance mechanism that has lately attracted considerable attention. In the present study, through an in-depth analysis of multiple EGFR-TKI refractory lesions obtained from an autopsy case, we observed a complementary relationship between SCLC transformation and EGFR T790M secondary mutation (resistance mutation). We also identified analogies and differences in genetic aberration between a TKI-refractory lesion with SCLC transformation and one with EGFR T790M mutation. In particular, target sequencing revealed a TP53 P151S mutation in all pre- and post-treatment lesions. PTEN M264I mutation was identified only in a TKI-refractory lesion with SCLC transformation, while PIK3CA and RB1 mutations were identified only in pre-treatment primary tumour samples. These results provide the groundwork for understanding acquired resistance to EGFR-TKIs via SCLC transformation. PMID:26400668

  16. Role of tumour-associated N-glycolylated variant of GM3 ganglioside in cancer progression: effect over CD4 expression on T cells.

    Science.gov (United States)

    de Leòn, Joel; Fernández, Audry; Mesa, Circe; Clavel, Marilyn; Fernández, Luis E

    2006-04-01

    Gangliosides have diverse biological functions including modulation of immune system response. These molecules are differentially expressed on malignant cells compared with the corresponding normal ones and are involved in cancer progression affecting, in different ways, the host's anti-tumour specific immune responses. Although in humans the N-glycolylated variant of GM3 ganglioside is almost exclusively expressed in tumour tissues, the significance of this glycolipid for malignant cell biology remains obscure, while for NAcGM3 strong immune suppressive effects have been reported. The present work demonstrates, for the first time, the capacity of NGcGM3 ganglioside to down-modulate CD4 expression in murine and human T lymphocytes, especially in non-activated T cells. Thirty and tenfold reductions in CD4 expression were induced by purified NGcGM3 ganglioside in murine and human T lymphocytes, respectively. The CD4 complete recovery in these cells occurred after 48 h of ganglioside removal, due to neo-synthesis. Restored T cells kept similar sensitivity to ganglioside-induced CD4 down-modulation after a new challenge. In addition, a clear association between NGcGM3 insertion in lymphocyte plasma membranes and the CD4 down-modulation effect was documented. Notably, a possible role of this ganglioside in tumour progression, taking advantage of the X63 myeloma model, was also outlined. The relevance of these findings, characterizing NGcGM3 as a possible tumour immunesurveillance inhibitor and supporting the reason for its neo-expression in certain human cancers, is contributing to this unique heterophilic ganglioside validation as target for cancer immunotherapy. PMID:16208470

  17. A Pilot Study Assessing the Potential Role of non-CD133 Colorectal Cancer Stem Cells as Biomarkers

    Directory of Open Access Journals (Sweden)

    Russell C. Langan, John E. Mullinax, Satyajit Ray, Manish T. Raiji, Nicholas Schaub, Hong-Wu Xin, Tomotake Koizumi, Seth M. Steinberg, Andrew Anderson, Gordon Wiegand, Donna Butcher, Miriam Anver, Anton J. Bilchik, Alexander Stojadinovic, Udo Rudloff, Itz

    2012-01-01

    Full Text Available Introduction: Over 50% of patients with colorectal cancer (CRC will progress and/or develop metastases. Biomarkers capable of predicting progression, risk stratification and therapeutic benefit are needed. Cancer stem cells are thought to be responsible for tumor initiation, dissemination and treatment failure. Therefore, we hypothesized that CRC cancer stem cell markers (CRCSC will identify a group of patients at high risk for progression.Methods: Paraffin-embedded tissue cores of normal (n=8, and histopathologically well-defined primary (n= 30 and metastatic (n=10 CRC were arrayed in duplicate on tissue microarrays (TMAs. Expression profiles of non-CD133 CRCSC (CD29, CD44, ALDH1A1, ALDH1B1, EpCam, and CD166 were detected by immunohistochemistry and the association with clinicopathological data and patient outcomes was determined using standard statistical methodology. An independent pathologist, blinded to the clinical data scored the samples. Scoring included percent positive cells (0 to 4, 0 = <10%, 1 = 10 - 24%, 2 = 25 - 49%, 3 = 50 - 74%, 4 = 75 - 100%, and the intensity of positively stained cells (0 to 4; 0 = no staining, 1 = diminutive intensity, 2 = low intensity, 3 = intermediate intensity, 4 = high intensity. The pathologic score represents the sum of these two values, reported in this paper as a combined IHC staining score (CSS.Results: Of 30 patients 7 were AJCC stage IIA, 10 stage IIIB, 7 stage IIIC and 6 stage IV. Median follow-up was 113 months. DFI was 17 months. Median overall survival (OS was not reached. Stage-specific OS was: II - not reached; III - not reached; IV - 11 months. In a univariate analysis, poor OS was associated with loss of CD29 expression; median OS, 32 months vs. not reached for CSS 3-7 vs. >7.5, respectively; p=0.052 comparing entire curves, after adjustment. In a Cox model analysis, loss of CD29 exhibited a trend toward association with survival (p=0.098 after adjusting for the effect of stage (p=0

  18. Role of CEACAM1, ECM, and Mesenchymal Stem Cells in an Ortho topic Model of Human Breast Cancer

    International Nuclear Information System (INIS)

    Carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) is a morphogens in an in vitro model for lumen formation and plays a similar role in breast epithelial cells implanted in humanized mammary fat pads in NOD-SCID mice. Although extra cellular matrix alone is sufficient to stimulate lumen formation in CEACAM1 transfected MCF-7 cells grown in 3D culture, there is an additional requirement for stromal or mesenchymal cells (MSCs) for these cells to form xenografts with glandular structures in an ortho topic site. We demonstrate that optimal in vitro conditions include both Matrigel and MSCs and that the inclusion of collagen I inhibits xenograft differentiation. Additionally, there is no need to remove the nascent murine mammary gland. The previously observed difference in gland development between the long and short cytoplasmic domain isoforms of CEACAM1 is no longer observed in pregnant NOD/SCID mice suggesting that stimulation of the mammary fat pad by pregnancy critically affects xenograft differentiation.

  19. The role of nitric oxide in cancer

    Institute of Scientific and Technical Information of China (English)

    WEIMING; XU; LI; ZHI; LIU; MARILENA; LOIZIDOU; MOHAMED; AHMED; IAN; G; CHARLES

    2002-01-01

    Nitric oxide (NO) is a pleiotropic regulator, critical to numerous biological processes, including va-sodilatation, neurotransmission and macrophage-mediated immunity. The family of nitric oxide synthases(NOS) comprises inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS). Interest-ingly, various studies have shown that all three isoforms can be involved in promoting or inhibiting theetiology of cancer. NOS activity has been detected in tumour cells of various histogenetic origins and hasbeen associated with tumour grade, proliferation rate and expression of important signaling componentsassociated with cancer development such as the oestrogen receptor. It appears that high levels of NOSexpression (for example, generated by activated macrophages) may be cytostatic or cytotoxic for tumorcells, whereas low level activity can have the opposite effect and promote tumour growth. Paradoxicallytherefore, NO (and related reactive nitrogen species) may have both genotoxic and angiogenic properties.Increased NO-generation in a cell may select mutant p53 cells and contribute to tumour angiogenesis byupregulating VEGF. In addition, NO may modulate tumour DNA repair mechanisms by upregulating p53,poly(ADP-ribose) polymerase (PARP) and the DNA-dependent protein kinase (DNA-PK). An understand-ing at the molecular level of the role of NO in cancer will have profound therapeutic implications for thediagnosis and treatment of disease.

  20. Role of PAX8 in the regulation of MET and RON receptor tyrosine kinases in non-small cell lung cancer

    International Nuclear Information System (INIS)

    Non-small cell lung cancers (NSCLC) are highly heterogeneous at the molecular level and comprise 75% of all lung tumors. We have previously shown that the receptor tyrosine kinase (RTK) MET frequently suffers gain-of-function mutations that significantly promote lung tumorigenesis. Subsequent studies from our lab also revealed that PAX5 transcription factor is preferentially expressed in small cell lung cancer (SCLC) and promotes MET transcription. PAX8, however, is also expressed in NSCLC cell lines. We therefore investigated the role of PAX8 in NSCLC. Using IHC analysis, PAX8 protein expression was determined in archival NSCLC tumor tissues (n = 254). In order to study the effects of PAX8 knockdown on NSCLC cellular functions such as apoptosis and motility, siRNA against PAX8 was used. Confocal fluorescence microscopy was used to monitor the localization of MET, RON and PAX8. The combinatorial effect of PAX8 knockdown and MET inhibition using SU11274 was investigated in NSCLC cell viability assay. Relative levels of PAX8 protein were elevated (≥ + 2 on a scale of 0–3) in adenocarcinoma (58/94), large cell carcinoma (50/85), squamous cell carcinoma (28/47), and metastatic NSCLC (17/28; lymph node). Utilizing early progenitors isolated from NSCLC cell lines and fresh tumor tissues, we observed robust overexpression of PAX8, MET, and RON. PAX8 knockdown A549 cells revealed abrogated PAX8 expression with a concomitant loss in MET and the related RON kinase expression. A dramatic colocalization between the active form of MET (also RON) and PAX8 upon challenging A549 cells with HGF was visualized. A similar colocalization of MET and EGL5 (PAX8 ortholog) proteins was found in embryos of C. elegans. Most importantly, knockdown of PAX8 in A549 cells resulted in enhanced apoptosis (~6 fold) and decreased cell motility (~45%), thereby making PAX8 a potential therapeutic target. However, the combinatorial approach of PAX8 knockdown and treatment with MET inhibitor, SU

  1. Stem Cells and Cancer; Celulas madre y cancer

    Energy Technology Data Exchange (ETDEWEB)

    Segrelles, C.; Paraminio, J. M.; Lorz, C.

    2014-04-01

    Stem cell research has thrived over the last years due to their therapeutic and regenerative potential. Scientific breakthroughs in the field are immediately translated from the scientific journals to the mass media, which is not surprising as the characterisation of the molecular mechanisms that regulate the biology of stem cells is crucial for the treatment of degenerative and cardiovascular diseases, as well as cancer. In the Molecular Oncology Unit at Ciemat we work to unravel the role of cancer stem cells in tumour development, and to find new antitumor therapies. (Author)

  2. The Role of Matrix Metalloproteinases in Colorectal Cancer

    OpenAIRE

    Anan H. Said; Jean-Pierre Raufman; Guofeng Xie

    2014-01-01

    In the United States, colorectal cancer (CRC) is the third leading cause of cancer mortality, with limited treatment options for those with advanced disease. Matrix metalloproteinases (MMPs) are important for maintaining extracellular homeostasis but also play a prominent role in cancer cell invasion and dissemination. Expression levels of MMP-1, -2, -7, -9 and -13 correlate with worse outcomes; MMP-12 expression appears to be protective. Hence, MMPs are attractive therapeutic targets. Previ...

  3. Role of the neural niche in brain metastatic cancer

    OpenAIRE

    Termini, John; Neman, Josh; Jandial, Rahul

    2014-01-01

    Metastasis is the relenteless pursuit of cancer to escape its primary site and colonize distant organs. This malignant evolutionary process is biologically heterogeneous, yet one unifying element is the critical role of the microenvironment for arriving metastatic cells. Historically brain metastases were rarely investigated since patients with advanced cancer were considered terminal. Fortunately, advances in molecular therapies have led to patients living longer with metastatic cancer. Howe...

  4. Stromal-cell and cancer-cell exosomes leading the metastatic exodus for the promised niche

    OpenAIRE

    Hoffman, Robert M.

    2013-01-01

    Exosomes are thought to play an important role in metastasis. Luga and colleagues have described the production of exosomes by stromal cells such as cancer-associated fibroblasts that are taken up by breast cancer cells and are then loaded with Wnt 11, which is associated with stimulation of the invasiveness and metastasis of the breast cancer cells. Previous studies have shown that exosomes produced by breast cancer cells are taken up by stromal fibroblasts and other stromal cells, suggestin...

  5. Role of chemotherapy in the treatment of lung cancer: evolving strategies for non-small cell histologies

    International Nuclear Information System (INIS)

    Lung cancer treatment has been considered to have made little progress except for advances in small cell carcinoma. For other histologies an attitude of nihilism has prevailed principally because of lack of effective systemic therapy and of no persuasive evidence that results could be improved by combined modality treatment. On the other hand, favorable results from surgery are confined to a small percent of all patients with this disease. This review emphasizes possibilities for progress in evolving new therapeutic strategies. Although improvement over other systemic therapies is modest, cisplatin-containing regimens yield more consistent response rates and apparent survival advantage relative to single agents. Immediate progression occurs in the minority of patients. In addition, regimens combining cisplatin with vinca alkaloids have no substantial deleterious effects on the lung, marrow or esophagus to aggravate radiation-induced complications. These features encourage the evolution of strategies which begin with chemotherapy and then use consolidation with radiation therapy. Clinical trials using these and newer strategies must be instituted if progress is to occur in the treatment of non-small cell histologies at all stages

  6. Role of chemotherapy in the treatment of lung cancer: evolving strategies for non-small cell histologies

    Energy Technology Data Exchange (ETDEWEB)

    Muggia, F.M. (NYU Medical Center, New York); Blum, R.H.; Foreman, J.D.

    1984-01-01

    Lung cancer treatment has been considered to have made little progress except for advances in small cell carcinoma. For other histologies an attitude of nihilism has prevailed principally because of lack of effective systemic therapy and of no persuasive evidence that results could be improved by combined modality treatment. On the other hand, favorable results from surgery are confined to a small percent of all patients with this disease. This review emphasizes possibilities for progress in evolving new therapeutic strategies. Although improvement over other systemic therapies is modest, cisplatin-containing regimens yield more consistent response rates and apparent survival advantage relative to single agents. Immediate progression occurs in the minority of patients. In addition, regimens combining cisplatin with vinca alkaloids have no substantial deleterious effects on the lung, marrow or esophagus to aggravate radiation-induced complications. These features encourage the evolution of strategies which begin with chemotherapy and then use consolidation with radiation therapy. Clinical trials using these and newer strategies must be instituted if progress is to occur in the treatment of non-small cell histologies at all stages.

  7. A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma

    International Nuclear Information System (INIS)

    Sunlight is a carcinogen to which everyone is exposed. Its UV component is the major epidemiologic risk factor for squamous cell carcinoma of the skin. Of the multiple steps in tumor progression, those that are sunlight-related would be revealed if they contained mutations specific to UV. In a series of New England and Swedish patients, the authors find that 14/24 (58%) of invasive squamous cell carcinomas of the skin contain mutations in the p53 tumor suppressor gene, each altering the amino acid sequence. Involvement of UV light in these p53 mutations is indicated by the presence in three of the tumors of a CC → TT double-base change, which is only known to be induced by UV. UV is also implicated by a UV-like occurrence of mutations exclusively at dipyrimidine sites, including a high frequency of C → T substitutions. p53 mutations in internal malignancies do not show these UV-specific mutations. The dipyrimidine specificity also implicates dipyrimidine photoproducts containing cytosine as oncogenic photoproducts. They believe these results identify a carcinogen-related step in a gene involved in the subsequent human cancer

  8. Cytokines and Growth Factors Stimulate Hyaluronan Production: Role of Hyaluronan in Epithelial to Mesenchymal-Like Transition in Non-Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Geraldine Chow

    2010-01-01

    Full Text Available In this study, we investigated the role of hyaluronan (HA in non-small cell lung cancer (NSCLC since close association between HA level and malignancy has been reported. HA is an abundant extracellular matrix component and its synthesis is regulated by growth factors and cytokines that include epidermal growth factor (EGF and interleukin-1β (IL-1β. We showed that treatment with recombinant EGF and IL-1β, alone or in combination with TGF-β, was able to stimulate HA production in lung adenocarcinoma cell line A549. TGF-β/IL-1β treatment induced epithelial to mesenchymal-like phenotype transition (EMT, changing cell morphology and expression of vimentin and E-cadherin. We also overexpressed hyaluronan synthase-3 (HAS3 in epithelial lung adenocarcinoma cell line H358, resulting in induced HA expression, EMT phenotype, enhanced MMP9 and MMP2 activities and increased invasion. Furthermore, adding exogenous HA to A549 cells and inducing HA H358 cells resulted in increased resistance to epidermal growth factor receptor (EGFR inhibitor, Iressa. Together, these results suggest that elevated HA production is able to induce EMT and increase resistance to Iressa in NSCLC. Therefore, regulation of HA level in NSCLC may be a new target for therapeutic intervention.

  9. Progesterone receptors - animal models and cell signaling in breast cancer: Role of steroid receptor coactivators and corepressors of progesterone receptors in breast cancer

    International Nuclear Information System (INIS)

    Progesterone, an ovarian steroid hormone, plays a key role in the development and function of the mammary gland, as it also does in the uterus and the ovary. The action of progesterone is mediated through its intracellular cognate receptor, the progesterone receptor (PR), which functions as a transcription factor that regulates gene expression. As with other nuclear receptors, coregulators (coactivators and corepressors) recruited by the liganded or unliganded PR, either to enhance or to suppress transcription activity, modulate the function of the PR. Mutation or aberrant expression of the coregulators might thus affect the normal function of the PR and hence disrupt the normal development of the mammary gland, which may lead to breast cancer

  10. Gastric cancer stem cells: A novel therapeutic target

    OpenAIRE

    Singh, Shree Ram

    2013-01-01

    Gastric cancer remains one of the leading causes of global cancer mortality. Multipotent gastric stem cells have been identified in both mouse and human stomachs, and they play an essential role in the self-renewal and homeostasis of gastric mucosa. There are several environmental and genetic factors known to promote gastric cancer. In recent years, numerous in vitro and in vivo studies suggest that gastric cancer may originate from normal stem cells or bone marrow–derived mesenchymal cells, ...

  11. A new prospect in cancer therapy: targeting cancer stem cells to eradicate cancer

    OpenAIRE

    Yi-Min Zhu; Li-Hua Yuan; Ke-Feng Pu; Bing Dong; An-Xin Wang; Li-Sha Chen

    2012-01-01

    According to the cancer stem cell theory, cancers can be initiated by cancer stem cells. This makes cancer stem cells prime targets for therapeutic intervention. Eradicating cancer stem cells by efficient targeting agents may have the potential to cure cancer. In this review, we summarize recent breakthroughs that have improved our understanding of cancer stem cells, and we discuss the therapeutic strategy of targeting cancer stem cells, a promising future direction for cancer stem cell resea...

  12. A new prospect in cancer therapy: targeting cancer stem cells to eradicate cancer

    Institute of Scientific and Technical Information of China (English)

    Li-Sha Chen; An-Xin Wang; Bing Dong; Ke-Feng Pu; Li-Hua Yuan; Yi-Min Zhu

    2012-01-01

    According to the cancer stem cell theory,cancers can be initiated by cancer stem cells.This makes cancer stem cells prime targets for therapeutic intervention.Eradicating cancer stem cells by efficient targeting agents may have the potential to cure cancer.In this review,we summarize recent breakthroughs that have improved our understanding of cancer stem cells,and we discuss the therapeutic strategy of targeting cancer stem cells,a promising future direction for cancer stem cell research.

  13. The roles of nucleolin subcellular localization in cancer.

    Science.gov (United States)

    Berger, Caroline Madeleine; Gaume, Xavier; Bouvet, Philippe

    2015-06-01

    Nucleolin (NCL) is one of the most abundant non ribosomal protein of the nucleolus where it plays a central role in polymerase I transcription. NCL is also found outside of the nucleolus, in the nucleoplasm, cytoplasm as well as on the cell membrane. It acts in all cell compartments to control cellular homeostasis and therefore each cellular pool of NCL can play a different role in cancer development. NCL overexpression and its increased localization at the cell membrane is a common feature of several tumor cells. In cancer cells, NCL overexpression influences cell survival, proliferation and invasion through its action on different cellular pathways. In this review, we describe how the multiple functions of NCL that are associated to its multiple cellular localization can participate to the development of cancer. PMID:25866190

  14. Immunotargeting of cancer stem cells

    OpenAIRE

    Kwiatkowska-Borowczyk, Eliza P.; Gąbka-Buszek, Agnieszka; Jankowski, Jakub; Mackiewicz, Andrzej

    2015-01-01

    Cancer stem cells (CSCs) represent a distinctive population of tumour cells that control tumour initiation, progression, and maintenance. Their influence is great enough to risk the statement that successful therapeutic strategy must target CSCs in order to eradicate the disease. Because cancer stem cells are highly resistant to chemo- and radiotherapy, new tools to fight against cancer have to be developed. Expression of antigens such as ALDH, CD44, EpCAM, or CD133, which distinguish CSCs fr...

