WorldWideScience
1

T-cadherin Supports Angiogenesis and Adiponectin Association with the Vasculature in a Mouse Mammary Tumor Model  

OpenAIRE

T-cadherin delineates endothelial, myoepithelial and ductal epithelial cells in the normal mouse mammary gland, and becomes progressively restricted to the vasculature during mammary tumorigenesis. To test the function of T-cadherin in breast cancer, we inactivated the T-cadherin gene in mice and evaluated tumor development and pathology after crossing the mutation into the MMTV-polyoma virus middle T (PyV-mT) transgenic model. We report that T-cadherin deficiency limits mammary tumor vascula...

Hebbard, Lionel W.; Garlatti, Michelle; Young, Lawrence J. T.; Cardiff, Robert D.; Oshima, Robert G.; Ranscht, Barbara

2008-01-01

2

Ionizing radiation and inhibition of angiogenesis in a spontaneous mammary carcinoma and in a syngenic heterotopic allograft tumor model: a comparative study  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background The combined treatment modality of ionizing radiation (IR with inhibitors of angiogenesis (IoA is a promising treatment modality based on preclinical in vivo studies using heterotopic xeno- and allograft tumor models. Nevertheless reservations still exist to translate this combined treatment modality into clinical trials, and more advanced, spontaneous orthotopic tumor models are required for validation to study the efficacy and safety of this treatment modality. Findings We therefore investigated the combined treatment modality of IR in combination with the clinically relevant VEGF receptor (VEGFR tyrosine kinase inhibitor PTK787 in the MMTV/c-neu induced mammary carcinoma model and a syngenic allograft tumor model using athymic nude mice. Mice were treated with fractionated IR, the VEGFR-inhibitor PTK787/ZK222584 (PTK787, or in combination, and efficacy and mechanistic-related endpoints were probed in both tumor models. Overall the treatment response to the IoA was comparable in both tumor models, demonstrating minimal tumor growth delay in response to PTK787 and PTK787-induced tumor hypoxia. Interestingly spontaneously growing tumors were more radiosensitive than the allograft tumors. More important combined treatment of irradiation with PTK787 resulted in a supraadditive tumor response in both tumor models with a comparable enhancement factor, namely 1.5 and 1.4 in the allograft and in the spontaneous tumor model, respectively. Conclusions These results demonstrate that IR in combination with VEGF-receptor tyrosine kinase inhibitors is a valid, promising treatment modality, and that the treatment responses in spontaneous mammary carcinomas and syngenic allografts tumor models are comparable.

Broggini-Tenzer Angela

2011-06-01

3

[Angiogenesis in cartilage tumors].  

Science.gov (United States)

In contrast to normal cartilage, which is avascular, angiogenesis is characteristic of cartilage tumors. In this review, we outline the basic principles of angiogenesis with regard to recent findings on differential morphological and molecular aspects of angiogenesis in cartilage tumors, including enchondromas, conventional chondrosarcomas and dedifferentiated chondrosarcomas. Furthermore, we describe the effects of hypoxia and interleukin-1? on angiogenic signaling in chondrosarcoma cells. PMID:20661574

Kalinski, T; Roessner, A

2010-10-01

4

Canine mammary tumors - clinical survey  

Directory of Open Access Journals (Sweden)

Full Text Available Mammary tumours are the second most frequent neoplasia in dogs, mainly affecting older female patients. Approximately 50% of the mammary tumours are malignant with high percentage of mortality if not treated in time. The aim of this study was to analyze the data of canine patients with mammary tumours, to evaluate the type of tumours, as well as the relationship between tumour incidence and dogs’ age, reproductive cycle and sterilization. The survey was used to retrieve the information in the period of two years from the patient data base of the University Veterinary Hospital at the Faculty of Veterinary medicine in Skopje. Patients included in this survey were subjected to routine clinical investigation and additional laboratory tests (cytological examination, x-rays imaging, CBC and biochemical profile, histopathology of the tumor samples. Aged female patients (12 – 13 years are the most susceptible category for development of mammary tumours. The reproductive history showed that five of the patients with malignant mammary tumourshave never whelped and were not treated with any exogenous hormones. Malignant tumours (adenocarcinoma were diagnosed in 90% of the patients. Three patients died due to lung metastasis. Late diagnosis is one of the major problems that results in lethal outcome due to lung metastases. Since ovarian steroids play an important role in the aetiology, the most effective prevention of mammary tumoursis elective ovariectomy of the bitch at an early age.

Elena Atanaskova Petrov

2014-10-01

5

Angiogenesis in canine mammary tumours: a morphometric and prognostic study.  

Science.gov (United States)

Angiogenesis in canine mammary tumours (CMTs) has been described previously; however, only the intratumoural (IT) region has been studied and information on peritumoural (PT) angiogenesis is lacking. In this study, the blood vessel density (BVD), blood vessel perimeter (BVP) and blood vessel area (BVA) in IT and PT regions of 56 benign CMTs, 55 malignant CMTs and 13 samples of normal mammary gland tissue were analyzed. In addition, the blood endothelial cell proliferation (BECP) as an indicator of ongoing angiogenesis was investigated. The prognostic value of each parameter was also examined. Blood vessels and proliferating blood endothelial cells were present in IT and PT regions of both benign and malignant tumours. The vessels in the PT region had a significantly higher area and perimeter compared with those in the IT region. Malignant tumours showed significantly more vessels with a smaller total BVA and a higher BECP compared with benign tumours and control tissue. In the PT regions there was a significantly higher BVD, BVA and BVP compared with the vessels in control tissue. Only the IT and PT BVD and PT BECP in benign tumours allowed prediction of survival. The morphology of blood vessels in CMTs shows similarities with those in human breast cancer, which strengthens the case for the use of dogs with CMTs in comparative oncology trials. PMID:24231306

Sleeckx, N; Van Brantegem, L; Van den Eynden, G; Fransen, E; Casteleyn, C; Van Cruchten, S; Veldhuis Kroeze, E; Van Ginneken, C

2014-01-01

6

Integrins in tumor angiogenesis and lymphangiogenesis.  

Science.gov (United States)

Angiogenesis, the formation of new blood vessel, plays an important role for the growth and metastasis of malignant tumors. The recent identification of specific growth factors for lymphatic vessels and of new lymphatic-specific markers provided evidence for an active role of the lymphatic system during the tumor growth and metastasis processes. Tumor lymphangiogenesis has been shown to play a role in promoting tumor growth and metastasis of tumor cells to distant sites. Integrins play keys roles in the regulation of angiogenesis and lymphangiogenesis during normal development and several diseases. Indeed, integrins control vascular and lymphatic endothelial cell adhesion, migration, and survival. Importantly, integrin inhibitors can block angiogenesis and lymphangiogenesis. In this chapter, we will highlight the role of integrins during angiogenesis and lymphangiogenesis as well as the function of individual integrins during vascular development, postnatal angiogenesis, and lymphangiogenesis. We discuss the role of integrins as potential therapeutic targets for the control of tumor angiogenesis, lymphangiogenesis, and metastatic spread in the treatment of cancer. We also describe methods to analyze expression and function of integrins during angiogenesis and lymphangiogenesis. PMID:21909928

Foubert, Philippe; Varner, Judith A

2012-01-01

7

Canine mammary tumors - clinical survey  

OpenAIRE

Mammary tumours are the second most frequent neoplasia in dogs, mainly affecting older female patients. Approximately 50% of the mammary tumours are malignant with high percentage of mortality if not treated in time. The aim of this study was to analyze the data of canine patients with mammary tumours, to evaluate the type of tumours, as well as the relationship between tumour incidence and dogs’ age, reproductive cycle and sterilization. The survey was used to retrieve the information in t...

Elena Atanaskova Petrov; Ksenija Ilievska; Plamen Trojacanec; Irena Celeska; Goran Nikolovski; Ivica Gjurovski; Toni Dovenski

2014-01-01

8

The role of microenvironment in tumor angiogenesis  

OpenAIRE

Tumor microenvironment is essential for tumor cell proliferation, angiogenesis, invasion and metastasis through its provision of survival signals, secretion of growth and pro-angiogenic factors, and direct adhesion molecule interactions. This review examines its importance in the induction of an angiogenic response in tumors and in multiple myeloma. The encouraging results of pre-clinical and clinical trials in which tumors have been treated by targeting the tumor microenvironment are also di...

Ribatti, Domenico; Vacca, Angelo

2008-01-01

9

Prevention of radiation-induced mammary tumors  

International Nuclear Information System (INIS)

The radiation-induced rat mammary tumor model is useful for studying tumor prevention by treatment in the initiation or promotion stage. In anti-initiation experiments, the administration of radical scavengers or spin-trapping agents before or immediately after irradiation reduced the incidence of mammary tumors, suggesting that free radicals produced by exposure are a potent initiator. To evaluate the role of nitric oxide (NO) in the initiation, NO-specific scavengers or NO synthase inhibitors were administered during the initiation. These agents partially prevented the tumorigenesis, suggesting that radiation-induced NO contributes to tumor initiation. The administration of curcumin during irradiation reduced the incidence of the tumors in the presence of tumor promotor. In anti-promotion experiments on preventing diethylstilbestrol (DES)-dependent tumor development from mammary primodial cells exposed to radiation, tamoxifen decreased the tumor incidence. From the results, estrogen itself or prolactin induced by estrogen may be a promoter for the tumorigenesis. Bezafibrate and simvastatin, agents inducing hypolipidemia and hypocholesterolemia respectively, cause a decrease in the DES-dependent promotion of radiation-induced tumorigenesis. The simultaneous administration of curcumin and DES significantly reduces the development of mammary tumors in irradiated rats. In this review, the endocrinologic and pharmacologic significance of the anti-initiation and anti-promcance of the anti-initiation and anti-promotion is discussed

10

Classification and grading of canine malignant mammary tumors  

OpenAIRE

Histological grading is a good parameter to stratify tumors according to their biological aggressiveness. The Elston and Ellis grading method in humans, invasive ductal breast carcinomas and other invasive tumors are routinely used. The aims of this study were classification of mammary gland tumors and also application of a human grading method in canine mammary carcinoma. The samples included 37 tumors of mammary glands. Mammary tumors were carcinomas (n = 32) and sarcomas (n = 5). The carci...