  15. Expression of TIMP-3 Gene by Construction of a Eukaryotic Cell Expression Vector and Its Role in Reduction of Metastasis in a Human Breast Cancer Cell Line

    Institute of Scientific and Technical Information of China (English)

    Xichun Han; Hong Zhang; Mingku Jia; Gang Han; Weidong Jiang

    2004-01-01

    The present study is aimed at studying the gene for TIMP-3, a mammalian tissue inhibitor, by constructing a recombinant eukaryotic cell vector for gene therapy in human breast cancer. We obtained the TIMP-3 gene from the human placent by RT-PCR. TIMP-3 gene was subcloned into pcDNA3.1 vetor from pMD18T vector by means of gene cloning to construct pcDNA3.1 recombinant vector. Human breast cancer cell line MDA-MB-453 was transfected with pcDNA3.1-TIMP3 recombinant vector using lipofectamine reagent. Then the expression of TIMP-3 and the effect on the metastasis of MDA-MB-453 were examined. The correct construction of pcDNA-TIMP3 was identified by means of restriction enzyme analysis, PCR amplication and nucleotide sequencing. Western blotting showed that the transfected cells were able to express TIMP-3,indicating that our construction of the pcDNA-TIMP3 eukaryotic expression vector was constructed successfully. Our experiments further indicated that the potential of metastasis was significantly reduced for the transfected cell line MDA-MB-453.

  16. A role for the cytoskeleton in STAT5 activation in MCF7 human breast cancer cells stimulated with EGF.

    Science.gov (United States)

    Lopez-Perez, Mario; Salazar, Eduardo Perez

    2006-01-01

    A rapid increase in the tyrosine phosphorylation of signal transducers and activators of transcription (STAT) proteins has been extensively documented in cells stimulated with cytokines and growth factors. However, the mechanisms by which these transcription factors translocate to the nucleus have not been studied in detail. Our results demonstrate that stimulation of MCF7 cells with epidermal growth factor (EGF) promoted an increase in the phosphorylation of STAT5 at Tyr-694, as revealed by site-specific antibodies that recognized the phosphorylated state of this residue. In addition, EGF stimulated STAT5 nuclear translocation and an increased in STAT5 DNA binding activity. Prevention of microtubules and microfilaments polymerization induced a partial inhibition of STAT5 nuclear translocation and STAT5 DNA binding activity. However, STAT5 phosphorylation at Tyr-694 was dependent on the integrity of microtubule network and it was independent of the integrity of actin cytoskeleton. Furthermore, EGF induced the formation of the associations STAT5-tubulin and STAT5-kinesin heavy chain in a fashion dependent of cytoskeleton integrity. In summary, our results demonstrate, for the first time, that cytoskeleton plays an important role in STAT5 activation and translocation into the nucleus in MCF7 cells stimulated with EGF. PMID:16765629

  17. Prostate stem cells and cancer

    OpenAIRE

    Nikitin, Alexander Y.; Matoso, A; Roy-Burman, P

    2007-01-01

    Properties shared by neoplastic and stem cells indicate a possibility that somatic stem cells or transit-amplifying cells that have reacquired stem cell properties, particularly the ability for self-renewal, represent favorable targets for malignant transformation. In this review we discuss significance of the stem cell model for understanding prostate cancer pathogenesis and describe relevant studies in animals. It is proposed that dissemination of rare cancer stem ce...

  18. Beneficial effects of the naturally occurring flavonoid silibinin on the prostate cancer microenvironment: role of monocyte chemotactic protein-1 and immune cell recruitment.

    Science.gov (United States)

    Ting, Harold; Deep, Gagan; Kumar, Sushil; Jain, Anil K; Agarwal, Chapla; Agarwal, Rajesh

    2016-06-01

    Tumor microenvironment plays an essential role in prostate carcinogenesis and offers novel opportunities to prevent and treat prostate cancer (PCA). Here, we investigated the ability of cancer-associated fibroblasts (CAFs) to promote PCA progression, and silibinin efficacy to target this response. We collected conditioned media from CAFs treated with vehicle or silibinin, and labeled as control conditioned media (CCM) or silibinin-treatment conditioned media (SBCM), respectively. Next, we characterized the effect of CCM and SBCM treatment in several PCA cell lines (RWPE-1, WPE-1 NA-22, WPE-1 NB-14 and PC3). Result showed that compared with SBCM, CCM significantly reduces E-cadherin expression and increases invasiveness and clonogenicity in PCA cells. Further molecular studies identified monocyte chemotactic protein-1 (MCP-1) as the key component of CCM that promotes PCA invasiveness, whereas silibinin treatment strongly reduced MCP-1 expression in CAFs by inhibiting the DNA-binding activity of MCP-1 transcriptional regulators-nuclear factor-kappaB and AP-1. In vivo, silibinin feeding (200mg/kg body weight) strongly reduced TRAMPC1 allografts growth (by 68%) in syngeneic C57Bl/6 mice. TRAMPC1 tumor analysis showed that silibinin reduced MCP-1 and CAFs' biomarkers (fibroblast activation protein, α-smooth muscle actin, transforming growth factor beta 2, vimentin etc.) and significantly modulated the recruitment of immune cells in the tumor microenvironment. Similar inhibitory effects of silibinin on MCP-1 and immune cells recruitment were also observed in TRAMP PCA tissues with reported silibinin efficacy. Overall, our data suggest that silibinin can target CAF-mediated invasiveness in PCA by inhibiting MCP-1 secretion. This, in turn, was associated with a reduction in immune cell recruitment in vivo along with a marked reduction in tumor growth. PMID:27207648

  19. General Information about Small Cell Lung Cancer

    Science.gov (United States)

    ... Cancer Prevention Lung Cancer Screening Research Small Cell Lung Cancer Treatment (PDQ®)–Patient Version General Information About Small Cell Lung Cancer Go to Health Professional Version Key Points Small ...

  20. Stages of Small Cell Lung Cancer

    Science.gov (United States)

    ... Cancer Prevention Lung Cancer Screening Research Small Cell Lung Cancer Treatment (PDQ®)–Patient Version General Information About Small Cell Lung Cancer Go to Health Professional Version Key Points Small ...

  1. Treatment Option Overview (Small Cell Lung Cancer)

    Science.gov (United States)

    ... Cancer Prevention Lung Cancer Screening Research Small Cell Lung Cancer Treatment (PDQ®)–Patient Version General Information About Small Cell Lung Cancer Go to Health Professional Version Key Points Small ...

  2. Role of retinoic acid in the modulation of benzo(a)pyrene-DNA adducts in human hepatoma cells: Implications for cancer prevention

    International Nuclear Information System (INIS)

    Carcinogen-DNA adducts could lead to mutations in critical genes, eventually resulting in cancer. Many studies have shown that retinoic acid (RA) plays an important role in inducing cell apoptosis. Here we have tested the hypothesis that levels of carcinogen-DNA adducts can be diminished by DNA repair and/or by eliminating damaged cells through apoptosis. Our results showed that the levels of total DNA adducts in HepG2 cells treated with benzo(a)pyrene (BP, 2 μM) + RA (1 μM) were significantly reduced compared to those treated with BP only (P = 0.038). In order to understand the mechanism of attenuation of DNA adducts, further experiments were performed. Cells were treated with BP (4 μM) for 24 h to initiate DNA adduct formation, following which the medium containing BP was removed, and fresh medium containing 1 μM RA was added. The cells were harvested 24 h after RA treatment. Interestingly, the levels of total DNA adducts were lower in the BP/RA group (390 ± 34) than those in the BP/DMSO group (544 ± 33), P = 0.032. Analysis of cell apoptosis showed an increase in BP + RA group, compared to BP or RA only groups. Our results also indicated that attenuation of BP-DNA adducts by RA was not primarily due to its effects on CYP1A1 expression. In conclusion, our results suggest a mechanistic link between cellular apoptosis and DNA adduct formation, phenomena that play important roles in BP-mediated carcinogenesis. Furthermore, these results help understand the mechanisms of carcinogenesis, especially in relation to the chemopreventive properties of nutritional apoptosis inducers.

  3. Noncoding RNAs in cancer and cancer stem cells

    Institute of Scientific and Technical Information of China (English)

    Tianzhi Huang; Angel Alvarez; Bo Hu; Shi-Yuan Cheng

    2013-01-01

    In recent years, it has become increasingly apparent that noncoding RNAs (ncRNA) are of crucial importance for human cancer. The functional relevance of ncRNAs is particularly evident for microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). miRNAs are endogenously expressed small RNA sequences that act as post-transcriptional regulators of gene expression and have been extensively studied for their roles in cancers, whereas lncRNAs are emerging as important players in the cancer paradigm in recent years. These noncoding genes are often aberrantly expressed in a variety of human cancers. However, the biological functions of most ncRNAs remain largely unknown. Recently, evidence has begun to accumulate describing how ncRNAs are dysregulated in cancer and cancer stem cells, a subset of cancer cells harboring self-renewal and differentiation capacities. These studies provide insight into the functional roles that ncRNAs play in tumor initiation, progression, and resistance to therapies, and they suggest ncRNAs as attractive therapeutic targets and potential y useful diagnostic tools.

  4. Role of androgen receptor in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    HiroyoshiSuzuki; HaruoIto

    1999-01-01

    The growth of prostate cancer is sensitive to androgen, and hormonal therapy has been used for treatment of ad-vanced cancer. About 80 % of prostate cancers initially respond to hormonal therapy, howcrver, more than half of the re-sponders gradtmlly become resistant to this therapy. Changes in tumors from an androgen-responsive to an androgen-unre-sponsive state have been widely discussed. Since androgen action is mediated by androgen receptor (AR), abnonnalitiesof AR is believed to play an important role of the loss of androgen responsiveness in prostate cancer. "Ilais article focusedon the role of AR in the progression of prostate cancer.

  5. Metformin induces apoptosis of pancreatic cancer cells

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    AIM: To assess the role and mechanism of mefformin in inducing apoptosis of pancreatic cancer cells. METHODS: The human pancreatic cancer cell lines ASPC-1, BxPc-3, PANC-1 and SW1990 were exposed to mefformin. The inhibition of cell proliferation and colony formation via apoptosis induction and S phase arrest in pancreatic cancer cell lines of mefformin was tested.RESULTS: In each pancreatic cancer cell line tested, metformin inhibited cell proliferation in a dose dependent manner in MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assays). Flow cytometric analysis showed that metformin reduced the number of cells in G1 and increased the percentage of cells in S phase as well as the apoptotic fraction. Enzymelinked immunosorbent assay (EUSA) showed that metformin induced apaptosis in all pancreatic cancer cell lines. In Western blot studies, metformin induced oly-ADP-ribose polymerase(PARP) cleavage (an indicator of aspase activation) in all pancreatic cancer cell lines. The general caspase inhibitor (VAD-fmk) completely abolished metformin-induced PARP cleavage and apoptosis in ASPC-1 BxPc-3 and PANC-1, the caspase-8 specific inhibitor (IETD-fmk) and the caspase-9 specific inhibitor (LEHD-fmk) only partially abrogated metformin-induced apoptosis and PARP cleavage in BxPc-3 and PANC-1 cells. We also observed that metformin treatment ramatically reduced epidermal growth factor receptor (EGFR) and phosphorylated mitogen activated protein kinase (P-MAPK) in both a time- and dose-dependent manner in all cell lines tested.CONCLUSION: Metformin significantly inhibits cell proliferation and apoptosis in all pancreatic cell lines. And the metformin-induced apoptosis is associated with PARP leavage, activation of caspase-3, -8, and -9 in a time- and dose-dependent manner. Hence, both caspase-8 and -9-initiated apoptotic signaling pathways contribute to metforrnin-induced apoptosis in pancreatic cell lines.

  6. Ovarian cancer: emerging concept on cancer stem cells

    OpenAIRE

    Ponnusamy Moorthy P; Batra Surinder K

    2008-01-01

    Abstract Emerging evidence suggests that the capacity of a tumor to grow and propagate is dependent on a small subset of cells within a tumor, termed cancer stem cells. In fact, cancer cells, like stem cells, can proliferate indefinitely through a dysregulated cellular self-renewal capacity. Cancer stem cells may originate due to the distribution into self-renewal and differentiation pathways occurring in multi-potential stem cells, tissue-specific stem cells, progenitor cells and cancer cell...

  7. DNA From Dead Cancer Cells Induces TLR9-Mediated Invasion and Inflammation In Living Cancer Cells

    Science.gov (United States)

    Tuomela, Johanna; Sandholm, Jouko; Kaakinen, Mika; Patel, Ankita; Kauppila, Joonas H.; Ilvesaro, Joanna; Chen, Dongquan; Harris, Kevin W.; Graves, David; Selander, Katri S.

    2014-01-01

    TLR9 is a cellular DNA-receptor, which is widely expressed in breast and other cancers. Although synthetic TLR9-ligands induce cancer cell invasion in vitro, the role of TLR9 in cancer pathophysiology has remained unclear. We show here that living cancer cells uptake DNA from chemotherapy-killed cancer cells. We discovered that such DNA induces TLR9- and cathepsin-mediated invasion in living cancer cells. To study whether this phenomenon contributes to treatment responses, triple negative, human MDA-MB-231 breast cancer cells stably expressing control or TLR9 siRNA were inoculated orthotopically into nude mice. The mice were treated with vehicle or doxorubicin. The tumor groups exhibited equal decreases in size in response to doxorubicin. However, while the weights of vehicle-treated mice were similar, mice bearing control siRNA tumors became significantly more cachectic in response to doxorubicin, as compared with similarly treated mice bearing TLR9 siRNA tumors, suggesting a TLR9-mediated inflammation at the site of the tumor. In conclusion, our findings propose that DNA released from chemotherapy-killed cancer cells has significant influence on TLR9-mediated biological effects in living cancer cells. Through these mechanisms, tumor TLR9 expression may affect treatment responses to chemotherapy. PMID:24212717

  8. Gap Junctions: The Claymore for Cancerous Cells

    Directory of Open Access Journals (Sweden)

    Ailar Nakhlband

    2011-07-01

    Full Text Available Introduction: Gap junctions play an important role in the cell proliferation in mammalian cells as well as carcinogenesis. However, there are controversial issues about their role in cancer pathogenesis. This study was designed to evaluate genotoxicity and cytotoxicity of Carbenoxolone (CBX as a prototype of inter-cellular gap junction blocker in MCF7 and BT20 human breast cancer cells. Methods: The MCF7and BT20 human breast cancer cell lines were cultivated, and treated at designated confluency with different doses of CBX. Cellular cytotoxicity was examined using standard colorimetric assay associated with cell viability tests. Gene expression evaluation was carried out using real time polymerase chain reaction (PCR. Results: MCF7 and BT20 cells were significantly affected by CBX in a dose dependent manner in cell viability assays. Despite varying expression of genes, down regulation of pro- and anti-apoptotic genes was observed in these cells. Conclusion: Based upon this investigation, it can be concluded that CBX could affect both low and high proliferative types of breast cancer cell lines and disproportionate down regulation of both pre- and anti-apoptotic genes may be related to interacting biomolecules, perhaps via gap junctions.

  9. The role of biliverdin reductase in colorectal cancer

    International Nuclear Information System (INIS)

    In recent years, the effects of biliverdin and bilirubin have been studied extensively, and an inhibitory effect of bile pigments in cancer progression has been proposed. In this study we focused on the effects of biliverdin reductase, the enzyme that converts biliverdin to bilirubin, in colorectal cancer. For in vitro experiments we used a human colorectal carcinoma cell line and transfected it with an expression construct of shRNA specific for biliverdin reductase, to create cells with stable knock-down of enzyme expression. Cell proliferation was analyzed using the CASY model TT cell counting device. Western blot protein analysis was performed to study intracellular signaling cascades. Samples of human colorectal cancer were analyzed using immunohistochemistry. We were able to confirm the antiproliferative effects of bile pigments on cancer cells in vitro. However, this effect was attenuated in biliverdin reductase knock down cells. ERK and Akt activation seen under biliverdin and bilirubin treatment was also reduced in biliverdin reductase deficient cells. Immunohistochemical analysis of tumor samples from patients with colorectal cancer showed elevated biliverdin reductase levels. High enzyme expression was associated with lower overall and disease free patient survival. We conclude that BVR is required for bile pigment mediated effects regarding cancer cell proliferation and modulation of intracellular signaling cascades. The role of BVR overexpression in vivo and its exact influence on cancer progression and patient survival need to be further investigated. (author)

  10. The expression and role of CXC chemokines in colorectal cancer.

    Science.gov (United States)

    Verbeke, Hannelien; Struyf, Sofie; Laureys, Geneviève; Van Damme, Jo

    2011-01-01

    Cancer is a life-threatening disease world-wide and colorectal cancer is the second common cause of cancer mortality. The interaction between tumor cells and stromal cells plays a crucial role in tumor initiation and progression and is partially mediated by chemokines. Chemokines predominantly participate in the chemoattraction of leukocytes to inflammatory sites. Nowadays, it is clear that CXC chemokines and their receptors (CXCR) may also modulate tumor behavior by several important mechanisms: regulation of angiogenesis, activation of a tumor-specific immune response by attracting leukocytes, stimulation of tumor cell proliferation and metastasis. Here, we review the expression and complex roles of CXC chemokines (CXCL1 to CXCL16) and their receptors (CXCR1 to CXCR6) in colorectal cancer. Overall, increased expression levels of CXC chemokines correlate with poor prognosis. PMID:22000992

  11. Overcoming Multidrug Resistance in Cancer Stem Cells

    Directory of Open Access Journals (Sweden)

    Karobi Moitra

    2015-01-01

    Full Text Available The principle mechanism of protection of stem cells is through the expression of ATP-binding cassette (ABC transporters. These transporters serve as the guardians of the stem cell population in the body. Unfortunately these very same ABC efflux pumps afford protection to cancer stem cells in tumors, shielding them from the adverse effects of chemotherapy. A number of strategies to circumvent the function of these transporters in cancer stem cells are currently under investigation. These strategies include the development of competitive and allosteric modulators, nanoparticle mediated delivery of inhibitors, targeted transcriptional regulation of ABC transporters, miRNA mediated inhibition, and targeting of signaling pathways that modulate ABC transporters. The role of ABC transporters in cancer stem cells will be explored in this paper and strategies aimed at overcoming drug resistance caused by these particular transporters will also be discussed.

  12. Role of prophylactic brain irradiation in limited stage small cell lung cancer: clinical, neuropsychologic, and CT sequelae

    International Nuclear Information System (INIS)

    Ninety-four patients with limited stage small cell lung cancer treated between 1981 and 1985 with a regimen including prophylactic brain irradiation (PBI) after combination chemotherapy were assessed for compliance with PBI, brain relapse, and neurologic morbidity. Seventy-seven percent of patients had PBI and of these, 22% developed brain metastases after a median time of 11 months post treatment. The brain was the apparent unique initial site of relapse in 10% of PBI cases but more commonly brain relapse was preceded or accompanied by failure at other sites, especially the chest. Brain metastases were the greatest cause of morbidity in 50% of PBI failures. Twelve of 14 PBI patients alive 2 years after treatment had oncologic, neurologic, and neuropsychological evaluation, and brain CT. All long-term survivors were capable of self care and none fulfilled diagnostic criteria for dementia, with three borderline cases. One third had pretreatment neurologic dysfunction and two thirds post treatment neurologic symptoms, most commonly recent memory loss. Fifty percent had subtle motor findings. Intellectual functioning was at the 38th percentile with most patients having an unskilled occupational history. Neuropsychologic impairment ratings were borderline in three cases and definitely impaired in seven cases. CT scans showed brain atrophy in all cases with mild progression in those having a pre-treatment baseline. Periventricular and subcortical low density lesions identical to the CT appearance of subcortical arteriosclerotic encephalopathy were seen in 82% of posttreatment CT studies, and lacunar infarcts in 54%. Neuropsychologic impairment scores and the extent of CT periventricular low density lesions were strongly associated

  13. Lung cancer - non-small cell

    Science.gov (United States)

    Cancer - lung - non-small cell; Non-small cell lung cancer; NSCLC; Adenocarcinoma - lung; Squamous cell carcinoma - lung ... Horn L, Eisenberg R, Gius D, et al. Cancer of the lung. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan ...

  14. Mitochondrial DNA determines androgen dependence in prostate cancer cell lines

    OpenAIRE

    Higuchi, M; Kudo, T; Suzuki, S.; Evans, TT; Sasaki, R.; Wada, Y; Shirakawa, T.; Sawyer, JR; Gotoh, A

    2006-01-01

    Prostate cancer progresses from an androgen-dependent to androgen-independent stage after androgen ablation therapy. Mitochondrial DNA plays a role in cell death and metastatic competence. Further, heteroplasmic large-deletion mitochondrial DNA is verycommon in prostate cancer. To investigate the role of mitochondrial DNA in androgen dependence of prostate cancers, we tested the changes of normal and deleted mitochondrial DNA in accordance with the progression of prostate cancer. We demonstra...