Abbas Tavasoly; Hannaneh Golshahi; Annahita Rezaie; Mohammad Farhadi

2013-01-01

11

Molecular Imaging System for Monitoring Tumor Angiogenesis  

Science.gov (United States)

In cancer, non-invasive imaging techniques that monitor molecular processes associated with the tumor angiogenesis could have a central role in the evaluation of novel antiangiogenic and proangiogenic therapies as well as early detection of the disease. Matrix metalloproteinases (MMP) can serve as specific biological targets for imaging of angiogenesis since expression of MMPs is required for angiogenesis and has been found to be upregulated in every type of human cancer and correlates with stage, invasive, metastatic properties and poor prognosis. However, for most cancers it is still unknown when, where and how MMPs are involved in the tumor angiogenesis [1]. Development of high-resolution, high sensitivity imaging techniques in parallel with the tumor models could prove invaluable for assessing the physical location and the time frame of MMP enzymatic acitivity. The goal of this study is to understand where, when and how MMPs are involved in the tumor angiogenesis. We will accomplish this goal by following two objectives: to develop a high sensitivity, high resolution molecular imaging system, to develop a virtual tumor simulator that can predict the physical location and the time frame of the MMP activity. In order to achieve our objectives, we will first develop a PAM system and develop a mathematical tumor model in which the quantitative data obtained from the PAM can be integrated. So, this work will develop a virtual tumor simulator and a molecular imaging system for monitoring tumor angiogenesis. 1.Kessenbrock, K., V. Plaks, and Z. Werb, MMP:regulators of the tumor microenvironment. Cell, 2010. 141(1)

Aytac, Esra; Burcin Unlu, Mehmet

2012-02-01

12

Nanotechnology-mediated targeting of tumor angiogenesis  

OpenAIRE

Abstract Angiogenesis is disregulated in many diseased states, most notably in cancer. An emerging strategy for the development of therapies targeting tumor-associated angiogenesis is to harness the potential of nanotechnology to improve the pharmacology of chemotherapeutics, including anti-angiogenic agents. Nanoparticles confer several advantages over that of free drugs, including their capability to carry high payloads of therapeutic agents, confer increased half-life and reduced toxicity ...

Banerjee Deboshri; Harfouche Rania; Sengupta Shiladitya

2011-01-01

13

Bovine lactoferrin inhibits tumor-induced angiogenesis.  

Science.gov (United States)

Recent studies have demonstrated that bovine lactoferrin (bLF) suppresses tumor growth and metastasis in the mouse and rat and moreover may inhibit angiogenesis. To determine whether angiogenesis inhibition might contribute to antitumor activity, we examined the influence of bLF on tumor-induced angiogenesis and endothelial cell functions as well as angiogenesis-related cytokine production. Bovine LF exhibited dose-dependent inhibition of angiogenesis on 4-6-day-old chick embryo chorioallantoic membranes (CAMs) that lack a mature immune response. This inhibition was reversed when bLF was simultaneously treated with basic fibroblast growth factor (bFGF). It also inhibited in vitro formation of tube-like structures of mouse endothelial KOP2.16 cells. Moreover, it potently suppressed bFGF- or VEGF-induced proliferation of mouse endothelial KOP2.16 cells, but not of mouse fibroblast A31 cells and Lewis lung carcinoma (3LL) cells. In mice, both orally and intraperitoneally administered bLF significantly and dose-dependently suppressed 3LL cell-induced angiogenesis in a dorsal air sac assay. As orally administered bLF was reported to exhibit antitumor activity through production of interferon (IFN)-gamma and interleukin (IL)-18 in intestinal mucosa (Kuhara T et al., Nutr Cancer 2000;38:192-9), production of these cytokines in mouse serum and peritoneal macrophages by bLF was examined. IFN-gamma was not detected in serum by bLF administration. However, bLF markedly elevated IL-18 concentration in serum by oral administration, but not by intraperitoneal administration. It also induced IL-18 in peritoneal macrophages in vitro. These results suggest that bLF participates as a regulator of angiogenesis, possibly explained by blocking endothelial function and inducing IL-18 production. Antitumor activity of bLF may thus be partly mediated by angiogenesis inhibition. PMID:15185351

Shimamura, Mariko; Yamamoto, Yukio; Ashino, Hiromi; Oikawa, Tsutomu; Hazato, Tadahiko; Tsuda, Hiroyuki; Iigo, Masaaki

2004-08-10

14

Amplification of mouse mammary tumor virus genomes in non-mammary tumor cells.  