  15. Hypoxia regulates stemness of breast cancer MDA-MB-231 cells

    OpenAIRE

    Xie, Jing; Xiao, Yong; Zhu, Xiao-Yan; Ning, Zhou-yu; Xu, Hai-fan; Wu, Hui-Min

    2016-01-01

    Human breast cancers include cancer stem cell populations as well as non-tumorigenic cancer cells. Breast cancer stem cells possess self-renewal capability and thus are the root cause of recurrence and metastasis of malignant tumors. Hypoxia is a fundamental pathological feature of solid tumor tissues and exerts a wide range of effects on the biological behavior of cancer cells. However, there is little information on the role of hypoxia in modulating the stemness of breast cancer cells. In t...

  16. Prostate cancer stem cell biology

    OpenAIRE

    Yu, Chunyan; Yao, Zhi; Jiang, Yuan; Keller, Evan T.

    2012-01-01

    The cancer stem cell (CSC) model provides insights into pathophysiology of cancers and their therapeutic response. The CSC model has been both controversial, yet provides a foundation to explore cancer biology. In this review, we provide an overview of CSC concepts, biology and potential therapeutic avenues. We then focus on prostate CSC including (1) their purported origin as either basal-derived or luminal-derived cells; (2) markers used for prostate CSC identification; (3) alterations of s...

  17. Hypoxia increases membrane metallo-endopeptidase expression in a novel lung cancer ex vivo model – role of tumor stroma cells

    International Nuclear Information System (INIS)

    Hypoxia-induced genes are potential targets in cancer therapy. Responses to hypoxia have been extensively studied in vitro, however, they may differ in vivo due to the specific tumor microenvironment. In this study gene expression profiles were obtained from fresh human lung cancer tissue fragments cultured ex vivo under different oxygen concentrations in order to study responses to hypoxia in a model that mimics human lung cancer in vivo. Non-small cell lung cancer (NSCLC) fragments from altogether 70 patients were maintained ex vivo in normoxia or hypoxia in short-term culture. Viability, apoptosis rates and tissue hypoxia were assessed. Gene expression profiles were studied using Affymetrix GeneChip 1.0 ST microarrays. Apoptosis rates were comparable in normoxia and hypoxia despite different oxygenation levels, suggesting adaptation of tumor cells to hypoxia. Gene expression profiles in hypoxic compared to normoxic fragments largely overlapped with published hypoxia-signatures. While most of these genes were up-regulated by hypoxia also in NSCLC cell lines, membrane metallo-endopeptidase (MME, neprilysin, CD10) expression was not increased in hypoxia in NSCLC cell lines, but in carcinoma-associated fibroblasts isolated from non-small cell lung cancers. High MME expression was significantly associated with poor overall survival in 342 NSCLC patients in a meta-analysis of published microarray datasets. The novel ex vivo model allowed for the first time to analyze hypoxia-regulated gene expression in preserved human lung cancer tissue. Gene expression profiles in human hypoxic lung cancer tissue overlapped with hypoxia-signatures from cancer cell lines, however, the elastase MME was identified as a novel hypoxia-induced gene in lung cancer. Due to the lack of hypoxia effects on MME expression in NSCLC cell lines in contrast to carcinoma-associated fibroblasts, a direct up-regulation of stroma fibroblast MME expression under hypoxia might contribute to enhanced

  18. Probiotics, dendritic cells and bladder cancer.

    Science.gov (United States)

    Feyisetan, Oladapo; Tracey, Christopher; Hellawell, Giles O

    2012-06-01

    What's known on the subject? and What does the study add? The suppressor effect of probiotics on superficial bladder cancer is an observed phenomenon but the specific mechanism is poorly understood. The evidence strongly suggests natural killer (NK) cells are the anti-tumour effector cells involved and NK cell activity correlates with the observed anti-tumour effect in mice. It is also known that dendritic cells (DC) cells are responsible for the recruitment and mobilization of NK cells so therefore it may be inferred that DC cells are most likely to be the interphase point at which probiotics act. In support of this, purification of NK cells was associated with a decrease in NK cells activity. The current use of intravesical bacille Calmette-Guérin in the management of superficial bladder cancer is based on the effect of a localised immune response. In the same way, understanding the mechanism of action of probiotics and the role of DC may potentially offer another avenue via which the immune system may be manipulated to resist bladder cancer. Probiotic foods have been available in the UK since 1996 with the arrival of the fermented milk drink (Yakult) from Japan. The presence of live bacterial ingredients (usually lactobacilli species) may confer health benefits when present in sufficient numbers. The role of probiotics in colo-rectal cancer may be related in part to the suppression of harmful colonic bacteria but other immune mechanisms are involved. Anti-cancer effects outside the colon were suggested by a Japanese report of altered rates of bladder tumour recurrence after ingestion of a particular probiotic. Dendritic cells play a central role to the general regulation of the immune response that may be modified by probiotics. The addition of probiotics to the diet may confer benefit by altering rates of bladder tumour recurrence and also alter the response to immune mechanisms involved with the application of intravesical treatments (bacille Calmette

  19. The c-MYC-ABCB5 axis plays a pivotal role in 5-fluorouracil resistance in human colon cancer cells

    OpenAIRE

    Kugimiya, Naruji; Nishimoto, Arata; Hosoyama, Tohru; Ueno, Koji; Enoki, Tadahiko; Li, Tao-Sheng; Hamano, Kimikazu

    2015-01-01

    c-MYC overexpression is frequently observed in various cancers including colon cancer and regulates many biological activities such as aberrant cell proliferation, apoptosis, genomic instability, immortalization and drug resistance. However, the mechanism by which c-MYC confers drug resistance remains to be fully elucidated. In this study, we found that the c-MYC expression level in primary colorectal cancer tissues correlated with the recurrence rate following 5-fluorouracil (5-FU)-based adj...

  20. The Role of Cholesterol in Cancer.

    Science.gov (United States)

    Kuzu, Omer F; Noory, Mohammad A; Robertson, Gavin P

    2016-04-15

    The roles played by cholesterol in cancer development and the potential of therapeutically targeting cholesterol homeostasis is a controversial area in the cancer community. Several epidemiologic studies report an association between cancer and serum cholesterol levels or statin use, while others suggest that there is not one. Furthermore, the Cancer Genome Atlas (TCGA) project using next-generation sequencing has profiled the mutational status and expression levels of all the genes in diverse cancers, including those involved in cholesterol metabolism, providing correlative support for a role of the cholesterol pathway in cancer development. Finally, preclinical studies tend to more consistently support the role of cholesterol in cancer, with several demonstrating that cholesterol homeostasis genes can modulate development. Because of space limitations, this review provides selected examples of the epidemiologic, TCGA, and preclinical data, focusing on alterations in cholesterol homeostasis and its consequent effect on patient survival. In melanoma, this focused analysis demonstrated that enhanced expression of cholesterol synthesis genes was associated with decreased patient survival. Collectively, the studies in melanoma and other cancer types suggested a potential role of disrupted cholesterol homeostasis in cancer development but additional studies are needed to link population-based epidemiological data, the TCGA database results, and preclinical mechanistic evidence to concretely resolve this controversy. Cancer Res; 76(8); 2063-70. ©2016 AACR. PMID:27197250

  1. Colorectal cancer cell lines made resistant to SN38-and Oxaliplatin: Roles of altered ion transporter function in resistance?

    DEFF Research Database (Denmark)

    Sandra, Christensen; Jensen, Niels Frank; Stoeckel, Johanne Danmark;

    2013-01-01

    Colorectal cancer (CRC) is the 3rd most common cancer globally, with 5year survival rates of ~50%. Response rates to standard treatments (irinotecan (SN38) or Oxaliplatin (Oxp)) are 31–56% and drug resistance is a major problem. Thus, we established in vitro CRC models to investigate SN38 and Oxp...... not previously been implicated in SN38 or Oxp resistance and are generally restricted to the CNS, they are potential novel biomarkers for resistance and interesting candidates for therapeutic targeting....

  2. Skp2 is over-expressed in breast cancer and promotes breast cancer cell proliferation.

    Science.gov (United States)

    Zhang, Wenwen; Cao, Lulu; Sun, Zijia; Xu, Jing; Tang, Lin; Chen, Weiwei; Luo, Jiayan; Yang, Fang; Wang, Yucai; Guan, Xiaoxiang

    2016-05-18

    The F box protein Skp2 is oncogenic. Skp2 and Skp2B, an isoform of Skp2 are overexpressed in breast cancer. However, little is known regarding the mechanism by which Skp2B promotes the occurrence and development of breast cancer. Here, we determined the expression and clinical outcomes of Skp2 in breast cancer samples and cell lines using breast cancer database, and investigated the role of Skp2 and Skp2B in breast cancer cell growth, apoptosis and cell cycle arrest. We obtained Skp2 is significantly overexpressed in breast cancer samples and cell lines, and high Skp2 expression positively correlated with poor prognosis of breast cancer. Both Skp2 and Skp2B could promote breast cancer cell proliferation, inhibit cell apoptosis, change the cell cycle distribution and induce the increased S phase cells and therefore induce cell proliferation in breast cancer cells. Moreover, the 2 isoforms could both suppress PIG3 expression via independent pathways in the breast cancer cells. Skp2 suppressed p53 and inhibited PIG3-induced apoptosis, while Skp2B attenuated the function of PIG3 by inhibiting PHB. Our results indicate that Skp2 and Skp2B induce breast cancer cell development and progression, making Skp2 and Skp2B potential molecular targets for breast cancer therapy. PMID:27111245

  3. Opposing roles of the two isoforms of ErbB3 binding protein 1 in human cancer cells.

    Science.gov (United States)

    Ko, Hyo Rim; Chang, Yun Sil; Park, Won Soon; Ahn, Jee-Yin

    2016-09-15

    The different functions of the two isoforms of ErbB3 binding protein 1 (Ebp1), p48 and p42, have recently become the focus of interest as they reveal contradictory roles in cell growth promoting ability. The conformational change that crystal structure of p42 was shown to lack α helices at the amino-terminus present in p48 represents the differential binding partners and protein modifications of two Ebp1 isoforms. N-terminal specific phosphorylation by CDK2 and deregulation of the p53 tumor suppressor through specific interaction with HDM2 and Akt activation is postulated to contribute to p48-mediated tumorigenesis. The short isoform p42 Ebp1, which is actual binding partner of ErbB3 has been implicated as a tumor suppressor with many binding partners such as Rb, HDAC2, Sin3A and the p85 subunit of PI3K with HSP70/CHIP, inhibiting its own antiproliferative activity or inhibiting PI3K activity. The aim of the current review is to provide a summary on distinctive cellular functions of two Ebp1 proteins and their molecular partners that might be responsible for the unique functions of each isoform of Ebp1. PMID:27130196

  4. High-Throughput Flow Cytometry Screening Reveals a Role for Junctional Adhesion Molecule A as a Cancer Stem Cell Maintenance Factor

    DEFF Research Database (Denmark)

    Lathia, Justin D; Li, Meizhang; Sinyuk, Maksim;

    2014-01-01

    Stem cells reside in niches that regulate the balance between self-renewal and differentiation. The identity of a stem cell is linked with the ability to interact with its niche through adhesion mechanisms. To identify targets that disrupt cancer stem cell (CSC) adhesion, we performed a flow...

  5. The role of cancer registries in cancer control.

    Science.gov (United States)

    Parkin, Donald Maxwell

    2008-04-01

    Cancer control aims to reduce the incidence, morbidity, and mortality of cancer and to improve the quality of life of cancer patients through the systematic implementation of evidence-based interventions in prevention, early diagnosis, treatment, and palliative care. In the context of a national cancer control program (NCCP), a cancer surveillance program (CSP), built around a population-based cancer registry, is an essential element. Data on the size and evolution of the cancer burden in the population are essential to evaluation of the current situation, to setting objectives for cancer control, and defining priorities. Cancer data are essential in monitoring the progress of the implementation of an NCCP, as well as providing an evaluation of the many individual cancer control activities. In the context of an NCCP, the CSP should provide a focus of epidemiological expertise, not only for providing statistical data on incidence, mortality, stage distribution, treatment patterns, and survival but also for conducting studies into the important causes of cancer in the local situation, and for providing information about the prevalence of exposure to these factors in the population. Cancer surveillance via the population-based registry therefore plays a crucial role in formulating cancer control plans, as well as in monitoring their success. PMID:18463952

  6. Role of the nervous system in cancer metastasis.

    Science.gov (United States)

    Li, Sha; Sun, Yanlai; Gao, Dongwei

    2013-04-01

    The notion that tumors lack innervation was proposed several years ago. However, nerve fibers are irregulatedly found in some tumor tissues. Their terminals interaction with cancer cells are considered to be neuro-neoplastic synapses. Moreover, neural-related factors, which are important players in the development and activity of the nervous system, have been found in cancer cells. Thus, they establish a direct connection between the nervous system and tumor cells. They modulate the process of metastasis, including degradation of base membranes, cancer cell invasion, migration, extravasation and colonization. Peripheral nerve invasion provides another pathway for the spread of cancer cells when blood and lymphatic metastases are absent, which is based on the interactions between the microenvironments of nerve fibers and tumor cells. The nervous system also modulates angiogenesis, the tumor microenvironment, bone marrow, immune functions and inflammatory pathways to influence metastases. Denervation of the tumor has been reported to enhance cancer metastasis. Stress, social isolation and other emotional factors may increase distant metastasis through releasing hormones from the brain, the hypothalamic-pituitary-adrenal axis and autonomic nervous system. Disruption of circadian rhythms will also promote cancer metastasis through direct and indirect actions of the nervous system. Therefore, the nervous system plays an important role in cancer metastasis. PMID:23599747

  7. NK cells and cancer: You can teach innate cells new tricks

    OpenAIRE

    Morvan, MG; Lanier, LL

    2015-01-01

    © 2016 Macmillan Publishers Limited. Natural killer (NK) cells are the prototype innate lymphoid cells endowed with potent cytolytic function that provide host defence against microbial infection and tumours. Here, we review evidence for the role of NK cells in immune surveillance against cancer and highlight new therapeutic approaches for targeting NK cells in the treatment of cancer.

  8. Role of Wnt Inhibitory Factor-1 in Inhibition of Bisdemethoxycurcumin Mediated Epithelial-to-Mesenchymal Transition in Highly Metastatic Lung Cancer 95D Cells

    OpenAIRE

    Jin-Hong Xu; He-Ping Yang; Xiang-Dong Zhou; Hai-Jing Wang; Liang Gong; Chun-Lan Tang

    2015-01-01

    Background: Bisdemethoxycurcumin (BDMC) is an active component of curcumin and a chemotherapeutic agent, which has been suggested to inhibit tumor growth, invasion and metastasis in multiple cancers. But its contribution and mechanism of action in invasion and metastasis of non-small cell lung cancer (NSCLC) are not very clear. Therefore, we tried to study the effects of BDMC on regulation of epithelial-to-mesenchymal transition (EMT), which is closely linked to tumor cell invasion and metast...

  9. Targeting homeostatic mechanisms of endoplasmic reticulum stress to increase susceptibility of cancer cells to fenretinide-induced apoptosis: the role of stress proteins ERdj5 and ERp57

    OpenAIRE

    Corazzari, M.; Lovat, P E; Armstrong, J L; Fimia, G M; Hill, D S; Birch-Machin, M; Redfern, C P F; Piacentini, M

    2007-01-01

    Endoplasmic reticulum (ER) malfunction, leading to ER stress, can be a consequence of genome instability and hypoxic tissue environments. Cancer cells survive by acquiring or enhancing survival mechanisms to counter the effects of ER stress and these homeostatic responses may be new therapeutic targets. Understanding the links between ER stress and apoptosis may be approached using drugs specifically to target ER stress responses in cancer cells. The retinoid analogue fenretinide [N-(4-hydrox...

  10. Activating Mutations in β-Catenin in Colon Cancer Cells Alter Their Interaction with Macrophages; the Role of Snail

    OpenAIRE

    Kaler, Pawan; Augenlicht, Leonard; Klampfer, Lidija

    2012-01-01

    Background Tumor cells become addicted to both activated oncogenes and to proliferative and pro-survival signals provided by the abnormal tumor microenvironment. Although numerous soluble factors have been identified that shape the crosstalk between tumor cells and stroma, it has not been established how oncogenic mutations in the tumor cells alter their interaction with normal cells in the tumor microenvironment. Principal Findings We showed that the isogenic HCT116 and Hke-3 cells, which di...

  11. Mouse models for cancer stem cell research

    OpenAIRE

    Cheng, Le; Ramesh, Anirudh V.; Flesken-Nikitin, Andrea; Choi, Jinhyang; Nikitin, Alexander Yu.

    2009-01-01

    Cancer stem cell concept assumes that cancers are mainly sustained by a small pool of neoplastic cells, known as cancer stem cells or tumor initiating cells, which are able to reproduce themselves and produce phenotypically heterogeneous cells with lesser tumorigenic potential. Cancer stem cells represent an appealing target for development of more selective and efficient therapies. However, direct testing of the cancer stem cell concept and assessment of its therapeutic implications in human...

  12. Characterization of cancer stem-like cells in the side population cells of human gastric cancer cell line MKN-45

    Institute of Scientific and Technical Information of China (English)

    Hai-hong ZHANG; Ai-zhen CAI; Xue-ming WEI; Li DING; Feng-zhi LI; Ai-ming ZHENG; Da-jiang DAI

    2013-01-01

    Objective:Side population (SP) cells may play a crucial role in tumorigenesis and the recurrence of cancer.Many kinds of cell lines and tissues have demonstrated the presence of SP cells,including several gastric cancer cell lines.This study is aimed to identify the cancer stem-like cells in the SP of gastric cancer cell line MKN-45.Methods:We used fluorescence activated cell sorting (FACS) to sort SP cells in the human gastric carcinoma cell line MKN-45 (cells labeled with Hoechst 33342) and then characterized the cancer stem-like properties of SP cells.Results:This study found that the SP cells had higher clone formation efficiency than major population (MP) cells.Five stemness-related gene expression profiles,including OCT-4,SOX-2,NANOG,CD44,and adenosine triphosphate (ATP)-binding cassette transporters gene ABCG2,were tested in SP and MP cells using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR).Western blot was used to show the difference of protein expression between SP and MP cells.Both results show that there was significantly higher protein expression in SP cells than in MP cells.When inoculated into non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice,SP cells show higher tumorigenesis tendency than MP cells.Conclusions:These results indicate that SP cells possess cancer stem cell properties and prove that SP cells from MKN-45 are gastric cancer stem-like cells.

  13. Hitting the Bull’s Eye: Targeting HMGA1 in Cancer Stem Cells

    OpenAIRE

    Yanagisawa, Breann L.; Resar, Linda M. S.

    2014-01-01

    Emerging evidence suggests that when cancer cells hijack normal stem cell properties, they acquire the ability to invade, metastasize to distant sites, and evade therapy. Thus, eliminating cancer cells with stem cell properties, or cancer stem cells, is of prime importance for the successful treatment of cancer, regardless of the tissue of origin. Previous efforts to target cancer stem cells, however, have been largely unsuccessful. Recent studies led to the discovery of a novel role for the ...

  14. Paracrine effects of stem cells in wound healing and cancer progression

    OpenAIRE

    DITTMER, JÜRGEN; Leyh, Benjamin

    2014-01-01

    Stem cells play an important role in tissue repair and cancer development. The capacity to self-renew and to differentiate to specialized cells allows tissue-specific stem cells to rebuild damaged tissue and cancer stem cells to initiate and promote cancer. Mesenchymal stem cells, attracted to wounds and cancer, facilitate wound healing and support cancer progression primarily by secreting bioactive factors. There is now growing evidence that, like mesenchymal stem cells, also tissue-specific...

  15. Emerging role for leucine-rich repeat-containing G-protein-coupled receptors LGR5 and LGR4 in cancer stem cells

    International Nuclear Information System (INIS)

    The concept of cancer stem cells has gained considerable interest in the last few decades, partly because of their potential implication in therapy resistance. However, the lack of specific cellular surface markers for these cells has impeded their isolation, making the characterization of this cellular subpopulation technically challenging. Recent studies have indicated that leucine-rich repeat-containing G-protein-coupled receptor 4 and 5 (LGR4 and LGR5) expression in multiple organs may represent a global marker of adult stem cells. This review aims to give an overview of LGR4 and LGR5 as cancer stem cell markers and their function in development

  16. Eradicating cancer cells: struggle with a chameleon

    OpenAIRE

    Di, Jiabo; Boer, Tjitske Duiveman-de; Figdor, Carl G.; Torensma, Ruurd

    2011-01-01

    Eradication of cancer stem cells to abrogate tumor growth is a new treatment modality. However, like normal cells cancer cells show plasticity. Differentiated tumor stem cells can acquire stem cell properties when they gain access to the stem cell niche. This indicates that eradicating of stem cells (emptying of the niche) alone will not lead to eradication of the tumor. Treatment should be directed to cancer stem cells ànd more mature cancer cells.

  17. Side population cells isolated from KATO Ⅲ human gastric cancer cell line have cancer stem cell-like characteristics

    Institute of Scientific and Technical Information of China (English)

    Jun-Jun She; Peng-Ge Zhang; Xuan Wang; Xiang-Ming Che; Zi-Ming Wang

    2012-01-01

    AIM:To investigate whether the side population (SP)cells possess cancer stem cell-like characteristics in vitro and the role of SP cells in tumorigenic process in gastric cancer.METHODS:We analyzed the presence of SP cells in different human gastric carcinoma cell lines,and then isolated and identified the SP cells from the KATO Ⅲ human gastric cancer cell line by flow cytometry.The clonogenic ability and self-renewal were evaluated by clone and sphere formation assays.The related genes were determined by reverse transcription polymerase chain reaction.To compare tumorigenic ability,SP and non-side population (NSP) cells from the KATO Ⅲ human gastric cancer cell line were subcutaneously injected into nude mice.RESULTS:SP cells from the total population accounted for 0.57% in KATO Ⅲ,1.04% in Hs-746T,and 0.02% in AGS (CRL-1739).SP cells could grow clonally and have self-renewal capability in conditioned media.The expression of ABCG2,MDRI,Bmi-1 and Oct-4 was different between SP and NSP cells.However,there was no apparent difference between SP and NSP cells when they were injected into nude mice.CONCLUSION:SP cells have some cancer stem celllike characteristics in vitro and can be used for studying the tumorigenic process in gastric cancer.

  18. Haptoglobin and CCR2 receptor expression in ovarian cancer cells that were exposed to ascitic fluid: exploring a new role of haptoglobin in the tumoral microenvironment.

    Science.gov (United States)

    Garibay-Cerdenares, O L; Hernández-Ramírez, V I; Osorio-Trujillo, J C; Gallardo-Rincón, D; Talamás-Rohana, P

    2015-01-01

    Haptoglobin (Hp) is an acute-phase protein that is produced by the liver to capture the iron that is present in the blood circulation, thus avoiding its accumulation in the blood. Moreover, Hp has been detected in a wide variety of tissues, in which it performs various functions. In addition, this protein is considered a potential biomarker in many diseases, such as cancer, including ovarian carcinoma; however, its participation in the cancerous processes has not yet been determined. The objective of this work was to demonstrate the expression of Hp and its receptor CCR2 in the ovarian cancer cells and its possible involvement in the process of cell migration through changes in the rearrangement of the actin cytoskeleton using western blot and wound-healing assays and confirming by confocal microscopy. Ovarian cancer cells express both Hp and its receptor CCR2 but only after exposure to ascitic fluid, inducing moderated cell migration. However, when the cells are exposed to exogenous Hp, the expression of CCR2 is induced together with drastic changes in the actin cytoskeleton rearrangement. At the same time, Hp induced cell migration in a much more efficient manner than did ascitic fluid. These effects were blocked when the CCR2 synthetic antagonist RS102895 was used to pretreat the cells. These results suggest that Hp-induced changes in the cell morphology, actin cytoskeleton structure, and migration ability of tumor cells, is possibly "preparing" these cells for the potential induction of the metastatic phenotype. PMID:26211665

  19. The role of intratumoral and systemic IL-6 in breast cancer

    DEFF Research Database (Denmark)

    Dethlefsen, Christine; Højfeldt, Grith Westergaard; Hojman, Pernille

    2013-01-01

    circulating IL-6 and risk of breast cancer, prognosis for patients with prevalent disease, adverse effects and interventions to control systemic IL-6 levels in patients are discussed. In summary, direct application of IL-6 on breast cancer cells inhibits proliferation in estrogen receptor positive cells......Chronic low-grade inflammation plays an important role in the pathogenesis of several cancer forms including breast cancer. The pleiotropic cytokine IL-6 is a key player in systemic inflammation, regulating both the inflammatory response and tissue metabolism during acute stimulations. Here, we...... review the associations between IL-6 and breast cancer ranging from in vitro cell culture studies to clinical studies, covering the role of IL-6 in controlling breast cancer cell growth, regulation of cancer stem cell renewal, as well as breast cancer cell migration. Moreover, associations between...

  20. The role of vitamin D in breast cancer

    Directory of Open Access Journals (Sweden)

    Tu Tu Aung

    2011-12-01

    Full Text Available The biological role of vitamin D outside of calcium homeostasis is still under evaluation. The ability of vitamin D to inhibit cell proliferation and induce differentiation makes it a potential modifier of neoplastic transformation. Vitamin D affects the cell cycle, apoptosis, hormone receptors, angiogenesis, and hypoxia, all of which are related to the breast cancer growth, progression and metastasis. A large percentage of the industrial-world population is deficient in vitamin D. Epidemiological evidence suggests that vitamin D deficiency increases the risk of breast cancer. Vitamin D may have synergistic, additive, or antagonistic effects when combined with other therapeutic agents against breast cancer. Vitamin D appears to depress aromatase inhibitor by acting through cytochrome P 450. This evidence along with pre-clinical and clinical studies, justify the inclusion of vitamin D in future clinical trials related to breast cancer in order to determine its efficacy as a part of the breast cancer therapeutic armament.

  1. Role of the Ink4a/Arf tumor suppressors in cerebellar development, stem cells and cancer

    NARCIS (Netherlands)

    Valk-Lingbeek, Merel Esmée

    2005-01-01

    In order to take proper cell fate decisions, cells have to guide their biochemical machinery through the appropriate decisions in both differentiation and proliferation. Especially for stem cells such decisions are critical as they have the capacity to self-renew, i.e. give rise to new daughter stem

  2. Immune and Inflammatory Cell Composition of Human Lung Cancer Stroma.

    Directory of Open Access Journals (Sweden)

    G-Andre Banat

    Full Text Available Recent studies indicate that the abnormal microenvironment of tumors may play a critical role in carcinogenesis, including lung cancer. We comprehensively assessed the number of stromal cells, especially immune/inflammatory cells, in lung cancer and evaluated their infiltration in cancers of different stages, types and metastatic characteristics potential. Immunohistochemical analysis of lung cancer tissue arrays containing normal and lung cancer sections was performed. This analysis was combined with cyto-/histomorphological assessment and quantification of cells to classify/subclassify tumors accurately and to perform a high throughput analysis of stromal cell composition in different types of lung cancer. In human lung cancer sections we observed a significant elevation/infiltration of total-T lymphocytes (CD3+, cytotoxic-T cells (CD8+, T-helper cells (CD4+, B cells (CD20+, macrophages (CD68+, mast cells (CD117+, mononuclear cells (CD11c+, plasma cells, activated-T cells (MUM1+, B cells, myeloid cells (PD1+ and neutrophilic granulocytes (myeloperoxidase+ compared with healthy donor specimens. We observed all of these immune cell markers in different types of lung cancers including squamous cell carcinoma, adenocarcinoma, adenosquamous cell carcinoma, small cell carcinoma, papillary adenocarcinoma, metastatic adenocarcinoma, and bronchioloalveolar carcinoma. The numbers of all tumor-associated immune cells (except MUM1+ cells in stage III cancer specimens was significantly greater than those in stage I samples. We observed substantial stage-dependent immune cell infiltration in human lung tumors suggesting that the tumor microenvironment plays a critical role during lung carcinogenesis. Strategies for therapeutic interference with lung cancer microenvironment should consider the complexity of its immune cell composition.

  3. Role of KCNMA1 in breast cancer.

    Directory of Open Access Journals (Sweden)

    Martin Oeggerli

    Full Text Available KCNMA1 encodes the α-subunit of the large conductance, voltage and Ca(2+-activated (BK potassium channel and has been reported as a target gene of genomic amplification at 10q22 in prostate cancer. To investigate the prevalence of the amplification in other human cancers, the copy number of KCNMA1 was analyzed by fluorescence-in-situ-hybridization (FISH in 2,445 tumors across 118 different tumor types. Amplification of KCNMA1 was restricted to a small but distinct fraction of breast, ovarian and endometrial cancer with the highest prevalence in invasive ductal breast cancers and serous carcinoma of ovary and endometrium (3-7%. We performed an extensive analysis on breast cancer tissue microarrays (TMA of 1,200 tumors linked to prognosis. KCNMA1 amplification was significantly associated with high tumor stage, high grade, high tumor cell proliferation, and poor prognosis. Immunofluorescence revealed moderate or strong KCNMA1 protein expression in 8 out of 9 human breast cancers and in the breast cancer cell line MFM223. KCNMA1-function in breast cancer cell lines was confirmed by whole-cell patch clamp recordings and proliferation assays, using siRNA-knockdown, BK channel activators such as 17ß-estradiol and the BK-channel blocker paxilline. Our findings revealed that enhanced expression of KCNMA1 correlates with and contributes to high proliferation rate and malignancy of breast cancer.

  4. Radiobiological characteristics of cancer stem cells from esophageal cancer cell lines

    OpenAIRE

    Wang, Jian-Lin; Yu, Jing-Ping; Zhi-qiang SUN; Sun, Su-Ping

    2014-01-01

    AIM: To study the cancer stem cell population in esophageal cancer cell lines KYSE-150 and TE-1 and identify whether the resulting stem-like spheroid cells display cancer stem cells and radiation resistance characteristics.

  5. The role of FDG-PET in the treatment of stereotactic body radiotherapy for early stage non-small cell lung cancer

    International Nuclear Information System (INIS)

    FDG-PET/CT plays various roles in diagnosis and treatment of malignancies. Currently, stereotactic body radiation therapy(SBRT) is considered as a treatment option for patients with medically inoperable early-stage non-small cell lung cancer. As it is relatively new treatment and is often used for inoperable, elder and/or frail patients, it has many controversial problems including diagnosis. Taking advantage of its non-invasiveness, FDG-PET/CT plays various roles in a process of SBRT as well. First, FDG-PET/CT assists diagnosis of solitary pulmonary nodules without pathological confirmation, along with clinical and tumor characteristics. Generally, the threshold SUVmax for malignancy is regarded as 2.5. SUVmax is used as one of the parameters to determine the probability of malignancy in solitary pulmonary nodule. Second, FDG-PET/CT is used for staging especially for hilar and mediastinal lymph node and distant metastasis. For treatment planning of SBRT, FDG-PET/CT provides useful information in differentiating a tumor from atelectasis. In follow-up, FDG-PET/CT can differentiate local recurrences from fibrotic opacities after SBRT more accurately than morphologic changes on CT images. Therefore, FDG-PET/CT is necessary in the entire process of SBRT. (author)

  6. Chemotherapy targeting cancer stem cells

    OpenAIRE

    Liu, Haiguang; Lv, Lin; Yang, Kai

    2015-01-01

    Conventional chemotherapy is the main treatment for cancer and benefits patients in the form of decreased relapse and metastasis and longer overall survival. However, as the target therapy drugs and delivery systems are not wholly precise, it also results in quite a few side effects, and is less efficient in many cancers due to the spared cancer stem cells, which are considered the reason for chemotherapy resistance, relapse, and metastasis. Conventional chemotherapy limitations and the cance...

  7. The Roles of MicroRNAs in Breast Cancer

    International Nuclear Information System (INIS)

    MicroRNAs (miRNAs) constitute a large family of small, approximately 20–22 nucleotide, non-coding RNAs that regulate the expression of target genes, mainly at the post-transcriptional level. Accumulating lines of evidence have indicated that miRNAs play important roles in the maintenance of biological homeostasis and that aberrant expression levels of miRNAs are associated with the onset of many diseases, including cancer. In various cancers, miRNAs play important roles in tumor initiation, drug resistance and metastasis. Recent studies reported that miRNAs could also be secreted via small endosome-derived vesicles called exosomes, which are derived from multiple cell types, including dendritic cells, lymphocytes, and tumor cells. Exosomal miRNAs play an important role in cell-to-cell communication and have been investigated as prognostic and diagnostic biomarkers. In this review, we summarize the major findings related to the functions of miRNAs in breast cancer, which is the most frequent cancer in women, and discuss the potential clinical uses of miRNAs, including their roles as therapeutic targets and diagnostic markers

  8. The Roles of MicroRNAs in Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, Ryou-u [Division of Molecular and Cellular Medicine, National Cancer Center Research Institute 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045 (Japan); Miyazaki, Hiroaki [Division of Molecular and Cellular Medicine, National Cancer Center Research Institute 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045 (Japan); Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, 1-5-8 Hatanodai Shinagawa-ku, Tokyo 142-8555 (Japan); Ochiya, Takahiro, E-mail: tochiya@ncc.go.jp [Division of Molecular and Cellular Medicine, National Cancer Center Research Institute 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045 (Japan)

    2015-04-09

    MicroRNAs (miRNAs) constitute a large family of small, approximately 20–22 nucleotide, non-coding RNAs that regulate the expression of target genes, mainly at the post-transcriptional level. Accumulating lines of evidence have indicated that miRNAs play important roles in the maintenance of biological homeostasis and that aberrant expression levels of miRNAs are associated with the onset of many diseases, including cancer. In various cancers, miRNAs play important roles in tumor initiation, drug resistance and metastasis. Recent studies reported that miRNAs could also be secreted via small endosome-derived vesicles called exosomes, which are derived from multiple cell types, including dendritic cells, lymphocytes, and tumor cells. Exosomal miRNAs play an important role in cell-to-cell communication and have been investigated as prognostic and diagnostic biomarkers. In this review, we summarize the major findings related to the functions of miRNAs in breast cancer, which is the most frequent cancer in women, and discuss the potential clinical uses of miRNAs, including their roles as therapeutic targets and diagnostic markers.

  9. Dominant B-cell epitopes from cancer/stem cell antigen SOX2 recognized by serum samples from cancer patients

    OpenAIRE

    Shih, Julia; Rahman, Munira; Luong, Quang T; Lomeli, Shirley H.; Riss, Joseph; Prins, Robert M.; Gure, Ali O.; Zeng, Gang

    2014-01-01

    Human sex determining region Y-box 2 (SOX2) is an important transcriptional factor involved in the pluripotency and stemness of human embryonic stem cells. SOX2 plays important roles in maintaining cancer stem cell activities of melanoma and cancers of the brain, prostate, breast, and lung. SOX2 is also a lineage survival oncogene for squamous cell carcinoma of the lung and esophagus. Spontaneous cellular and humoral immune responses against SOX2 present in cancer patients classify it as a tu...

  10. Role of nucleostemin in growth regulation of gastric cancer,liver cancer and other malignancies

    Institute of Scientific and Technical Information of China (English)

    Si-Jin Liu; Zi-Wei Cai; Ya-Jun Liu; Mei-Yu Dong; Li-Qiu Sun; Guo-Fa Hu; Ying-Yun Wei; Wei-De Lao

    2004-01-01

    AIM: To examine the role of nucleostemin in the growth regulation of gastric cancer, liver cancer and other cancers.METHODS: RT-PCR was used to clone the fragment ofnucleostemin cDNA from HEK 293 cells. Eighteen kinds of malignant tumor tissues including gastric adenocarcinoma and liver cancer tissues, 3 kinds of benign tumor tissues, 3kinds of benign hyperplastic tissues and normal tissues were employed to examine nucleostemin gene expression by RT-PCR, Slot blot, Northern blot andin situ hybridization.RESULTS: We successfully cloned a 570 bp fragment of nucleostemin-cDNA from HEK-293 cells. All detected malignant tumor tissues, benign tumor tissues, and benign hyperplastic tissues had high levels of nucleostemin expression. Nucleostemin was also expressed in human placenta tissue at a high level. In terminally differentiated normal human adult kidney and mammary gland tissues,no nucleostemin expression could be detected.CONCLUSION: Nucleostemin can help regulate the proliferation of both cancer cells and stem cells. It might play an important role in the growth regulation of gastric cancer, liver cancer and other cancers.

  11. Single cancer cell analysis on a chip

    OpenAIRE

    Yang, Yoonsun

    2016-01-01

    Cancer cells in blood may represent “a real time liquid biopsy” through the interrogation of single cancer cells thereby determining the outspread of their heterogeneity and guiding therapy. In this thesis, we focused on single cancer cell analysis downstream of the isolation of cancer cells from blood. We designed and developed various microfluidic devices for genetic and phenotypic characterization of single cancer cells. The limited DNA content in a single cell requires DNA amplification t...

  12. Cell of origin of lung cancer

    OpenAIRE

    Hanna, Jennifer M.; Onaitis, Mark W.

    2013-01-01

    Lung cancer is the leading cause of cancer deaths worldwide, and current therapies are disappointing. Elucidation of the cell(s) of origin of lung cancer may lead to new therapeutics. In addition, the discovery of putative cancer-initiating cells with stem cell properties in solid tumors has emerged as an important area of cancer research that may explain the resistance of these tumors to currently available therapeutics. Progress in our understanding of normal tissue stem cells, tumor cell o...

  13. Head and Neck Cancer Stem Cells

    OpenAIRE

    Krishnamurthy, S.; Nör, J.E.

    2012-01-01

    Most cancers contain a small sub-population of cells that are endowed with self-renewal, multipotency, and a unique potential for tumor initiation. These properties are considered hallmarks of cancer stem cells. Here, we provide an overview of the field of cancer stem cells with a focus on head and neck cancers. Cancer stem cells are located in the invasive fronts of head and neck squamous cell carcinomas (HNSCC) close to blood vessels (perivascular niche). Endothelial cell-initiated signalin...

  14. Colorectal cancer cell lines made resistant to SN38-and Oxaliplatin: Roles of altered ion transporter function in resistance?

    DEFF Research Database (Denmark)

    Sandra, Christensen; Jensen, Niels Frank; Stoeckel, Johanne Danmark; Belling, Kirstine C.; Romer, Maria Unni; Gupta, Ramneek; Brunner, Nils; Pedersen, Stine Helene Falsig; Stenvang, Jan

    2013-01-01

    resistance in HCT-116, HT-29 and LoVo cells. Microarray analysis and qPCR validation showed that mRNA expression of glutamate transporters SLC1A1 and SLC1A3 were markedly altered in resistant cells. Remarkably, mRNA levels of SLC1A3 were increased by ~40-and ~2500-fold in SN38-and Oxp-resistant HT29 cells...

  15. A novel role for 3, 4-dichloropropionanilide (DCPA) in the inhibition of prostate cancer cell migration, proliferation, and hypoxia-inducible factor 1alpha expression

    International Nuclear Information System (INIS)

    The amide class compound, 3, 4-dichloropropionanilide (DCPA) is known to affect multiple signaling pathways in lymphocyte and macrophage including the inhibition of NF-κB ability. However, little is known about the effect of DCPA in cancer cells. Hypoxia-inducible factor 1 (HIF-1) regulates the expression of many genes including vascular endothelial growth factor (VEGF), heme oxygenase 1, inducible nitric oxide synthase, aldolase, enolase, and lactate dehydrogenase A. HIF-1 expression is associated with tumorigenesis and angiogenesis. We used Transwell assay to study cell migration, and used immunoblotting to study specific protein expression in the cells. In this report, we demonstrate that DCPA inhibited the migration and proliferation of DU145 and PC-3 prostate cancer cells induced by serum, insulin, and insulin-like growth factor I (IGF-I). We found that DCPA inhibited HIF-1 expression in a subunit-specific manner in these cancer cell lines induced by serum and growth factors, and decreased HIF-1α expression by affecting its protein stability. DCPA can inhibit prostate cancer cell migration, proliferation, and HIF-1α expression, suggesting that DCPA could be potentially used for therapeutic purpose for prostate cancer in the future

  16. Experimental study of targeting MMP-9 deoxyribozyme role of adhesion and migration in human lung adenocarcinoma cancer cell

    Directory of Open Access Journals (Sweden)

    Weizhong ZENG

    2008-12-01

    Full Text Available Background and objective Deoxyribozyme has high biocatalytic activity and sequence specificity against the target mRNA and inhibits gene expression at mRNA level. The aim of this study is to investigate the impact of targeting MMP-9 deoxyribozyme to cell adhesion and migration in human lung adenocarcinoma cell line A549. Methods The targeting MMP-9 deoxyribozyme was designed by oligofectamine into human lung adenocarcinoma cell line A549.The expression of MMP-9 in cell was detected by Western blot. The cell adhesion and migration after the intervention of deoxyribozyme was observed. Results After targeting MMP-9 deoxyribozyme intervention, the expression of MMP-9 inthe cells compared with the control group was significantly lower (P <0.01, at the same time, the rate of cell adhesion andmigration were significantly decreased. Conclusion Targeting MMP-9 deoxyribozyme inhibited the expression of MMP-9 in human lung adenocarcinoma cell line A549 and effectively prevent cell adhesion and migration.

  17. Myeloid-derived suppressor cells have a central role in attenuated Listeria monocytogenes-based immunotherapy against metastatic breast cancer in young and old mice

    OpenAIRE

    Chandra, D; Jahangir, A.; Quispe-Tintaya, W; Einstein, M H; Gravekamp, C

    2013-01-01

    Background: Myeloid-derived suppressor cells (MDSCs) are present in large numbers in blood of mice and humans with cancer, and they strongly inhibit T-cell and natural killer (NK) cell responses, at young and old age. We found that a highly attenuated bacterium Listeria monocytogenes (Listeriaat)-infected MDSC and altered the immune-suppressing function of MDSC. Methods: Young (3 months) and old (18 months) BALB/cByJ mice with metastatic breast cancer (4T1 model) were immunised with Listeriaa...