OpenAIRE

Extra proviral copies of mouse mammary tumor virus (MMTV) are known to be present in the genomes of certain T-cell lymphomas of mice. Analysis of additional non-mammary tumor cell types known to express MMTV transcripts and antigens revealed the presence of extra acquired MMTV proviruses in a pituitary tumor cell line, a macrophage line, and Leydig testicular tumor cells. The nature of the amplified MMTV proviruses in these various tumor cell types differed with regard to copy number and pres...

Racevskis, J.; Beyer, H.

1989-01-01

15

Inorganic nanomaterials for tumor angiogenesis imaging  

Energy Technology Data Exchange (ETDEWEB)

Tumor angiogenesis plays an important role in cancer development and metastasis. Noninvasive detection of angiogenic activities is thus of great importance in cancer diagnosis as well as evaluation of cancer therapeutic responses. Various angiogenesis-related molecular targets have been identified and used in tumor vasculature targeting and imaging. Recently, inorganic nanomaterials with various unique intrinsic physical properties have attracted growing interest in biomedical imaging applications. This article will review current progresses in the applications of inorganic nanoprobes in molecular angiogenesis imaging. Several types of nanomaterials with various optical properties, including semiconductor quantum dots (QDs), single-walled carbon nanotubes (SWNTs), upconversion nanoparticles (UCNPs), and surface-enhanced Raman scattering (SERS) nanoparticles, have been used as novel optical probes to image angiogenic events. Besides optical imaging, magnetic resonance imaging (MRI) of angiogenesis using magnetic nanoparticles has also been intensively investigated. Moreover, nanomaterials provide unique platforms for the integration of various imaging modalities together with therapeutic functionalities for multi-modality imaging and therapy. Although the application of inorganic nanomaterials in clinical imaging and diagnosis is still facing many challenges, the unique properties and functions of these novel nanoprobes make them very promising agents in angiogenesis imaging and could bring great opportunities to this fast-growing field. (orig.)

Liu, Zhuang; Peng, Rui [Soochow University, Functional Nano and Soft Materials Laboratory (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Suzhou, Jiangsu (China)

2010-08-15

16

Imaging tumor angiogenesis with fluorescent proteins.  

Science.gov (United States)

We have developed three unique mouse models to image angiogenesis with fluorescent proteins, which are described in this review. First, we have adapted the surgical orthotopic implantation (SOI) model to image angiogenesis of human tumors labeled with green fluorescent protein (GFP) transplanted in nude mice. The nonluminous induced capillaries are clearly visible by contrast against the very bright tumor fluorescence examined either intravitally or by whole-body imaging in real time. Intravital images of an SOI model of human pancreatic tumors expressing GFP visualized angiogenic capillaries at both primary and metastatic sites. Whole-body optical imaging showed that blood vessel density increased linearly over a 20-week period in an SOI model of human breast cancer expressing GFP. Opening a reversible skin-flap in the light path markedly reduces signal attenuation, increasing detection sensitivity many-fold and enabling vessels to be externally visualized in GFP-expressing tumors growing on internal organs. The second model utilizes dual-color fluorescence imaging, effected by using red fluorescent protein (RFP)-expressing tumors growing in GFP-expressing transgenic mice that express GFP in all cells. This dual-color model visualizes with great clarity the details of the tumor-stroma interaction, especially tumor-induced angiogenesis. The GFP-expressing tumor vasculature, both nascent and mature, are readily distinguished interacting with the RFP-expressing tumor cells. Using a spectral imaging system based on liquid crystal tunable filters, we were able to separate individual spectral species on a pixel-by-pixel basis. Such techniques non-invasively visualized the presence of host GFP-expressing vessels within an RFP-labeled orthotopic human breast tumor by real-time whole-body imaging. The third model involves a transgenic mouse in which the regulatory elements of the stem cell marker nestin drive GFP. The nestin-GFP mouse expresses GFP in areas of the brain, hair follicle stem cells, and in a network of blood vessels in the skin interconnecting hair follicles. RFP-expressing tumors transplanted to nestin-GFP mice enable specific visualization of nascent vessels in skin-growing tumors such as melanoma. Thus, fluorescent proteins expressed in vivo offer very high resolution and sensitivity for real-time imaging of angiogenesis. PMID:15563308

Hoffman, Robert M

2004-01-01

17

Myeloid Cells in the Tumor Microenvironment: Modulation of Tumor Angiogenesis and Tumor Inflammation  

OpenAIRE

Myeloid cells are a heterogeneous population of bone marrow-derived cells that play a critical role during growth and metastasis of malignant tumors. Tumors exhibit significant myeloid cell infiltrates, which are actively recruited to the tumor microenvironment. Myeloid cells promote tumor growth by stimulating tumor angiogenesis, suppressing tumor immunity, and promoting metastasis to distinct sites. In this review, we discuss the role of myeloid cells in promoting tumor angiogenesis. Furthe...