  18. A novel activating role of SRC and STAT3 on HGF transcription in human breast cancer cells

    Directory of Open Access Journals (Sweden)

    Elliott Bruce E

    2007-10-01

    Full Text Available Abstract We have previously determined that the HGF promoter can be transactivated by a combination of activated Src and wild-type Stat3 in the mouse breast cell lines HC11 and SP1. To determine if this pathway is of relevance for the human disease, a series of human breast and other human cells lines were examined, and the status of key proteins in these cells determined. All of the human breast cell lines exhibited strong transactivation by a combination of activated Src and Stat3. This activation was dependent on a Stat3 recognition element present at nt-95. The exception was the ErbB2 over-expressing cell line SK-BR-3 where Stat3 alone could transactivate HGF though Src augmented this effect. Increased phosphorylation of Stat3 tyrosine 705 was also observed in this line. Analysis of three ovarian cell lines revealed that Src/Stat3 expression was not able to activate the HGF promoter in two of these lines (SKOV3 and IOSE-80PC. Src/Stat3 expression did activate HGF transcription in OVCAR3 cells, but this effect was not mediated by the Stat3 site at nt-95. Stat3 phosphorylation at tyrosine 705 was observed in IOSE-80PC cells, but was insufficient to allow for activation of the HGF promoter. Human kidney (HEK293 and cervical carcinoma (HeLa cells were also not Src/Stat3 permissive, despite high levels of Stat3 phospho-Y705. These results suggest that human breast cells are a uniquely permissive environment for HGF transactivation by Src/Stat3 which may allow for the inappropriate activation of HGF transcription during the early stages of breast transformation. This could lead to paracrine or autocrine activation of the Met receptor in breast carcinoma cells.

  19. Induction of pyroptosis in colon cancer cells by LXRβ

    Science.gov (United States)

    Rébé, Cédric; Derangère, Valentin; Ghiringhelli, François

    2015-01-01

    Liver X receptors (LXRs) have been proposed to have some anticancer properties. We recently identified a new non-genomic role of LXRβ in colon cancer cells. Under LXR agonist treatment, LXRβ induces pyroptosis of these cells in vitro and in vivo, raising the possibility of targeting this isoform in cancer treatment.

  20. Critical role of △DNMT3B4/2 in regulating RASSF1A promoter specific DNA methylation in non-small cell lung cancer

    Institute of Scientific and Technical Information of China (English)

    WANG Shu-hang; LIU Nin-hong; WANG Jie; BAI Hua; MAO Li

    2008-01-01

    Background △DNMT3B (a new DNMT3B subfamily) expression is initiated through a novel promoter.We identified at least 7 transcription variants of △DNMT3B as a result of alternative pre-mRNA processing.The aim of this study was to detect the expression pattern of △DNMT3B variants in non-small cell lung cancer (NSCLC) and to explore the role of △DNMT3B variants in regulating the promoter-specific DNA methylation.Methods Specific polymerase chain reaction (PCR) primer sets were designed to distinguish individual △DNMT3B variants according to their splicing pattems.The expressions of seven △DNMT3B variants were measured in 13 cell lines,109 NSCLC patients,and the corresponding normal lung tissues using reverse transcription-PCR (RT-PCR).The status of the p16 and RASSF1A promoter methylations in the tumors was detected using a methylation specific PCR (MSP).The relationships of the expression patterns of the △DNMT3B variants were analyzed by observing the status of p16 and RASSF1A promoter methylations in the tumors.The siRNA and the anti-sense oligo-dioxynucleotide specifically targeting the junction of exon 5 and 7 of △DNMT3B were designed and transfected by lipofectmane 2000 into H1299 and H358 cell lines.RASSF1A promoter methylation from cells treated by siRNA-△DNMT3B4/2 was detected using MSP and Bisulfite sequencing,and Western blotting was used to detect the protein expression of DNMT3B and △DNMT3B.Cell growth and cell cycle distribution were measured by applying real-time cell growth analysis and flowcytometry,respectively.Results △DNMT3B variants,not DNMT3B,were the predominant transcripts in both NSCLC cell lines and primary tumors.The expression of △DNMT3B4 strongly correlated to the promoter methylation status of RASSFIA in a primary NSCLC.The knockdown of △DNMT3B4/2 by RNA-interference or anti-sense approaches resulted in a complete demethylation of RASSF1A promoter with the reactJvation of a RASSFIA gene expression in less than 12

  1. The role of PET in thyroid cancer

    Energy Technology Data Exchange (ETDEWEB)

    Seok, Yeo Jeong [College of Medicine, Ulsan Univ., Seoul (Korea, Republic of)

    2002-06-01

    The role of PET in the diagnosis and management of thyroid cancer is discussed. The major role of F-18 FDG PET is in patients with discordant negative I-131 scan and a positive serum thyroglobulin values. F-18 FDG PET scan localized metastatic sites in I-131 scan-negative thyroid carcinoma patients with high accuracy. F-18 PET is also valuable in medullary thyroid cancer with high calcitonin level. Focal thyroid uptake in patients with non-thyroidal disease has high likelihood of thyroid cancer.

  2. New insights into pancreatic cancer stem cells

    Institute of Scientific and Technical Information of China (English)

    Chinthalapally V Rao; Altaf Mohammed

    2015-01-01

    Pancreatic cancer (PC) has been one of the deadliest of allcancers, with almost uniform lethality despite aggressivetreatment. Recently, there have been important advancesin the molecular, pathological and biological understandingof pancreatic cancer. Even after the emergence of recentnew targeted agents and the use of multiple therapeuticcombinations, no treatment option is viable in patients withadvanced cancer. Developing novel strategies to targetprogression of PC is of intense interest. A small populationof pancreatic cancer stem cells (CSCs) has been foundto be resistant to chemotherapy and radiation therapy.CSCs are believed to be responsible for tumor initiation,progression and metastasis. The CSC research has recentlyachieved much progress in a variety of solid tumors,including pancreatic cancer to some extent. This leads tofocus on understanding the role of pancreatic CSCs. Thefocus on CSCs may offer new targets for prevention andtreatment of this deadly cancer. We review the most salientdevelopments in important areas of pancreatic CSCs. Here,we provide a review of current updates and new insightson the role of CSCs in pancreatic tumor progression withspecial emphasis on DclK1 and Lgr5, signaling pathwaysaltered by CSCs, and the role of CSCs in prevention andtreatment of PC.

  3. Lung cancer brain metastases – the role of neurosurgery

    Directory of Open Access Journals (Sweden)

    V. A. Aleshin

    2016-01-01

    Full Text Available Lung cancer is mostly common occurring oncological disease in the developed countries. Currently lung cancers are subdivided into nonsmall-cell (adenocarcinoma, large-cell, squamous cell and small-cell. The difference in the clinical and morphological picture leads to the necessity of choosing therapeutic approaches to patients of various groups.Lung cancer should be referred to encephalotropic diseases since metastatic lesion of the central nervous system is sufficiently common complication. Successes of complex treatment of primary tumor result in increase of total longlivety currently ther is ageing of patients suffering lung cancer. These factors increase the risk of metastatic lesions of the brain.Interest to the problem of neurosurgical treatment of patients suffering lung cancer is determined by frequency of lesion, varicosity of morphological variants of the disease, requiring various algorithms of treatment and diagnosis.The main role of neurosurgical intervention in cerebral metastases of lung cancer consist in creation of the paled of carrying out combined therapy. Ideally, a neurosurgical operation should be carried out with clearcut observance of oncological principles of ablasty.Adequate comprehensive approach to treatment or patients with cerebral metastases of various forms of lung cancer with the developed of optimal tactics of and stages of treatment would make it possible to increase duration and quality of life of patients.

  4. Nanoquinacrine induced apoptosis in cervical cancer stem cells through the inhibition of hedgehog-GLI1 cascade: Role of GLI-1.

    Science.gov (United States)

    Nayak, Anmada; Satapathy, Shakti Ranjan; Das, Dipon; Siddharth, Sumit; Tripathi, Neha; Bharatam, Prasad V; Kundu, ChanakyaNath

    2016-01-01

    To improve the pharmacokinetics and to study the anti-cervical cancer and anti-stem cells (CSCs) mechanism of Quinacrine (QC), a spherical nano particle of QC (i.e. NQC) was prepared and characterized. QC and NQC showed higher cytotoxicity in multiple cancer cells than the normal epithelial cells. NQC exhibited more toxicity in cervical cancer cells and its CSCs than QC. A dose-dependent decreased expression of Hedgehog-GLI (HH-GLI) components were noted in NQC treated HeLa cells and its CSCs. NQC increased the expressions of negatively regulated HH-GLI components (GSK3β, PTEN) and caused apoptosis in CSCs. Reduction of GLI1 at mRNA and promoter level were noted after NQC exposure. The expressions of HH-GLI components, GLI1 promoter activity and apoptosis were unaltered in NQC treated GLI1-knockdown cells. In silico, cell based and in vitro reconstitution assay revealed that NQC inhibit HH-GLI cascade by binding to the consensus sequence (5'GACCACCCA3') of GLI1 in GLI-DNA complex through destabilizing DNA-GLI1 complex. NQC reduced the tumors size and proliferation marker Ki-67 in an in vivo xenograft mice model. Thus, NQC induced apoptosis in cancers through inhibition of HH-GLI cascade by GLI1. Detail interaction of QC-DNA-GLI complex can pave path for anticancer drug design. PMID:26846872

  5. Cancer Stem Cell Hypothesis: Implication for Cancer Prevention and Treatment

    OpenAIRE

    Anna Meiliana; Nurrani Mustika Dewi; Andi Wijaya

    2016-01-01

    BACKGROUND: Cancer is a disease of genomic instability, evasion of immune cells, and adaptation of the tumor cells to the changing environment. Genetic heterogeneity caused by tumors and tumor microenvironmental factors forms the basis of aggressive behavior of some cancer cell populations. CONTENT: Cancers arise in self-renewing cell populations and that the resulting cancers, like their normal organ counterparts, are composed of hierarchically organized cell populations. Self–renewing “...

  6. Prostate Cancer Stem Cells: Research Advances

    OpenAIRE

    Dagmara Jaworska; Wojciech Król; Ewelina Szliszka

    2015-01-01

    Cancer stem cells have been defined as cells within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor. Experimental evidence showed that these highly tumorigenic cells might be responsible for initiation and progression of cancer into invasive and metastatic disease. Eradicating prostate cancer stem cells, the root of the problem, has been considered as a promising target in prostate cancer treatment to improve th...

  7. Role of Pericellular Matrix in the Regulation of Cancer Stemness.

    Science.gov (United States)

    Avnet, Sofia; Cortini, Margherita

    2016-08-01

    Cancer stem cells (CSC) are a prominent component of the tumor bulk and extensive research has now identified them as the subpopulation responsible for tumor relapse and resistance to anti-cancer treatments. Surrounding the bulk formed of tumor cells, an extracellular matrix contributes to cancer growth; the main component of the tumor micro-environment is hyaluronan, a large disaccharide forming a molecular network surrounding the cells. The hyaluronan-dependent coat can regulate cell division and motility in cancer progression and metastasis. One of the receptors of hyaluronan is CD44, a surface protein frequently used as a CSC marker. Indeed, tumor cells with high levels of CD44 appear to exhibit CSC properties and are characterized by elevated relapse rate. The CD44-hyaluronan-dependent interactions are Janus-faced: on one side, they have been shown to be crucial in both malignancy and resistance to therapy; on the other, they represent a potential value for future therapies, as disturbing the CD44-hyaluronan axis would not only impair the pericellular matrix but also the subpopulation of self-renewing oncogenic cells. Here, we will review the key roles of HA and CD44 in CSC maintenance and propagation and will show that CSC-like spheroids from a rabdhomyosarcoma cell line, namely RD, have a prominent pericellular coat necessary for sphere formation and for elevated migration. Thus, a better understanding of the hyaluronan-CD44 interactions holds the potential for ameliorating current cancer therapies and eradicating CSC. PMID:27193782

  8. The role of stem cells in the prevention and treatment of radiation-induced xerostomia in patients with head and neck cancer.

    Science.gov (United States)

    Nevens, Daan; Nuyts, Sandra

    2016-06-01

    Xerostomia is an important complication following radiotherapy (RT) for head and neck cancer. Current treatment approaches are insufficient and can only temporarily relieve symptoms. New insights into the physiopathology of radiation-induced xerostomia might help us in this regard. This review discusses the current knowledge of salivary gland stem cells in radiation-induced xerostomia and their value in the prevention and treatment of this complication. Salivary gland stem cell transplantation, bone marrow-derived cell mobilization, molecular regulation of parotid stem cells, stem cell sparing RT, and adaptive RT are promising techniques that are discussed in this study. PMID:26880659

  9. Transcriptional profiling of human breast cancer cells cultured under microgravity conditions revealed the key role of genetic gravity sensors previously detected in Drosophila melanogaster

    Science.gov (United States)

    Valdivia-Silva, Julio E.; Lavan, David; Diego Orihuela-Tacuri, M.; Sanabria, Gabriela

    2016-07-01

    Currently, studies in Drosophila melanogaster has shown emerging evidence that microgravity stimuli can be detected at the genetic level. Analysis of the transcriptome in the pupal stage of the fruit flies under microgravity conditions versus ground controls has suggested the presence of a few candidate genes as "gravity sensors" which are experimentally validated. Additionally, several studies have shown that microgravity causes inhibitory effects in different types of cancer cells, although the genes involved and responsible for these effects are still unknown. Here, we demonstrate that the genes suggested as the sensors of gravitational waves in Drosophila melanogaster and their human counterpart (orthologous genes) are highly involved in carcinogenesis, proliferation, anti-apoptotic signals, invasiveness, and metastatic potential of breast cancer cell tumors. The transcriptome analyses suggested that the observed inhibitory effect in cancer cells could be due to changes in the genetic expression of these candidates. These results encourage the possibility of new therapeutic targets managed together and not in isolation.

  10. A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma.

    OpenAIRE

    Brash, D E; Rudolph, J A; Simon, J A; Lin, A.; McKenna, G J; Baden, H P; Halperin, A J; Pontén, J

    1991-01-01

    Sunlight is a carcinogen to which everyone is exposed. Its UV component is the major epidemiologic risk factor for squamous cell carcinoma of the skin. Of the multiple steps in tumor progression, those that are sunlight-related would be revealed if they contained mutations specific to UV. In a series of New England and Swedish patients, we find that 14/24 (58%) of invasive squamous cell carcinomas of the skin contain mutations in the p53 tumor suppressor gene, each altering the amino acid seq...

  11. Identification of genes involved in breast cancer and breast cancer stem cells

    Directory of Open Access Journals (Sweden)

    Apostolou P

    2015-07-01

    Full Text Available Panagiotis Apostolou, Maria Toloudi, Ioannis Papasotiriou Research and Development Department, Research Genetic Cancer Centre Ltd, Florina, Greece Abstract: Breast cancer is the most frequent type of cancer in women. Great progress has been made in its treatment but relapse is common. One hypothesis to account for the high recurrence rates is the presence of cancer stem cells (CSCs, which have the ability to self-renew and differentiate into multiple malignant cell types. This study aimed to determine genes that are expressed in breast cancer and breast CSCs and to investigate their correlation with stemness. RNA was extracted from established breast cancer cell lines and from CSCs derived from five different breast cancer patients. DNA microarray analysis was performed and any upregulated genes were also studied in other cancer types, including colorectal and lung cancer. For genes that were expressed only in breast cancer, knockdown-based experiments were performed. Finally, the gene expression levels of stemness transcription factors were measured. The outcome of the analysis indicated a group of genes that were aberrantly expressed mainly in breast cancer cells with stemness properties. Knockdown experiments confirmed the impact of several of these on NANOG, OCT3/4, and SOX2 transcription factors. It seems that several genes that are not directly related with hormone metabolism and basic signal transduction pathways might have an important role in relapse and disease progression and, thus, can be targeted for new treatment approaches for breast cancer. Keywords: breast cancer, cancer stem cells, stemness, DNA microarray

  12. Mechanisms of Translocation of ER Chaperones to the Cell Surface and Immunomodulatory Roles in Cancer and Autoimmunity

    NARCIS (Netherlands)

    Wiersma, Valerie; Michalak, Marek; Abdullah, Trefa M; Bremer, Edwin; Eggleton, Paul

    2015-01-01

    Endoplasmic reticulum (ER) chaperones (e.g., calreticulin, heat shock proteins, and isomerases) perform a multitude of functions within the ER. However, many of these chaperones can translocate to the cytosol and eventually the surface of cells, particularly during ER stress induced by e.g., drugs,

  13. Cytosolic Phospholipase A2 and Its Role in Cancer

    Directory of Open Access Journals (Sweden)

    Jia-jia Hu

    2011-06-01

    Full Text Available Cytosolic phospholipase A2a (cPLA2a catalyzes the release of arachidonic acid (AA and lysophosphoglyceride from membrane phospholipids. Although the roles of AA and eicosanoids in cellular viability, the processes of inflammation and cancer cell development have been extensively studied, the function of cPLA2α in the processes of inflammation and cancer cell development is not clear. This review summarizes published evidences for the biochemical properties and regulatory mechanisms of cPLA2a. The potential for use of cPLA2a as a novel diagnostic target and predictive biomarker for tumors is also discussed.

  14. The cancer-germline antigen SSX2 causes cell cycle arrest and DNA damage in cancer cells

    DEFF Research Database (Denmark)

    Greve, Katrine Buch Vidén; Lindgreen, Jonas; Terp, Mikkel Green;

    2011-01-01

    increase in the number of gamma-H2AX ‘DNA damage foci’, indicating replicative stress, which may lead to genomic instability. As the p53 tumor suppressor is an inducer of G1 arrest after DNA damage and often deregulated in cancer cells, we investigated if the growth reduction due to SSX2 expression was p53...... dependent. The growth reduction was similar in isogenic colon cancer cells with and without p53, indicating that SSX2 is able to inhibit the growth of cancer cells, even in absence of functional p53. Our results show that SSX2 acts as an inhibitor of cancer cell proliferation, possibly through replicative......The SSX family of cancer and germline antigens is mainly expressed in the germ cells of healthy individuals as well as wide range of cancers and is therefore potential targets for immunotherapy. However, little is known about the role of SSX proteins in tumorigenesis and normal cell function. Here...

  15. Viral oncogenesis and its role in nonmelanoma skin cancer.

    LENUS (Irish Health Repository)

    Tuttleton Arron, S

    2011-06-01

    In recent years, the contribution of viruses to cutaneous oncogenesis has steadily gained recognition. The archetype is human herpesvirus 8, which is well established as the causative agent in Kaposi sarcoma. Other viruses believed to play a role in nonmelanoma skin cancer include human papillomavirus and the recently described Merkel cell polyomavirus. We review the mechanisms by which these three viruses interact with the host cell, ultraviolet radiation and immunosuppression to result in carcinogenesis.

  16. The role of vitamin D in breast cancer

    OpenAIRE

    Tu Tu Aung; Chandana, Sreenivasa R; Karl J. D’Silva; Dimitrov, Nikolay V.

    2011-01-01

    The biological role of vitamin D outside of calcium homeostasis is still under evaluation. The ability of vitamin D to inhibit cell proliferation and induce differentiation makes it a potential modifier of neoplastic transformation. Vitamin D affects the cell cycle, apoptosis, hormone receptors, angiogenesis, and hypoxia, all of which are related to the breast cancer growth, progression and metastasis. A large percentage of the industrial-world population is deficient in vitamin D. Epidemiolo...

  17. Stem cells in human breast cancer

    OpenAIRE

    Roberto Oliveira, Lucinei; Jeffrey, Stefanie S; Ribeiro Silva, Alfredo

    2010-01-01

    Increasing data support cancer as a stem cell-based disease. Cancer stem cells (CSCs) have beenfound in different human cancers, and recent evidenceindicates that breast cancer originates from and ismaintained by its own CSCs, as well as the normalmammary gland. Mammary stem cells and breast CSCshave been identified and purified in in vitroculturesystems, transplantation assays and/or by cell surfaceantigen identification. Cell surface markers enable thefunctional isolation of stem cells that...

  18. Spheroid formation of human thyroid cancer cells under simulated microgravity: a possible role of CTGF and CAV1

    OpenAIRE

    Warnke, Elisabeth; Pietsch, Jessica; Wehland, Markus; Bauer, Johann; Infanger, Manfred; Görög, Mark; Hemmersbach, Ruth; Braun, Markus; Ma, Xiao; Sahana, Jayashree; Grimm, Daniela

    2014-01-01

    Background: Multicellular tumor spheroids (MCTS) formed scaffold-free under microgravity are of high interest for research and medicine. Their formation mechanism can be studied in space in real microgravity or on Earth using ground-based facilities (GBF), which simulate microgravity. On Earth, these experiments are more cost-efficient and easily performable. However, each GBF might exert device-specific and altered superimposingly gravity-dependent effects on the cells. Result...