Varner, Judith A.; Schmid, Michael C.

2010-01-01

18

Granular-cell tumor: A rare variant of mammary tumor  

Directory of Open Access Journals (Sweden)

Full Text Available Background. Granular cell tumor (GCT is a rare variant of mammary tumor beset with diagnostic dilemmas that may be resolved by using numerous, very complex, enzymohistochemical and immunohistochemical methods. Case reports. We reported three female patients 16, 21 and 65 years old, operated on for mammary tumor at the Surgical Clinic of the School of Medicine in Niš, over the period of thirty years, 1977 to 2007. During this period 14.022 mammary tumors were diagnosed, including these three cases. These tumors had benign characteristics, without associated tumors in other localizations. A typical histological feature of GCT was a granular cytoplasm in large ovoid cells, organized like nests or like a trabecular arrangement. The tumors were analyzed by sets of histochemical, enzymohistochemical, immunohistochemical methods as well as ultrastructural examination. Protein, S-100 neuron-specific enolase and vimentin expressed a diffuse and intensive immunohistochemical activity, while expression of estrogen and progesterone receptors, as well as HER-2 oncoprotein was negative. The ultrastructural analysis confirmed that the tumor cells were enriched by lysosomes and consequential disorganization of cytoplasm. Conclusion. The reported enzymo- and immunohistochemical combined methods provide a precise diagnosis and confirm the GCT's neural origin, which has been disputed for years.

Ili? Ivan

2008-01-01

19

Magnetic Nanoparticles in the Imaging of Tumor Angiogenesis  

OpenAIRE

Angiogenesis, the growth of new capillary blood vessels, is central to the growth of tumors. Non-invasive imaging of tumor angiogenesis will allow for earlier detection of tumors and also the development of surrogate markers for assessing response to treatment. Steady state magnetic resonance imaging with magnetic nanoparticles is one method to assess angiogenesis. In this article we explain the theory behind steady state magnetic resonance imaging and review the available literature.

Shaunagh McDermott; Guimaraes, Alexander R.

2012-01-01

20

Dll4-Notch signaling in regulation of tumor angiogenesis.  

Science.gov (United States)

Tumor angiogenesis is a complex process and involves the tight interplay of tumor cells, endothelial cells, phagocytes and their secreted factors, which may act as promoters or inhibitors of angiogenesis. Many signaling pathways involved in these processes such as vascular endothelial growth factor (VEGF), fibroblast growth factors, Wnt and mTOR signaling pathway. Though research has confirmed that VEGF can play an important role in tumor angiogenesis, and has designed a lot of drugs that target VEGF, both experimental and clinical studies showed that these pathways mentioned above including VEGF did not play key roles in tumor angiogenesis. With the deepening of the research, people find that of all the signaling pathways involved in tumor angiogenesis, Notch signaling is the most notable one and plays crucial role in tumor angiogenesis. It was previously recognized that the Notch signaling plays a key role only in physiological angiogenesis such as development, wound healing and pregnancy. However, an increasing number of studies have proved that Notch signaling is also involved in pathological angiogenesis such as tumor angiogenesis and plays a critical role in these processes. More importantly, compared to resistance caused by anti-VEGF or other signaling pathways, experimental evidence revealed that Notch was involved in anticancer drug resistance, indicating that targeting Notch could be a novel therapeutic approach to the treatment for cancer by overcoming drug resistance of cancer cells. More recently, research has demonstrated that Notch ligands Delta-like 4 (Dll4) plays a key role in tumor angiogenesis. Data show that Dll4 functions as a negative regulator of tumor angiogenesis and is upregulated in tumor vasculature. This review focus on recent insights into Dll4-Notch signaling in tumor angiogenesis and its mechanisms, which may be utilized for a potential pharmacological use as a target for anti-angiogenic cancer therapy. PMID:24114288

Liu, Zhaoguo; Fan, Fangtian; Wang, Aiyun; Zheng, Shizhong; Lu, Yin

2014-04-01

21

Muscarinic receptors are involved in LMM3 tumor cells proliferation and angiogenesis  

International Nuclear Information System (INIS)

Angiogenesis is a process of new blood vessel development from pre-existing vasculature and it plays an essential role in tumor growth and metastases. Here, we investigate the expression of muscarinic acetylcholine receptors (mAchR) and their participation in tumor cell proliferation and angiogenesis ability. Saturation binding assays with the tritiated muscarinic antagonist quinuclidinyl benzilate indicate that LMM3 cells derived from a murine mammary adenocarcinoma express a single class of functional mAchR. Competition binding assays with selective muscarinic antagonists indicate a predominance of M3 receptor subtype. The muscarinic agonist carbachol (CARB) stimulates LMM3 cell proliferation in a concentration dependent manner. The maximal effect induced by 10-9 M CARB was totally blunted by atropine and by the selective M3 and M1 antagonists, para-fluoro hexahydro sila-difenidol (pf-HHSiD) and pirenzepine, respectively. In addition, pf-HHSiD completely blocked in vivo CARB-induced neovascular formation and vascular endothelial growth factor-A in LMM3 tumor cells. We can conclude that mAchR expressed in LMM3 mammary tumor cells positively regulate proliferation and angiogenesis required for tumor progression

22

Microenvironmental Regulation of Tumor Angiogenesis: Biological and Engineering Considerations  

Science.gov (United States)

Tumor angiogenesis is fundamental to tumor growth and metastasis, and antiangiogenic therapies have been developed to target this process. However, the clinical success of these treatments has been limited, which may be due, in part, to an incomplete understanding of cell-microenvironment interactions and their role in tumor angiogenesis. Traditionally, two-dimensional (2D) culture approaches have been used to study tumor progression in vitro, but these systems fail to faithfully recreate tumor microenvironmental conditions contributing to tumor angiogenesis in vivo. By integrating cancer biology with tissue engineering and drug delivery approaches, the development of biologically inspired tumor models has emerged. Such 3D model systems allow studying the specific role of soluble factor signaling, cell-extracellular matrix (ECM) interactions, cell-cell interactions, mechanical cues, and metabolic stress. This chapter discusses specific biological and engineering design considerations for tissue-engineered tumor models and highlights their application for defining the underpinnings of tumor angiogenesis.

Infanger, David W.; Pathi, Siddharth P.; Fischbach, Claudia

23

Hybrid modeling of tumor-induced angiogenesis  

CERN Document Server

When modeling of tumor-driven angiogenesis, a major source of analytical and computational complexity is the strong coupling between the kinetic parameters of the relevant stochastic branching-and-growth of the capillary network, and the family of interacting underlying fields. To reduce this complexity, we take advantage of the system intrinsic multiscale structure: we describe the stochastic dynamics of the cells at the vessel tip at their natural mesoscale, whereas we describe the deterministic dynamics of the underlying fields at a larger macroscale. Here, we set up a conceptual stochastic model including branching, elongation, and anastomosis of vessels and derive a mean field approximation for their densities. This leads to a deterministic integro-partial differential system that describes the formation of the stochastic vessel network. We discuss the proper capillary injecting boundary conditions and include the results of relevant numerical simulations.

Bonilla, L L; Alvaro, M; Carretero, M

2014-01-01

24

TUMOR ANGIOGENESIS–IMPLICATIONS IN CANCER THERAPY  

Directory of Open Access Journals (Sweden)

Full Text Available Neovascularization is a crucial component of cancer cell growth and progression. Cancer cells are dependent on blood vessels for growth and metastases. Angiogenesis is finely balanced by pro- and anti-angiogenetic factors. Under normal conditions, the balance leans toward the anti-angiogenetic phenotype. Hypoxia is the major element of the angiogenetic switch, which leads to overexpression of angiogenetic factors, mostly vascular endothelial growth factor (VEGF, favoring new vessel formation. VEGF appears to be one of the key players, and therefore current anti-angiogenetic strategies are mainly aimed at targeting the VEGF pathway. A variety of approaches to targeting VEGF and its signaling system have been developed: anti-VEGF antibodies such as bevacizumab (for metastatic colorectal, breast, lung and renal cancers and small molecules like sunitinib (for renal cancers and gastrointestinal stromal tumors, sorafenib (for hepatocellular and renal cell carcinoma, pazopanib and motesanib (for metastatic breast cancer.

M. Marinca

2010-05-01

25

Experimental studies on mammary tumors in rats  

International Nuclear Information System (INIS)

The purpose of this study was to assess the effects of dietary fat components in radiation-induced rat mammary carcinogenesis, and the response of chemically- or radiation-induced rat mammary tumors (MT) to experimental radiotherapy. Female rats of F344 strain were fed, for 400 days after neutron irradiation, with a synthetic diet containing various fat components with different proportion. Transplanted MTs were tested for their response to radiotherapy in terms of their hormone dependency and antigenicity. An incidence rate of MT was significantly higher in rats given 20% corn oil than in those given 5% or 1% corn oil (61.5% vs 23.0% and 23.8%). In giving diet composed of different fat components with a constant rate of 20%, fish oil significantly inhibited the incidence of MT (16.7%) as compared with lard oil (77.0%) and corn oil (61.5%). In the case of corn oil, an MT incidence rate of 61.5% was reduced to 16.7% when the total caloric intake was decreased by 70%. No association was found between the MT incidence and serum levels of estrogen or prolactin in groups of different fat components. In rats transplanted with 7, 12-dimethylbenz(a)anthracene (DMBA), some of DMBA-induced MTs were spontaneously reduced, suggesting a high antigenicity. Other DMBA-induced MTs were rejected by syngeneic recipients upon cellular transplantation. A high antigenicity may be explained by tumor take and growth with a short latency upon transplantation into immunosuppressed syngeneic rantation into immunosuppressed syngeneic recipients. Ovarian hormone-dependent MTs tended to have a higher radiosensitivity than hormone-independent autonomous MTs. DMBA-induced MTs began to reduce 10 days and were completely destroyed 30 days after irradiation, irrespective of whether they were directly exposed to or shielded from neutron. This abscopal effect can be explained by immunological reaction of the host. (Namekawa, K) 87 refs