  19. Cancer stem cell markers in common cancers - therapeutic implications

    DEFF Research Database (Denmark)

    Klonisch, Thomas; Wiechec, Emilia; Hombach-Klonisch, Sabine;

    2008-01-01

    Rapid advance in the cancer stem cell field warrants optimism for the development of more reliable cancer therapies within the next 2-3 decades. Below, we characterize and compare the specific markers that are present on stem cells, cancer cells and cancer stem cells (CSC) in selected tissues......, the last part of the review discusses future directions of this intriguing new research field in the context of new diagnostic and therapeutic opportunities....

  20. Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells

    OpenAIRE

    Chang W. Song; Hyemi Lee; Dings, Ruud P. M.; Brent Williams; John Powers; Troy Dos Santos; Bo-Hwa Choi; Heon Joo Park

    2012-01-01

    The anti-cancer effects of metformin, the most widely used drug for type 2 diabetes, alone or in combination with ionizing radiation were studied with MCF-7 human breast cancer cells and FSaII mouse fibrosarcoma cells. Clinically achievable concentrations of metformin caused significant clonogenic death in cancer cells. Importantly, metformin was preferentially cytotoxic to cancer stem cells relative to non-cancer stem cells. Metformin increased the radiosensitivity of cancer cells in vitro, ...

  1. The emerging role of histology in the choice of first-line treatment of advanced non-small cell lung cancer: implication in the clinical decision-making.

    Science.gov (United States)

    Rossi, Antonio; Maione, Paolo; Bareschino, Maria Anna; Schettino, Clorinda; Sacco, Paola Claudia; Ferrara, Marianna Luciana; Castaldo, Vincenzo; Gridelli, Cesare

    2010-01-01

    Lung cancer is the leading cause of cancer mortality worldwide. Non-small cell lung cancer (NSCLC), accounting for about 85% of all lung cancers, includes squamous carcinoma, adenocarcinoma and undifferentiated large cell carcinoma. The majority of patients have advanced disease at diagnosis, and medical treatment is the cornerstone of management. Several randomized trials comparing third-generation platinum-based doublets concluded that all such combinations are comparable in their clinical efficacy, failing to document a difference based on histology. However, recent evidences, arising from the availability of pemetrexed, have shown that histology represents an important variable in the decision making. The major progresses in the understanding cancer biology and mechanism of oncogenesis have allowed the development of several potential molecular targets for cancer treatment such as vascular growth factor and its receptors and epidermal growth factor receptor. Targeted drugs seem to be safer or more effective in a specific histology subtype. All of these data have led to choose the optimal first-line treatment of advanced NSCLC based on histologic diagnosis. However, this scenario raises a diagnostic issue: a specific diagnosis of NSCLC histologic subtype is mandatory. This review will discuss these new evidences in the first-line treatment of advanced NSCLC and their implication in the current clinical decision-making. PMID:20156162

  2. Urinary bladder cancer: role of MR imaging.

    Science.gov (United States)

    Verma, Sadhna; Rajesh, Arumugam; Prasad, Srinivasa R; Gaitonde, Krishnanath; Lall, Chandana G; Mouraviev, Vladimir; Aeron, Gunjan; Bracken, Robert B; Sandrasegaran, Kumaresan

    2012-01-01

    Urinary bladder cancer is a heterogeneous disease with a variety of pathologic features, cytogenetic characteristics, and natural histories. It is the fourth most common cancer in males and the tenth most common cancer in females. Urinary bladder cancer has a high recurrence rate, necessitating long-term surveillance after initial therapy. Early detection is important, since up to 47% of bladder cancer-related deaths may have been avoided. Conventional computed tomography (CT) and magnetic resonance (MR) imaging are only moderately accurate in the diagnosis and local staging of bladder cancer, with cystoscopy and pathologic staging remaining the standards of reference. However, the role of newer MR imaging sequences (eg, diffusion-weighted imaging) in the diagnosis and local staging of bladder cancer is still evolving. Substantial advances in MR imaging technology have made multiparametric MR imaging a feasible and reasonably accurate technique for the local staging of bladder cancer to optimize treatment. In addition, whole-body CT is the primary imaging technique for the detection of metastases in bladder cancer patients, especially those with disease that invades muscle. PMID:22411938

  3. Cancer Stem Cells: Biological Functions and Therapeutically Targeting

    Directory of Open Access Journals (Sweden)

    Marius Eugen Ciurea

    2014-05-01

    Full Text Available Almost all tumors are composed of a heterogeneous cell population, making them difficult to treat. A small cancer stem cell population with a low proliferation rate and a high tumorigenic potential is thought to be responsible for cancer development, metastasis and resistance to therapy. Stem cells were reported to be involved in both normal development and carcinogenesis, some molecular mechanisms being common in both processes. No less controversial, stem cells are considered to be important in treatment of malignant diseases both as targets and drug carriers. The efforts to understand the role of different signalling in cancer stem cells requires in depth knowledge about the mechanisms that control their self-renewal, differentiation and malignant potential. The aim of this paper is to discuss insights into cancer stem cells historical background and to provide a brief review of the new therapeutic strategies for targeting cancer stem cells.

  4. Breast cancer stem cell markers – the rocky road to clinical applications

    OpenAIRE

    Dontu, Gabriela

    2008-01-01

    Lately, understanding the role of cancer stem cells in tumor initiation and progression became a major focus in stem cell biology and in cancer research. Considerable efforts, such as the recent studies by Honeth and colleagues, published in the June issue of Breast Cancer Research, are directed towards developing clinical applications of the cancer stem cell concepts. This work shows that the previously described CD44+CD24- stem cell phenotype is associated with basal-type breast cancers in ...

  5. On the origin and destination of cancer stem cells: a conceptual evaluation

    OpenAIRE

    van de Stolpe, Anja

    2013-01-01

    Despite remaining uncertainties and ongoing research it is possible to draw up a model for the role of (cancer) stem cells in both the initiation and progression of cancer towards metastasis. The cancer stem cell of origin and the cancer stem cell are, despite phenotypic similarities, genotypically different entities. Given the right circumstances provided by a combination of genomic changes and biochemical and physical interactions with its microenvironment, an epithelial cancer cell may und...

  6. Role of autophagy in the ω-3 long chain polyunsaturated fatty acid-induced death of lung cancer A549 cells

    OpenAIRE

    Yao, Qinghua; Fu, Ting; Wang, Lu; LAI, YUEBIAO; Wang, Yuqi; Xu, Chao; Huang, Lulu; Guo, Yong

    2015-01-01

    The present study identified that ω-3 long chain polyunsaturated fatty acids (ω-3 PUFAs), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) demonstrate anti-proliferative effects in lung cancer A549 cells. MTS and cytotoxicity assays were conducted to confirm that ω-3 PUFAs induced cell death. Autophagy-associated gene and signaling pathways were also detected. Microtubule-associated protein light chain 3 (LC3) expression was found to be increased subsequent to treatment with DHA and...

  7. Wnt/β-catenin signaling regulates cancer stem cells in lung cancer A549 cells

    International Nuclear Information System (INIS)

    Wnt/β-catenin signaling plays an important role not only in cancer, but also in cancer stem cells. In this study, we found that β-catenin and OCT-4 was highly expressed in cisplatin (DDP) selected A549 cells. Stimulating A549 cells with lithium chloride (LiCl) resulted in accumulation of β-catenin and up-regulation of a typical Wnt target gene cyclin D1. This stimulation also significantly enhanced proliferation, clone formation, migration and drug resistance abilities in A549 cells. Moreover, the up-regulation of OCT-4, a stem cell marker, was observed through real-time PCR and Western blotting. In a reverse approach, we inhibited Wnt signaling by knocking down the expression of β-catenin using RNA interference technology. This inhibition resulted in down-regulation of the Wnt target gene cyclin D1 as well as the proliferation, clone formation, migration and drug resistance abilities. Meanwhile, the expression of OCT-4 was reduced after the inhibition of Wnt/β-catenin signaling. Taken together, our study provides strong evidence that canonical Wnt signaling plays an important role in lung cancer stem cell properties, and it also regulates OCT-4, a lung cancer stem cell marker.

  8. Cancer of the prostate - role of PSA

    International Nuclear Information System (INIS)

    Since 1979 when prostate specific antigen (PSA), found in the cytoplasm of benign and malignant prostatic cells, was first purified, it has attained world wide popularity in prostate cancer detection. It is also a sensitive test for skeletal meta states from carcinoma of the prostate. Prostate cancer has become the number one cancer in men and constitutes 11% of all cancers. Approximately 50% of men over 50 years have symptoms referable to the lower urinary tract. 50% or more of patients at Ibadan present an advanced stage of the disease and are therefore not curable. Thus, lacking the skill to manage advanced manifestations, early detection and screening programs are the best means to reduce mortality due to prostate cancer

  9. Dendritic Cell-Induced Th1 and Th17 Cell Differentiation for Cancer Therapy

    OpenAIRE

    Julia Terhune; Erik Berk; Czerniecki, Brian J.

    2013-01-01

    The success of cellular immunotherapies against cancer requires the generation of activated CD4+ and CD8+ T-cells. The type of T-cell response generated (e.g., Th1 or Th2) will determine the efficacy of the therapy, and it is generally assumed that a type-1 response is needed for optimal cancer treatment. IL-17 producing T-cells (Th17/Tc17) play an important role in autoimmune diseases, but their function in cancer is more controversial. While some studies have shown a pro-cancerous role for ...

  10. Role of Uncoupling Proteins in Cancer

    International Nuclear Information System (INIS)

    Uncoupling proteins (UCPs) are a family of inner mitochondrial membrane proteins whose function is to allow the re-entry of protons to the mitochondrial matrix, by dissipating the proton gradient and, subsequently, decreasing membrane potential and production of reactive oxygen species (ROS). Due to their pivotal role in the intersection between energy efficiency and oxidative stress, UCPs are being investigated for a potential role in cancer. In this review we compile the latest evidence showing a link between uncoupling and the carcinogenic process, paying special attention to their involvement in cancer initiation, progression and drug chemoresistance

  11. Role of Uncoupling Proteins in Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Valle, Adamo; Oliver, Jordi; Roca, Pilar, E-mail: pilar.roca@uib.es [Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d' Investigació en Ciències de la Salut, Universitat de les Illes Balears/Cra. Valldemossa km 7.5, E-07122, Palma de Mallorca, Illes Balears (Spain)

    2010-04-16

    Uncoupling proteins (UCPs) are a family of inner mitochondrial membrane proteins whose function is to allow the re-entry of protons to the mitochondrial matrix, by dissipating the proton gradient and, subsequently, decreasing membrane potential and production of reactive oxygen species (ROS). Due to their pivotal role in the intersection between energy efficiency and oxidative stress, UCPs are being investigated for a potential role in cancer. In this review we compile the latest evidence showing a link between uncoupling and the carcinogenic process, paying special attention to their involvement in cancer initiation, progression and drug chemoresistance.

  12. Role of Uncoupling Proteins in Cancer

    Directory of Open Access Journals (Sweden)

    Adamo Valle

    2010-04-01

    Full Text Available Uncoupling proteins (UCPs are a family of inner mitochondrial membrane proteins whose function is to allow the re-entry of protons to the mitochondrial matrix, by dissipating the proton gradient and, subsequently, decreasing membrane potential and production of reactive oxygen species (ROS. Due to their pivotal role in the intersection between energy efficiency and oxidative stress, UCPs are being investigated for a potential role in cancer. In this review we compile the latest evidence showing a link between uncoupling and the carcinogenic process, paying special attention to their involvement in cancer initiation, progression and drug chemoresistance.

  13. BM-26CD15 AND E-SELECTIN MEDIATION OF ADHESION OF NON-SMALL CELL LUNG CANCER CELLS TO BRAIN ENDOTHELIUM IN LUNG-BRAIN METASTASIS

    OpenAIRE

    Pilkington, Geoffrey; Jassam, Samah; Maherally, Zaynah; Smith, James; Fillmore, Helen

    2014-01-01

    BACKGROUND: Lung metastases to the brain are common secondary cancers, representing over 50% of fatal complications of systemic cancer. Metastasis of cancer cells involves multiple steps including intravasation, cancer cell-endothelial rolling and adhesion, extravasation and cerebral colonization. Here, we focused on metastatic Non-Small Cell lung cancer cells adhesion to brain endothelial cells. Specifically, we investigated the role of CD15 in lung cancer and its interaction with E-selectin...

  14. Nanomechanical analysis of cells from cancer patients

    Science.gov (United States)

    Cross, Sarah E.; Jin, Yu-Sheng; Rao, Jianyu; Gimzewski, James K.

    2007-12-01

    Change in cell stiffness is a new characteristic of cancer cells that affects the way they spread. Despite several studies on architectural changes in cultured cell lines, no ex vivo mechanical analyses of cancer cells obtained from patients have been reported. Using atomic force microscopy, we report the stiffness of live metastatic cancer cells taken from the body (pleural) fluids of patients with suspected lung, breast and pancreas cancer. Within the same sample, we find that the cell stiffness of metastatic cancer cells is more than 70% softer, with a standard deviation over five times narrower, than the benign cells that line the body cavity. Different cancer types were found to display a common stiffness. Our work shows that mechanical analysis can distinguish cancerous cells from normal ones even when they show similar shapes. These results show that nanomechanical analysis correlates well with immunohistochemical testing currently used for detecting cancer.

  15. Metformin inhibition of mTORC1 activation, DNA synthesis and proliferation in pancreatic cancer cells: Dependence on glucose concentration and role of AMPK

    Energy Technology Data Exchange (ETDEWEB)

    Sinnett-Smith, James; Kisfalvi, Krisztina; Kui, Robert [Division of Digestive Diseases, Department of Medicine, CURE: Digestive Diseases Research Center, David Geffen School of Medicine and Molecular Biology Institute, University of California at Los Angeles, CA (United States); Rozengurt, Enrique, E-mail: erozengurt@mednet.ucla.edu [Division of Digestive Diseases, Department of Medicine, CURE: Digestive Diseases Research Center, David Geffen School of Medicine and Molecular Biology Institute, University of California at Los Angeles, CA (United States)

    2013-01-04

    Highlights: Black-Right-Pointing-Pointer Metformin inhibits cancer cell growth but the mechanism(s) are not understood. Black-Right-Pointing-Pointer We show that the potency of metformin is sharply dependent on glucose in the medium. Black-Right-Pointing-Pointer AMPK activation was enhanced in cancer cells incubated in physiological glucose. Black-Right-Pointing-Pointer Reciprocally, metformin potently inhibited mTORC1, DNA synthesis and proliferation. Black-Right-Pointing-Pointer Metformin, at low concentrations, inhibited DNA synthesis through AMPK. -- Abstract: Metformin, a widely used anti-diabetic drug, is emerging as a potential anticancer agent but the mechanisms involved remain incompletely understood. Here, we demonstrate that the potency of metformin induced AMPK activation, as shown by the phosphorylation of its substrates acetyl-CoA carboxylase (ACC) at Ser{sup 79} and Raptor at Ser{sup 792}, was dramatically enhanced in human pancreatic ductal adenocarcinoma (PDAC) cells PANC-1 and MiaPaCa-2 cultured in medium containing physiological concentrations of glucose (5 mM), as compared with parallel cultures in medium with glucose at 25 mM. In physiological glucose, metformin inhibited mTORC1 activation, DNA synthesis and proliferation of PDAC cells stimulated by crosstalk between G protein-coupled receptors and insulin/IGF signaling systems, at concentrations (0.05-0.1 mM) that were 10-100-fold lower than those used in most previous reports. Using siRNA-mediated knockdown of the {alpha}{sub 1} and {alpha}{sub 2} catalytic subunits of AMPK, we demonstrated that metformin, at low concentrations, inhibited DNA synthesis through an AMPK-dependent mechanism. Our results emphasize the importance of using medium containing physiological concentrations of glucose to elucidate the anticancer mechanism of action of metformin in pancreatic cancer cells and other cancer cell types.

  16. Metformin inhibition of mTORC1 activation, DNA synthesis and proliferation in pancreatic cancer cells: Dependence on glucose concentration and role of AMPK

    International Nuclear Information System (INIS)

    Highlights: ► Metformin inhibits cancer cell growth but the mechanism(s) are not understood. ► We show that the potency of metformin is sharply dependent on glucose in the medium. ► AMPK activation was enhanced in cancer cells incubated in physiological glucose. ► Reciprocally, metformin potently inhibited mTORC1, DNA synthesis and proliferation. ► Metformin, at low concentrations, inhibited DNA synthesis through AMPK. -- Abstract: Metformin, a widely used anti-diabetic drug, is emerging as a potential anticancer agent but the mechanisms involved remain incompletely understood. Here, we demonstrate that the potency of metformin induced AMPK activation, as shown by the phosphorylation of its substrates acetyl-CoA carboxylase (ACC) at Ser79 and Raptor at Ser792, was dramatically enhanced in human pancreatic ductal adenocarcinoma (PDAC) cells PANC-1 and MiaPaCa-2 cultured in medium containing physiological concentrations of glucose (5 mM), as compared with parallel cultures in medium with glucose at 25 mM. In physiological glucose, metformin inhibited mTORC1 activation, DNA synthesis and proliferation of PDAC cells stimulated by crosstalk between G protein-coupled receptors and insulin/IGF signaling systems, at concentrations (0.05–0.1 mM) that were 10–100-fold lower than those used in most previous reports. Using siRNA-mediated knockdown of the α1 and α2 catalytic subunits of AMPK, we demonstrated that metformin, at low concentrations, inhibited DNA synthesis through an AMPK-dependent mechanism. Our results emphasize the importance of using medium containing physiological concentrations of glucose to elucidate the anticancer mechanism of action of metformin in pancreatic cancer cells and other cancer cell types.

  17. The interaction between LYVE-1 with hyaluronan on the cell surface may play a role in the diversity of adhesion to cancer cells.

    Directory of Open Access Journals (Sweden)

    Yan Du

    Full Text Available Hyaluronan (HA, a simple disaccharide unit, can polymerize and is considered a primary component of the extracellular matrix, which has a wide range of biological functions. In recent years, HA was found on the surface of tumor cells. According to previous reports, differing HA content on the cell surface of tumor cells is closely related to lymph node metastases, but the mechanisms mediating this process remained unclear. This research intended to study the surface content of HA on tumor cells and analyze cell adhesive changes caused by the interaction between HA and its lymphatic endothelial receptor (LYVE-1. We screened and observed high HA content on HS-578T breast cells and low HA content on MCF-7 breast cells through particle exclusion, immunofluorescence and flow cytometry experiments. The expression of LYVE-1, the lymph-vessel specific HA receptor, was consistent with our previous report and enhanced the adhesion of HA(high-HS-578T cells to COS-7(LYVE-1(+ through HA in cell static adhesion and dynamic parallel plate flow chamber experiments. MCF-7 breast cells contain little HA on the surface; however, our results showed little adhesion difference between MCF-7 cells and COS-7(LYVE-1(+ and COS-7(LYVE-1(- cells. Similar results were observed concerning the adhesion of HS-578T cells or MCF-7 cells to SVEC4-10 cells. Furthermore, we observed for the first time that the cell surface HA content of high transfer tumor cells was rich, and we visualized the cross-linking of HA cable structures, which may activate LYVE-1 on lymphatic endothelial cells, promoting tumor adhesion. In summary, high-low cell surface HA content of tumor cells through the interaction with LYVE-1 leads to adhesion differences.