26

Anti-CD73 therapy impairs tumor angiogenesis.  

Science.gov (United States)

CD73 is an ecto-nucleotidase overexpressed in various types of tumors that catabolizes the generation of extracellular adenosine, a potent immunosuppressor. We and others have shown that targeted blockade of CD73 can rescue anti-tumor T cells from the immunosuppressive effects of extracellular adenosine. Another important function of extracellular adenosine is to regulate adaptive responses to hypoxia. However, the importance of CD73 for tumor angiogenesis and the effect of anti-CD73 therapy on tumor angiogenesis remain unknown. In this study, we demonstrated that CD73 expression on tumor cells and host cells contribute to tumor angiogenesis. Our data revealed that tumor-derived CD73 enhances the production of vascular endothelial growth factor (VEGF) by tumor cells that host-derived CD73 is required for in vivo angiogenic responses and that endothelial cells require CD73 expression for tube formation and migration. Notably, the pro-angiogeneic effects of CD73 relied on both enzymatic and non-enzymatic functions. Using a mouse model of breast cancer, we demonstrated that targeted blockade of CD73 with a monoclonal antibody significantly decreased tumor VEGF levels and suppressed tumor angiogenesis in vivo. Taken together, our study strongly suggests that targeted blockade of CD73 can significantly block tumor angiogenesis, and further supports its clinical development for cancer treatment. PMID:23982901

Allard, Bertrand; Turcotte, Martin; Spring, Kathleen; Pommey, Sandra; Royal, Isabelle; Stagg, John

2014-03-15

27

Endothelial cell pseudopods and angiogenesis of breast cancer tumors  

OpenAIRE

Abstract Background A neoplastic tumor cannot grow beyond a millimeter or so in diameter without recruitment of endothelial cells and new blood vessels to supply nutrition and oxygen for tumor cell survival. This study was designed to investigate formation of new blood vessels within a human growing breast cancer tumor model (MDA MB231 in mammary fat pad of nude female mouse). Once the tumor grew to 35 mm3, it developed a well-vascularized capsule. Histological sections of tumors greater than...

Sun LuZhe; Short Nicholas; Cameron Ivan L; Elaine, Hardman W.

2005-01-01

28

Global microRNA depletion suppresses tumor angiogenesis.  

Science.gov (United States)

MicroRNAs delicately regulate the balance of angiogenesis. Here we show that depletion of all microRNAs suppresses tumor angiogenesis. We generated microRNA-deficient tumors by knocking out Dicer1. These tumors are highly hypoxic but poorly vascularized, suggestive of deficient angiogenesis signaling. Expression profiling revealed that angiogenesis genes were significantly down-regulated as a result of the microRNA deficiency. Factor inhibiting hypoxia-inducible factor 1 (HIF-1), FIH1, is derepressed under these conditions and suppresses HIF transcription. Knocking out FIH1 using CRISPR/Cas9-mediated genome engineering reversed the phenotypes of microRNA-deficient cells in HIF transcriptional activity, VEGF production, tumor hypoxia, and tumor angiogenesis. Using multiplexed CRISPR/Cas9, we deleted regions in FIH1 3' untranslated regions (UTRs) that contain microRNA-binding sites, which derepresses FIH1 protein and represses hypoxia response. These data suggest that microRNAs promote tumor responses to hypoxia and angiogenesis by repressing FIH1. PMID:24788094

Chen, Sidi; Xue, Yuan; Wu, Xuebing; Le, Cong; Bhutkar, Arjun; Bell, Eric L; Zhang, Feng; Langer, Robert; Sharp, Phillip A

2014-05-15

29

Equine estrogen-induced mammary tumors in rats.  