  18. Tamoxifen-resistant breast cancer cells possess cancer stem-like cell properties

    Institute of Scientific and Technical Information of China (English)

    LIU Hui; ZHANG Heng-wei; SUN Xian-fu; GUO Xu-hui; HE Ya-ning; CUI Shu-de; FAN Qing-xia

    2013-01-01

    Background Cancer stem cells (CSCs) are the cause of cancer recurrence because they are resistant to conventional therapy and contribute to cancer growth and metastasis.Endocrinotherapy is the most common breast cancer therapy and acquired tamoxifen (TAM) resistance is the main reason for endocrinotherapy failure during such therapy.Although acquired resistance to endocrine treatment has been extensively studied,the underlying mechanisms are unclear.We hypothesized that breast CSCs played an important role in TAM-induced resistance during breast cancer therapy.Therefore,we investigated the biological characteristics of TAM-resistant (TAM-R) breast cancer cells.Methods Mammosphere formation and tumorigenicity of wild-type (WT) and TAM-R MCF7 cells were tested by a mammosphere assay and mouse tumor xenografts respectively.Stem-cell markers (SOX-2,OCT-4,and CD133) and epithelial-mesenchymal transition (EMT) markers were tested by quantitative real-time (qRT)-PCR.Morphological observation was performed to characterize EMT.Results After induction of TAM resistance,TAM-R MCF7 cells exhibited increased proliferation in the presence of TAM compared to that of WT MCF7 cells (P <0.05),indicating enhanced TAM resistance of TAM-R MCF7 cells compared to that of WT MCF7 cells.TAM-R MCF7 cells showed enhanced mammosphere formation and tumorigenicity in nude mice compared to that of WT MCF7 cells (P <0.01),demonstrating the elevated CSC properties of TAM-R MCF7 cells.Consistently,qRT-PCR revealed that TAM-R MCF7 cells expressed increased mRNA levels of stem cell markers including SOX-2,OCT-4,and CD133,compared to those of WT MCF7 cells (P <0.05).Morphologically,TAM-R MCF7 cells showed a fibroblastic phenotype,but WT MCF7 cells were epithelial-like.After induction of TAM resistance,qRT-PCR indicated that MCF7 cells expressed increased mRNA levels of Snail,vimentin,and N-cadherin and decreased levels of E-cadherin,which are considered as EMT characteristics (P <0

  19. Do Cell Phones Cause Cancer?

    CERN Document Server

    Leikind, Bernard

    2010-01-01

    Do cell phones, household electrical power wiring or appliance, or high voltage power lines cause cancer? Fuggedaboudit! No way! When pigs fly! When I'm the Pope! Don't text while you're driving, however, or eat your cell phone. All organisms absorb microwave radiation directly as thermal energy. In living organisms, the organisms' thermal control systems, including the blood flow, and various cooling mechanisms, such as sweating in humans, that work to maintain a stable body temperature rapidly transfer the absorbed energy to the environment. Any temperature rise is small or even unobserved. Any proposed mechanism by which cell phone radiation might cause cancer must begin with this fact. But the amount of radiation absorbed from a cell phone is less than that produced by normal metabolic processes, and much less than that produced by, for example, exercise. None of these normal metabolic processes cause cancer. Therefore, the much smaller amounts of energy from cell phones doesn't cause cancer either. All f...

  20. The Role of Matrine and Mitogen-Ativated Protein Kinase/Extracellular Signal-Regulated Kinase Signal Transduction in the Inhibition of the Proliferation and Migration of Human Umbilical Veins Endothelial Cells Induced by Lung Cancer cells

    Directory of Open Access Journals (Sweden)

    Ming BAI

    2009-07-01

    Full Text Available Background and objective Matrine, one of the major alkaloid components of the traditional Chinese medicine Sophora roots, has a wide range of pharmacological effects including anti-inflammatory activities, growth inhibition and induction of cell differentiation and apoptosis. Motigen-activated protein kinase (MAPK/extracellular signal-regulated kinase (ERK has found to be a crucial signaling pathway in endothelial cells. The aim of this study is to investigate the role of Matrine and MAPK/ERK signal transduction in the inhibition of the proliferation and migration of human umbilical veins endothelial cells (HUVECs induced by lung cancer cells. Methods HUVECs were cultured with A549CM. Mat or PD98059 (i.e PD, specific inhibitor of MAPK/ERK, was added into the A549CM. The proliferation of the HUVECs was measured by cell counting. The migration of the HUVECs was observed by wound healing assay. The expression levels of ERK and p-ERK protein were detected by Western Blot analysis. Results On 24 hours after intervention, the A549CM significantly stimulated the proliferation, migration and expression of p-ERK of HUVECs. Compared with the A549CM group, Mat significantly inhibited the proliferation, migration and p-ERK expression of HUVECs induced by A549CM. While PD only decreased the proliferation and p-ERK expression of HUVECs induced by A549CM. PD had no effect in the migration of HUVECs. Conclusion The results demonstrated that Mat and PD98059 can effectively decrease proliferation and expression of p-ERK of HUVECs induced by A549CM. Furthermore Mat can also inhibit migration of HUVECs induced by A549CM that did not changed by PD98059. These data implied that suppressing MAPK/ERK signal transduction may play the crucial role in resisting lung cacinoma angiogenesis with Mat.

  1. The Role of Genetic Polymorphisms as Related to One-Carbon Metabolism, Vitamin B6, and Gene–Nutrient Interactions in Maintaining Genomic Stability and Cell Viability in Chinese Breast Cancer Patients

    Directory of Open Access Journals (Sweden)

    Xiayu Wu

    2016-06-01

    Full Text Available Folate-mediated one-carbon metabolism (FMOCM is linked to DNA synthesis, methylation, and cell proliferation. Vitamin B6 (B6 is a cofactor, and genetic polymorphisms of related key enzymes, such as serine hydroxymethyltransferase (SHMT, methionine synthase reductase (MTRR, and methionine synthase (MS, in FMOCM may govern the bioavailability of metabolites and play important roles in the maintenance of genomic stability and cell viability (GSACV. To evaluate the influences of B6, genetic polymorphisms of these enzymes, and gene–nutrient interactions on GSACV, we utilized the cytokinesis-block micronucleus assay (CBMN and PCR-restriction fragment length polymorphism (PCR-RFLP techniques in the lymphocytes from female breast cancer cases and controls. GSACV showed a significantly positive correlation with B6 concentration, and 48 nmol/L of B6 was the most suitable concentration for maintaining GSACV in vitro. The GSACV indexes showed significantly different sensitivity to B6 deficiency between cases and controls; the B6 effect on the GSACV variance contribution of each index was significantly higher than that of genetic polymorphisms and the sample state (tumor state. SHMT C1420T mutations may reduce breast cancer susceptibility, whereas MTRR A66G and MS A2756G mutations may increase breast cancer susceptibility. The role of SHMT, MS, and MTRR genotype polymorphisms in GSACV is reduced compared with that of B6. The results appear to suggest that the long-term lack of B6 under these conditions may increase genetic damage and cell injury and that individuals with various genotypes have different sensitivities to B6 deficiency. FMOCM metabolic enzyme gene polymorphism may be related to breast cancer susceptibility to a certain extent due to the effect of other factors such as stress, hormones, cancer therapies, psychological conditions, and diet. Adequate B6 intake may be good for maintaining genome health and preventing breast cancer.

  2. The Role of Genetic Polymorphisms as Related to One-Carbon Metabolism, Vitamin B6, and Gene-Nutrient Interactions in Maintaining Genomic Stability and Cell Viability in Chinese Breast Cancer Patients.

    Science.gov (United States)

    Wu, Xiayu; Xu, Weijiang; Zhou, Tao; Cao, Neng; Ni, Juan; Zou, Tianning; Liang, Ziqing; Wang, Xu; Fenech, Michael

    2016-01-01

    Folate-mediated one-carbon metabolism (FMOCM) is linked to DNA synthesis, methylation, and cell proliferation. Vitamin B6 (B6) is a cofactor, and genetic polymorphisms of related key enzymes, such as serine hydroxymethyltransferase (SHMT), methionine synthase reductase (MTRR), and methionine synthase (MS), in FMOCM may govern the bioavailability of metabolites and play important roles in the maintenance of genomic stability and cell viability (GSACV). To evaluate the influences of B6, genetic polymorphisms of these enzymes, and gene-nutrient interactions on GSACV, we utilized the cytokinesis-block micronucleus assay (CBMN) and PCR-restriction fragment length polymorphism (PCR-RFLP) techniques in the lymphocytes from female breast cancer cases and controls. GSACV showed a significantly positive correlation with B6 concentration, and 48 nmol/L of B6 was the most suitable concentration for maintaining GSACV in vitro. The GSACV indexes showed significantly different sensitivity to B6 deficiency between cases and controls; the B6 effect on the GSACV variance contribution of each index was significantly higher than that of genetic polymorphisms and the sample state (tumor state). SHMT C1420T mutations may reduce breast cancer susceptibility, whereas MTRR A66G and MS A2756G mutations may increase breast cancer susceptibility. The role of SHMT, MS, and MTRR genotype polymorphisms in GSACV is reduced compared with that of B6. The results appear to suggest that the long-term lack of B6 under these conditions may increase genetic damage and cell injury and that individuals with various genotypes have different sensitivities to B6 deficiency. FMOCM metabolic enzyme gene polymorphism may be related to breast cancer susceptibility to a certain extent due to the effect of other factors such as stress, hormones, cancer therapies, psychological conditions, and diet. Adequate B6 intake may be good for maintaining genome health and preventing breast cancer. PMID:27347936

  3. The Role of Genetic Polymorphisms as Related to One-Carbon Metabolism, Vitamin B6, and Gene–Nutrient Interactions in Maintaining Genomic Stability and Cell Viability in Chinese Breast Cancer Patients

    Science.gov (United States)

    Wu, Xiayu; Xu, Weijiang; Zhou, Tao; Cao, Neng; Ni, Juan; Zou, Tianning; Liang, Ziqing; Wang, Xu; Fenech, Michael

    2016-01-01

    Folate-mediated one-carbon metabolism (FMOCM) is linked to DNA synthesis, methylation, and cell proliferation. Vitamin B6 (B6) is a cofactor, and genetic polymorphisms of related key enzymes, such as serine hydroxymethyltransferase (SHMT), methionine synthase reductase (MTRR), and methionine synthase (MS), in FMOCM may govern the bioavailability of metabolites and play important roles in the maintenance of genomic stability and cell viability (GSACV). To evaluate the influences of B6, genetic polymorphisms of these enzymes, and gene–nutrient interactions on GSACV, we utilized the cytokinesis-block micronucleus assay (CBMN) and PCR-restriction fragment length polymorphism (PCR-RFLP) techniques in the lymphocytes from female breast cancer cases and controls. GSACV showed a significantly positive correlation with B6 concentration, and 48 nmol/L of B6 was the most suitable concentration for maintaining GSACV in vitro. The GSACV indexes showed significantly different sensitivity to B6 deficiency between cases and controls; the B6 effect on the GSACV variance contribution of each index was significantly higher than that of genetic polymorphisms and the sample state (tumor state). SHMT C1420T mutations may reduce breast cancer susceptibility, whereas MTRR A66G and MS A2756G mutations may increase breast cancer susceptibility. The role of SHMT, MS, and MTRR genotype polymorphisms in GSACV is reduced compared with that of B6. The results appear to suggest that the long-term lack of B6 under these conditions may increase genetic damage and cell injury and that individuals with various genotypes have different sensitivities to B6 deficiency. FMOCM metabolic enzyme gene polymorphism may be related to breast cancer susceptibility to a certain extent due to the effect of other factors such as stress, hormones, cancer therapies, psychological conditions, and diet. Adequate B6 intake may be good for maintaining genome health and preventing breast cancer. PMID:27347936

  4. The role and potential mechanisms of LncRNA-TATDN1 on metastasis and invasion of non-small cell lung cancer.

    Science.gov (United States)

    Zequn, Niu; Xuemei, Zhang; Wei, Li; Zongjuan, Ming; Yujie, Zhong; Yanli, Hou; Yuping, Zhang; Xia, Meng; Wei, Wang; Wenjing, Deng; Na, Fan; Shuanying, Yang

    2016-04-01

    The invasion and metastasis of malignant tumor cells lead to normal tissue destruction and are major prognostic factors for many malignant cancers. Long non-coding RNA (LncRNA) is associated with occurrence, development and prognoses of non-small cell lung cancer (NSCLC), but its mechanisms of action involved in tumor invasion and metastasis are not clear. In this study, we screened and detected the expression of LncRNA in two NSCLC lines 95D and 95C by using high throughput LncRNA chip. We found that TATDN1 (Homo sapiens TatD DNase domain containing 1, TATDN1), one of LncRNAs, was highly expressed in 95D cells and NSCLC tumor tissues compared to 95C cells. Knockdown of TATDN1-1 by shRNA significantly inhibited cell proliferation, adhesion, migration and invasion in 95D cells. Further mechanism study showed that TATDN1 knockdown suppressed the expression of E-cadherin, HER2, β-catenin and Ezrin. Moreover, knockdown TATDN1 also inhibited tumor growth and metastasis in a 95D mouse model in vivo by inhibiting β-catenin and Ezrin. These data indicate that TATDN1 expression is associated with 95D cells' higher potential of invasion and metastasis, and suggest that TATDN1 may be a potential prognostic factor and therapeutic target for NSCLCs. PMID:26943769

  5. Studying the Role of Alveolar Macrophages in Breast Cancer Metastasis.

    Science.gov (United States)

    Vadrevu, Surya Kumari; Sharma, Sharad; Chintala, Navin; Patel, Jalpa; Karbowniczek, Magdalena; Markiewski, Maciej

    2016-01-01

    This paper describes the application of the syngeneic model of breast cancer (4T1) to the studies on a role of pulmonary alveolar macrophages in cancer metastasis. The 4T1 cells expressing GFP in combination with imaging and confocal microscopy are used to monitor tumor growth, track metastasizing tumor cells, and quantify the metastatic burden. These approaches are supplemented by digital histopathology that allows the automated and unbiased quantification of metastases. In this method the routinely prepared histological lung sections, which are stained with hematoxylin and eosin, are scanned and converted to the digital slides that are then analyzed by the self-trained pattern recognition software. In addition, we describe the flow cytometry approaches with the use of multiple cell surface markers to identify alveolar macrophages in the lungs. To determine impact of alveolar macrophages on metastases and antitumor immunity these cells are depleted with the clodronate-containing liposomes administrated intranasally to tumor-bearing mice. This approach leads to the specific and efficient depletion of this cell population as confirmed by flow cytometry. Tumor volumes and lung metastases are evaluated in mice depleted of alveolar macrophages, to determine the role of these cells in the metastatic progression of breast cancer. PMID:27403530

  6. The prognostic role of mTOR and p-mTOR for survival in non-small cell lung cancer: a systematic review and meta-analysis.

    Directory of Open Access Journals (Sweden)

    Lei Li

    Full Text Available The mammalian target of rapamycin (mTOR and phosphorylated mTOR (p-mTOR are potential prognostic markers and therapeutic targets for non-small cell lung cancer (NSCLC. However, the association between mTOR/p-mTOR expression and NSCLC patients' prognosis remains controversial. Thus, a meta-analysis of existing studies evaluating the prognostic role of mTOR/p-mTOR expression for NSCLC was conducted.A systemically literature search was performed via Pubmed, Embase, Medline as well as CNKI (China National Knowledge Infrastructure. Studies were included that reported the hazard ratio (HR and 95%CI for the association between mTOR/p-mTOR expression and NSCLC patients' survival. Random-effects model was used to pool HRs.Ten eligible studies were included in this meta-analysis, with 4 about m-TOR and 7 about p-mTOR. For mTOR, the pooled HR of overall survival (OS was 1.00 (95%CI 0.5 to 1.99 by univariate analysis and 1.22 (95%CI 0.53 to 2.82 by multivariate analysis. For p-mTOR, the pooled HR was 1.39 (95%CI 0.97 to 1.98 by univariate analysis and 1.42 (95%CI 0.56 to 3.60 by multivariate analysis.The results indicated that no statistically significant association was found between mTOR/p-mTOR expression and NSCLC patients' prognosis.

  7. Clinical applications of circulating tumor cells in lung cancer patients by CellSearch system

    Directory of Open Access Journals (Sweden)

    AnnaTruini

    2014-09-01

    In the present review the significance of CTC detection in lung cancer is examined through the analysis of the published studies in both non-small cell and small cell lung cancers; additionally the prognostic and the clinical role of CTC enumeration in treatment monitoring will be reported and discussed.

  8. The cytoprotective role of gemcitabine-induced autophagy associated with apoptosis inhibition in triple-negative MDA-MB-231 breast cancer cells.

    Science.gov (United States)

    Chen, Ming; He, Mengye; Song, Yinjing; Chen, Luoquan; Xiao, Peng; Wan, Xiaopeng; Dai, Feng; Shen, Peng

    2014-07-01

    Triple-negative breast cancer (TNBC), which is estrogen receptor (ER)-negative, progesterone receptor‑negative and is also negative for HER2 expression, remains a great clinical challenge due to its strong resistance to chemotherapy at the late stage of treatment and relatively unfavorable prognosis. Gemcitabine has been approved by the FDA/SFDA for use as a first-line therapeutic drug against advanced or metastatic breast cancer. Therefore, the clarification of the mechanisms underlying gemcitabine-acquired resistance is of particular importance for the optimal management of TNBC. A number of studies have revealed that autophagy, which has been found to protect cancer cells from anti-cancer drug-induced death, may contribute to the development of drug resistance. However, the association between autophagy and gemcitabine treatment in TNBC cells has yet to be defined. Our study clearly demonstrates that gemcitabine is able to induce mTOR-independent autophagy in human triple‑negative MDA-MB-231 breast cancer cells. In addition, we demonstrate that autophagy protects MDA-MB-231 cells from gemcitabine-induced cell growth inhibition and apoptosis, indicating that gemcitabine can activate autophagy to impair the sensitivity of MDA-MB‑231 cells. Furthermore, as shown by our results, the inhibition of gemcitabine-induced autophagy by chloroquine shifts the expression of the p53 protein, Bcl-2 family proteins and the relative Bax/Bcl-xL ratio in favor of promoting apoptosis. These results reveal that the inhibition of apoptosis may be one of the mechanisms of autophagy-induced cytoprotection in gemcitabine-treated MDA-MB-231 cells. The apoptotic and autophagic processes constitute a mutual inhibition system and jointly seal the fate of TNBC cells that are exposed to gemcitabine. Thus, our study suggests that the combination of an autophagic inhibitor and gemcitabine as a therapeutic strategy may represent a promising approach with greater clinical efficacy for

  9. Treatment Option Overview (Renal Cell Cancer)

    Science.gov (United States)

    ... Genetics of Kidney Cancer Research Renal Cell Cancer Treatment (PDQ®)–Patient Version General Information About Renal Cell ... Certain factors affect prognosis (chance of recovery) and treatment options. The prognosis (chance of recovery ) and treatment ...

  10. Treatment Options for Renal Cell Cancer

    Science.gov (United States)

    ... Genetics of Kidney Cancer Research Renal Cell Cancer Treatment (PDQ®)–Patient Version General Information About Renal Cell ... Certain factors affect prognosis (chance of recovery) and treatment options. The prognosis (chance of recovery ) and treatment ...

  11. Effects of Src on Proliferation and Invasion of Lung Cancer Cells

    OpenAIRE

    ZHENG, Rui; Qin, Xiaosong; Li, Wenjie; Kang, Jian

    2011-01-01

    Background and objective It has been proven that Src played pivotal roles in carcinogenesis, cancer progression and metastasis. The aim of this study is to explore the roles of Src phosphorylation on lung cancer cells. Methods Western blot and immunoprecipitation was used to detect the expression and phosphorylation of Src in lung cancer cells. MTT and Boyden chamber assay was used to examine the effects of inhibition of Src phosphorylation on proliferation and invasion of lung cancer cells i...

  12. Cancer Stem and Progenitor-Like Cells as Pharmacological Targets in Breast Cancer Treatment

    OpenAIRE

    Valéria B. de Souza; Schenka, André A

    2015-01-01

    The present review is focused on the current role of neoplastic stem and progenitor-like cells as primary targets in the pharmacotherapy of cancer as well as in the development of new anticancer drugs. We begin by summarizing the main characteristics of these tumor-initiating cells and key concepts that support their participation in therapeutic failure. In particular, we discuss the differences between the major carcinogenesis models (ie, clonal evolution vs cancer stem cell (CSC) model) wit...

  13. Cancer Stem Cells Accountability in Progression of Head and Neck Squamous Cell Carcinoma: The Most Recent Trends!

    Directory of Open Access Journals (Sweden)

    Samapika Routray

    2014-01-01

    Full Text Available Cancer stem cells (CSCs play a major role in local recurrence and metastatic spread in head and neck squamous cell carcinomas (HNSCC. Evidence suggests that cancer stem cells are resistant to conventional therapy. So the emerging concepts of the role of cancer stem cells in the pathobiology of HNSCC should be understood carefully to be able to create new paradigms in treatment plans.

  14. Emerging targets in cancer management: role of the CXCL12/CXCR4 axis

    Directory of Open Access Journals (Sweden)

    Cojoc M

    2013-09-01

    Full Text Available Monica Cojoc,1 Claudia Peitzsch,1 Franziska Trautmann,1 Leo Polishchuk,2 Gennady D Telegeev,2 Anna Dubrovska11OncoRay National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany; 2Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, UkraineAbstract: The chemokine CXCL12 (SDF-1 and its cell surface receptor CXCR4 were first identified as regulators of lymphocyte trafficking to the bone marrow. Soon after, the CXCL12/CXCR4 axis was proposed to regulate the trafficking of breast cancer cells to sites of metastasis. More recently, it was established that CXCR4 plays a central role in cancer cell proliferation, invasion, and dissemination in the majority of malignant diseases. The stem cell concept of cancer has revolutionized the understanding of tumorigenesis and cancer treatment. A growing body of evidence indicates that a subset of cancer cells, referred to as cancer stem cells (CSCs, plays a critical role in tumor initiation, metastatic colonization, and resistance to therapy. Although the signals generated by the metastatic niche that regulate CSCs are not yet fully understood, accumulating evidence suggests a key role of the CXCL12/CXCR4 axis. In this review we focus on physiological functions of the CXCL12/CXCR4 signaling pathway and its role in cancer and CSCs, and we discuss the potential for targeting this pathway in cancer management.Keywords: epithelial-to-mesenchymal transition, cancer stem cells, metastasis

  15. NAC selectively inhibit cancer telomerase activity: A higher redox homeostasis threshold exists in cancer cells

    OpenAIRE

    Pengying Li; Meilin Wu; Jing Wang; Yilun Sui; Shanlin Liu; Dongyun Shi

    2016-01-01

    Telomerase activity controls telomere length, and this plays an important role in stem cells, aging and tumors. Antioxidant was shown to protect telomerase activity in normal cells but inhibit that in cancer cells, but the underlying mechanism is elusive. Here we found that 7721 hepatoma cells held a higher redox homeostasis threshold than L02 normal liver cells which caused 7721 cells to have a higher demand for ROS; MnSOD over-expression in 7721 decreased endogenous reactive oxygen species ...

  16. Colon cancer stem cells: implications in carcinogenesis

    OpenAIRE

    Sanders, Matthew A.; Majumdar, Adhip P. N.

    2011-01-01

    The cancer stem cell model was described for hematologic malignancies in 1997 and since then evidence has emerged to support it for many solid tumors as well, including colon cancer. This model proposes that certain cells within the tumor mass are pluripotent and capable of self-renewal and have an enhanced ability to initiate distant metastasis. The cancer stem cell model has important implications for cancer treatment, since most current therapies target actively proliferating cells and may...

  17. Pancreatic Cancer Cell Exosome-Mediated Macrophage Reprogramming and the Role of MicroRNAs 155 and 125b2 Transfection using Nanoparticle Delivery Systems.

    Science.gov (United States)

    Su, Mei-Ju; Aldawsari, Hibah; Amiji, Mansoor

    2016-01-01

    Exosomes are nano-sized endosome-derived small intraluminal vesicles, which are important facilitators of intercellular communication by transporting contents, such as protein, mRNA, and microRNAs, between neighboring cells, such as in the tumor microenvironment. The purpose of this study was to understand the mechanisms of exosomes-mediated cellular communication between human pancreatic cancer (Panc-1) cells and macrophages (J771.A1) using a Transwell co-culture system. Following characterization of exosome-mediated cellular communication and pro-tumoral baseline M2 macrophage polarization, the Panc-1 cells were transfected with microRNA-155 (miR-155) and microRNA-125b-2 (miR-125b2) expressing plasmid DNA using hyaluronic acid-poly(ethylene imine)/hyaluronic acid-poly(ethylene glycol) (HA-PEI/HA-PEG) self-assembling nanoparticle-based non-viral vectors. Our results show that upon successful transfection of Panc-1 cells, the exosome content was altered leading to differential communication and reprogramming of the J774.A1 cells to an M1 phenotype. Based on these results, genetic therapies targeted towards selective manipulation of tumor cell-derived exosome content may be very promising for cancer therapy. PMID:27443190

  18. Pancreatic Cancer Cell Exosome-Mediated Macrophage Reprogramming and the Role of MicroRNAs 155 and 125b2 Transfection using Nanoparticle Delivery Systems

    Science.gov (United States)

    Su, Mei-Ju; Aldawsari, Hibah; Amiji, Mansoor

    2016-01-01

    Exosomes are nano-sized endosome-derived small intraluminal vesicles, which are important facilitators of intercellular communication by transporting contents, such as protein, mRNA, and microRNAs, between neighboring cells, such as in the tumor microenvironment. The purpose of this study was to understand the mechanisms of exosomes-mediated cellular communication between human pancreatic cancer (Panc-1) cells and macrophages (J771.A1) using a Transwell co-culture system. Following characterization of exosome-mediated cellular communication and pro-tumoral baseline M2 macrophage polarization, the Panc-1 cells were transfected with microRNA-155 (miR-155) and microRNA-125b-2 (miR-125b2) expressing plasmid DNA using hyaluronic acid-poly(ethylene imine)/hyaluronic acid-poly(ethylene glycol) (HA-PEI/HA-PEG) self-assembling nanoparticle-based non-viral vectors. Our results show that upon successful transfection of Panc-1 cells, the exosome content was altered leading to differential communication and reprogramming of the J774.A1 cells to an M1 phenotype. Based on these results, genetic therapies targeted towards selective manipulation of tumor cell-derived exosome content may be very promising for cancer therapy. PMID:27443190

  19. What makes cancer stem cell markers different?

    OpenAIRE

    Karsten, Uwe; Goletz, Steffen

    2013-01-01

    Since the cancer stem cell concept has been widely accepted, several strategies have been proposed to attack cancer stem cells (CSC). Accordingly, stem cell markers are now preferred therapeutic targets. However, the problem of tumor specificity has not disappeared but shifted to another question: how can cancer stem cells be distinguished from normal stem cells, or more specifically, how do CSC markers differ from normal stem cell markers? A hypothesis is proposed which might help to solve t...

  20. Dendritic Cells in the Cancer Microenvironment

    Directory of Open Access Journals (Sweden)

    Yang Ma, Galina V. Shurin, Zhu Peiyuan, Michael R. Shurin

    2013-01-01

    Full Text Available The complexity of the tumor immunoenvironment is underscored by the emergence and discovery of different subsets of immune effectors and regulatory cells. Tumor-induced polarization of immune cell differentiation and function makes this unique environment even more intricate and variable. Dendritic cells (DCs represent a special group of cells that display different phenotype and activity at the tumor site and exhibit differential pro-tumorigenic and anti-tumorigenic functions. DCs play a key role in inducing and maintaining the antitumor immunity, but in the tumor environment their antigen-presenting function may be lost or inefficient. DCs might be also polarized into immunosuppressive/tolerogenic regulatory DCs, which limit activity of effector T cells and support tumor growth and progression. Although various factors and signaling pathways have been described to be responsible for abnormal functioning of DCs in cancer, there are still no feasible therapeutic modalities available for preventing or reversing DC malfunction in tumor-bearing hosts. Thus, better understanding of DC immunobiology in cancer is pivotal for designing novel or improved therapeutic approaches that will allow proper functioning of DCs in patients with cancer.

  1. Lung cancer - non-small cell

    Science.gov (United States)

    Cancer - lung - non-small cell; Non-small cell lung cancer; NSCLC; Adenocarcinoma - lung; Squamous cell carcinoma - lung ... Smoking causes most cases (around 90%) of lung cancer. The risk ... day and for how long you have smoked. Being around the smoke ...

  2. Chromatin Repressive Complexes in Stem Cells, Development, and Cancer

    DEFF Research Database (Denmark)

    Laugesen, Anne; Helin, Kristian

    2014-01-01

    The chromatin environment is essential for the correct specification and preservation of cell identity through modulation and maintenance of transcription patterns. Many chromatin regulators are required for development, stem cell maintenance, and differentiation. Here, we review the roles of the...... polycomb repressive complexes, PRC1 and PRC2, and the HDAC1- and HDAC2-containing complexes, NuRD, Sin3, and CoREST, in stem cells, development, and cancer, as well as the ongoing efforts to develop therapies targeting these complexes in human cancer. Furthermore, we discuss the role of repressive...... complexes in modulating thresholds for gene activation and their importance for specification and maintenance of cell fate....

  3. Prognostic Value of Homotypic Cell Internalization by Nonprofessional Phagocytic Cancer Cells

    Directory of Open Access Journals (Sweden)

    Manuela Schwegler

    2015-01-01

    Full Text Available Background. In this study, we investigated the prognostic role of homotypic tumor cell cannibalism in different cancer types. Methods. The phenomenon of one cell being internalized into another, which we refer to as “cell-in-cell event,” was assessed in 416 cases from five head and neck cancer cohorts, as well as one anal and one rectal cancer cohort. The samples were processed into tissue microarrays and immunohistochemically stained for E-cadherin and cleaved caspase-3 to visualize cell membranes and apoptotic cell death. Results. Cell-in-cell events were found in all of the cohorts. The frequency ranged from 0.7 to 17.3 cell-in-cell events per mm2. Hardly any apoptotic cells were found within the cell-in-cell structures, although apoptotic cell rates were about 1.6 to two times as high as cell-in-cell rates of the same tissue sample. High numbers of cell-in-cell events showed adverse effects on patients’ survival in the head and neck and in the rectal cancer cohorts. In multivariate analysis, high frequency was an adverse prognostic factor for overall survival in patients with head and neck cancer (p=0.008. Conclusion. Cell-in-cell events were found to predict patient outcomes in various types of cancer better than apoptosis and proliferation and might therefore be used to guide treatment strategies.

  4. The Dual Role of TGFβ in Human Cancer: From Tumor Suppression to Cancer Metastasis

    Science.gov (United States)

    Lebrun, Jean-Jacques

    2012-01-01

    The transforming growth factor-beta (TGFβ) superfamily encompasses widespread and evolutionarily conserved polypeptide growth factors that regulate and orchestrate growth and differentiation in all cell types and tissues. While they regulate asymmetric cell division and cell fate determination during early development and embryogenesis, TGFβ family members play a major regulatory role in hormonal and immune responses, cell growth, cell death and cell immortalization, bone formation, tissue remodeling and repair, and erythropoiesis throughout adult life. The biological and physiological functions of TGFβ, the founding member of this family, and its receptors are of central importance to human diseases, particularly cancer. By regulating cell growth, death, and immortalization, TGFβ signaling pathways exert tumor suppressor effects in normal cells and early carcinomas. Thus, it is not surprising that a high number of human tumors arise due to mutations or deletions in the genes coding for the various TGFβ signaling components. As tumors develop and progress, these protective and cytostatic effects of TGFβ are often lost. TGFβ signaling then switches to promote cancer progression, invasion, and tumor metastasis. The molecular mechanisms underlying this dual role of TGFβ in human cancer will be discussed in depth in this paper, and it will highlight the challenge and importance of developing novel therapeutic strategies specifically aimed at blocking the prometastatic arm of the TGFβ signaling pathway without affecting its tumor suppressive effects.

  5. Surgery for nonsmall cell lung cancer

    Directory of Open Access Journals (Sweden)

    Loïc Lang-Lazdunski

    2013-09-01

    Full Text Available Surgery remains the best curative option in patients with early stage lung cancer (stage I and II. Developments in minimally invasive techniques now allow surgeons to perform lung resections on elderly patients, patients with poor pulmonary function or significant cardiopulmonary comorbidities. New techniques, such as stereotactic radiotherapy and ablative procedures, are being evaluated in early-stage lung cancer and may represent an alternative to surgery in patients unfit for lung resection. Perioperative mortality rates have dropped significantly at most institutions in the past two decades and complications are managed more efficiently. Progress in imaging and staging techniques have helped cut futile thoracotomy rates and offer patients the most adequate treatment options. Large randomised trials have helped clarify the role of neoadjuvant, induction and adjuvant chemotherapy, as well as radiotherapy. Surgery remains an essential step in the multimodality therapy of selected patients with advanced-stage lung cancer (stage III and IV. Interventional and endoscopic techniques have reduced the role of surgery in the diagnosis and staging of nonsmall cell lung cancer, but surgery remains an important tool in the palliation of advanced-stage lung cancer. Large national/international surgical databases have been developed and predictive risk-models for surgical mortality/morbidity published by learned surgical societies. Nonetheless, lung cancer overall survival rates remain deceptively low and it is hoped that early detection/screening, better understanding of tumour biology and development of biomarkers, and development of efficient targeted therapies will help improve the prognosis of lung cancer patients in the next decade.

  6. Cancer stem cells and resistance to chemo and radio therapy.

    Science.gov (United States)

    Malik, Babar; Nie, Daotai

    2012-01-01

    Cancer stem cells (CSCs, or tumor initiating cells) are responsible for tumor initiation. If cancer treatment kills most of cancer cells in the stage of transit amplifying and differentiation without killing the stem cells, the surviving CSCs will eventually lead to recurrence of tumors. Studies have suggested that CSCs may be the primary mediators of resistance to chemo- and radio-therapy, leading to failure in cancer therapy. Numerous targets are being investigated for their potential involvement in the self-renewal and chemo- and radio-resistance of cancer cells. However, despite the intensive efforts invested into characterizing the role of cancer stem cells, there is a sense of uncertainty regarding the identity and number of these cells as well as the implications in cancer treatment. In this review, we will discuss the identification of CSCs by cell surface markers, the biology of CSCs, and the role of CSCs in resistance to radio- and chemo-therapy. This review will discuss the advances in targeting CSCs to improve the efficacy of chemo- and radio-therapy. PMID:22202026

  7. Role of Wnt Inhibitory Factor-1 in Inhibition of Bisdemethoxycurcumin Mediated Epithelial-to-Mesenchymal Transition in Highly Metastatic Lung Cancer 95D Cells

    Directory of Open Access Journals (Sweden)

    Jin-Hong Xu

    2015-01-01

    Full Text Available Background: Bisdemethoxycurcumin (BDMC is an active component of curcumin and a chemotherapeutic agent, which has been suggested to inhibit tumor growth, invasion and metastasis in multiple cancers. But its contribution and mechanism of action in invasion and metastasis of non-small cell lung cancer (NSCLC are not very clear. Therefore, we tried to study the effects of BDMC on regulation of epithelial-to-mesenchymal transition (EMT, which is closely linked to tumor cell invasion and metastasis. Methods: In this study, we first induced transforming growth factor-β1 (TGF-β1 mediated EMT in highly metastatic lung cancer 95D cells. Thereafter, we studied the effects of BDMC on invasion and migration of 95D cells. In addition, EMT markers expressions were also analyzed by western blot and immunofluorescence assays. The contribution of Wnt inhibitory factor-1 (WIF-1 in regulating BDMC effects on TGF-β1 induced EMT were further analyzed by its overexpression and small interfering RNA knockdown studies. Results: It was observed that BDMC inhibited the TGF-β1 induced EMT in 95D cells. Furthermore, it also inhibited the Wnt signaling pathway by upregulating WIF-1 protein expression. In addition, WIF-1 manipulation studies further revealed that WIF-1 is a central molecule mediating BDMC response towards TGF-β1 induced EMT by regulating cell invasion and migration. Conclusions: Our study concluded that BDMC effects on TGF-β1 induced EMT in NSCLC are mediated through WIF-1 and elucidated a novel mechanism of EMT regulation by BDMC.

  8. AMPK inhibits MTDH expression via GSK3β and SIRT1 activation: potential role in triple negative breast cancer cell proliferation.

    Science.gov (United States)

    Gollavilli, Paradesi Naidu; Kanugula, Anantha Koteswararao; Koyyada, Rajeswari; Karnewar, Santosh; Neeli, Praveen Kumar; Kotamraju, Srigiridhar

    2015-10-01

    Recent studies have highlighted the involvement of metadherin (MTDH), an oncogenic protein, in promoting cancer progression, metastasis and chemoresistance in many cancers including mammary carcinomas. However, the molecular regulation of MTDH is still not completely understood. In this study we document that AMP activated protein kinase (AMPK) activation-induced anti-proliferative effects are, in part, mediated by inhibiting MTDH expression in MDA-MB-231 and BT-549 triple negative breast cancer (TNBC) cells. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator, caused growth arrest, inhibition of migration and invasion of TNBC cells. Intriguingly, AICAR or metformin treatment resulted in significant downregulation of MTDH expression via inhibiting c-Myc expression. In contrast, treatment of cells with compound C, an inhibitor of AMPK, increased both c-Myc and MTDH expressions in TNBC cells. Also, AMPK activation caused increased glycogen synthase kinase 3β (GSK3β) activity by inhibiting the inactive phosphorylation at Ser9, on the one hand, and activation of sirtuin1 (SIRT1) by inhibiting Ser47 phosphorylation, as evidenced by deacetylation of p53, on the other hand. Moreover, AMPK-induced GSK3β and SIRT1 activities were found to be responsible for inhibiting c-Myc-mediated upregulation of MTDH, as LiCl (an inhibitor of GSK3β) and EX-527 (an inhibitor of SIRT1) reversed AICAR-mediated downregulation of c-Myc and MTDH expressions. Similar results were observed with siSIRT1 treatment. Furthermore, AICAR and EX-527 treatments caused increased cell death under MTDH-depleted conditions. Finally, we uncovered a novel regulation of MTDH expression and showed that AMPK activation by inducing GSK3β and SIRT1 downregulates MTDH expression via inhibiting c-Myc in TNBC cells. PMID:26236947

  9. Cancer preventive role of selected dietary factors

    Directory of Open Access Journals (Sweden)

    Ray Amitabha

    2005-01-01

    Full Text Available Dietary behavior seems to be an important modifiable determinant for the risk of cancer. The evidences from several epidemiological studies suggest that higher intakes of fruits and vegetables have been associated with lower risk of cancer. Dietary phenolic and polyphenolic substances, terpenoids, dietary fibers, fish oils, some micronutrients present in foods of both plant and animal origin, and a reduction of caloric intake appear to inhibit the process of cancer development. Many dietary factors possess antioxidant and anti-inflammatory properties and cause induction of phase II enzymes like glutathione-S-transferases. It has been suggested that cruciferous vegetables play an important role in cancer prevention, and their chemopreventive effects are due to high glucosinolate content which under enzymatic hydrolysis produces bioactive compound isothiocyanates. Further, isothiocyanates of a wide variety of cruciferous vegetables are powerful inhibitors of carcinogenesis in experimental animal models. Several flavonoids present in fruits, tea, soya beans, etc. may be useful as cancer preventive agents. Similarly, ellagic acid, perillyl alcohol and resveratrol found in various fruits may have chemoprotective effect. Moreover, different vanilloids such as curcumin and gingerol have been shown to possess antioxidative properties. Nevertheless, in spite of several studies, still the effects of various ingredients are not clearly distinguished. In human, little convincing evidence has been established for the proposed protective effects of dietary constituents. It is an important future research goal to provide necessary evidences to support the chemopreventive role of different dietary factors, and also to clarify misunderstandings in this perplexing area.

  10. Breast cancer cells with acquired antiestrogen resistance are sensitized to cisplatin-induced cell death

    DEFF Research Database (Denmark)

    Yde, Christina Westmose; Gyrd-Hansen, Mads; Lykkesfeldt, Anne E; Issinger, Olaf-Georg; Stenvang, Jan

    2007-01-01

    future breast cancer treatment. In this study, we have investigated the effect of the chemotherapeutic compound cisplatin using a panel of antiestrogen-resistant breast cancer cell lines established from the human breast cancer cell line MCF-7. We show that the antiestrogen-resistant cells are...... parental MCF-7 cells. Our data show that Bcl-2 can protect antiestrogen-resistant breast cancer cells from cisplatin-induced cell death, indicating that the reduced expression of Bcl-2 in the antiestrogen-resistant cells plays a role in sensitizing the cells to cisplatin treatment.......Antiestrogens are currently used for treating breast cancer patients who have estrogen receptor-positive tumors. However, patients with advanced disease will eventually develop resistance to the drugs. Therefore, compounds effective on antiestrogen-resistant tumors will be of great importance for...

  11. Important Role of FTO in the Survival of Rare Panresistant Triple-Negative Inflammatory Breast Cancer Cells Facing a Severe Metabolic Challenge.

    Science.gov (United States)

    Singh, Balraj; Kinne, Hannah E; Milligan, Ryan D; Washburn, Laura J; Olsen, Mark; Lucci, Anthony

    2016-01-01

    We have previously shown that only 0.01% cells survive a metabolic challenge involving lack of glutamine in culture medium of SUM149 triple-negative Inflammatory Breast Cancer cell line. These cells, designated as SUM149-MA for metabolic adaptability, are resistant to chemotherapeutic drugs, and they efficiently metastasize to multiple organs in nude mice. We hypothesized that obesity-related molecular networks, which normally help in cellular and organismal survival under metabolic challenges, may help in the survival of MA cells. The fat mass and obesity-associated protein FTO is overexpressed in MA cells. Obesity-associated cis-acting elements in non-coding region of FTO regulate the expression of IRX3 gene, thus activating obesity networks. Here we found that IRX3 protein is significantly overexpressed in MA cells (5 to 6-fold) as compared to the parental SUM149 cell line, supporting our hypothesis. We also obtained evidence that additional key regulators of energy balance such as ARID5B, IRX5, and CUX1 P200 repressor could potentially help progenitor-like TNBC cells survive in glutamine-free medium. MO-I-500, a pharmacological inhibitor of FTO, significantly (>90%) inhibited survival and/or colony formation of SUM149-MA cells as compared to untreated cells or those treated with a control compound MO-I-100. Curiously, MO-I-500 treatment also led to decreased levels of FTO and IRX3 proteins in the SUM149 cells initially surviving in glutamine-free medium as compared to MO-I-100 treatment. Interestingly, MO-I-500 treatment had a relatively little effect on cell growth of either the SUM149 or SUM149-MA cell line when added to a complete medium containing glutamine that does not pose a metabolic challenge. Importantly, once selected and cultured in glutamine-free medium, SUM149-MA cells w