Science.gov (United States)

Long-term hormone replacement therapy is associated with an increased risk of breast, ovarian and endometrial cancers in women. Equine estrogens are a principal component of hormone replacement therapy; however, their tumorigenic potential toward mammary tissue and reproductive organs has not been extensively explored. A pellet containing equilin was inserted under the skin of female ACI rats and the development of mammary tumors was monitored. Histological examination revealed premalignant lesions such as apocrine metaplasia in whole-mount preparations of mammary gland from the equilin-treated rats. ACI rats given 10mg equilin developed palpable mammary tumors at 13 weeks of treatment, and 37.5% of the rats developed mammary tumors within 15 weeks. For 2.5mg equilin, palpable tumors were observed in 8.3% of the rats after 8 weeks' treatment; the frequency was lower than that (42.9%) observed with 2.5mg E(2). No tumors were observed in the untreated rats. Evidently, equilin is a mammary carcinogen, and this potential may be associated with development of breast and reproductive cancers in women receiving hormone replacement therapy. PMID:20096754

Okamoto, Yoshinori; Liu, Xiaoping; Suzuki, Naomi; Okamoto, Kanako; Kim, Hyo Jeong; Laxmi, Y R Santosh; Sayama, Kazutoshi; Shibutani, Shinya

2010-04-01

30

Roles of Integrins in Tumor Angiogenesis and Lymphangiogenesis  

OpenAIRE

The lifelong dedication of Dr. Judah Folkman to understand how tumors co-opt vasculature to promote tumor growth and spread resulted in the development of an astounding body of knowledge and development of new clinical therapeutics for cancer. Angiogenesis is a critical point in the development and dissemination of most human tumors. Tumor-associated lymphangiogenesis also plays an important role in mediating tumor spread to lymph nodes. The molecular regulations of these processes are comple...

Garmy-susini, Barbara; Varner, Judith A.

2008-01-01

31

ARTEMIN Promotes De Novo Angiogenesis in ER Negative Mammary Carcinoma through Activation of TWIST1-VEGF-A Signalling  

OpenAIRE

The neurotrophic factor ARTEMIN (ARTN) has been reported to possess a role in mammary carcinoma progression and metastasis. Herein, we report that ARTN modulates endothelial cell behaviour and promotes angiogenesis in ER-mammary carcinoma (ER-MC). Human microvascular endothelial cells (HMEC-1) do not express ARTN but respond to exogenously added, and paracrine ARTN secreted by ER-MC cells. ARTN promoted endothelial cell proliferation, migration, invasion and 3D matrigel tube formation. Angiog...

Banerjee, Arindam; Wu, Zheng-sheng; Qian, Peng-xu; Kang, Jian; Liu, Dong-xu; Zhu, Tao; Lobie, Peter E.

2012-01-01

32

Classification and grading of canine malignant mammary tumors  

Science.gov (United States)

Histological grading is a good parameter to stratify tumors according to their biological aggressiveness. The Elston and Ellis grading method in humans, invasive ductal breast carcinomas and other invasive tumors are routinely used. The aims of this study were classification of mammary gland tumors and also application of a human grading method in canine mammary carcinoma. The samples included 37 tumors of mammary glands. Mammary tumors were carcinomas (n = 32) and sarcomas (n = 5). The carcinomas were classified as simple carcinoma 56.8% (n = 21), complex carcinoma 13.5% (n = 5), carcinoma arising from benign tumor 10.8% (n= 4) and special type of carcinoma 5.4% (n = 2). Out of 32 carcinomas studied, 37.5% (n = 12) grade I, 46.9% (n = 15) grade II and 15.6% (n = 5) grade III. This study demonstrated that the Elston and Ellis method of histological grading in canine mammary tumor is a reliable prognostic factor which is correlated with histopathological classification. PMID:25593682

Tavasoly, Abbas; Golshahi, Hannaneh; Rezaie, Annahita; Farhadi, Mohammad

2013-01-01

33

Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer.  

Science.gov (United States)

Angiogenesis is necessary for the continued growth of solid tumors, invasion and metastasis. Several studies clearly showed that heme oxygenase-1 (HO-1) plays an important role in angiogenesis. In this study, we used the vital microscope system, transparent skinfold model, lung colonization model and transduced pancreatic cancer cell line (Panc-1)/human heme oxygenase-1 (hHO-1) cells, to precisely analyze, for the first time, the effect of hHO-1 gene on tumor growth, angiogenesis and metastasis. Our results revealed that HO-1 stimulates angiogenesis of pancreatic carcinoma in severe combined immune deficient mice. Overexpression of human hHO-1 after its retroviral transfer into Panc-1 cells did not interfere with tumor growth in vitro. While in vivo the development of tumors was accelerated upon transfection with hHO-1. On the other hand, inhibition of heme oxygenase (HO) activity by stannous mesoporphyrin was able transiently to delay tumor growth in a dose dependent manner. Tumor angiogenesis was markedly increased in Panc-1/hHO-1 compared to mock transfected and wild type. Lectin staining and Ki-67 proliferation index confirmed these results. In addition hHO-1 stimulated in vitro tumor angiogenesis and increased endothelial cell survival. In a lung colonization model, overexpression of hHO-1 increased the occurrence of metastasis, while inhibition of HO activity by stannous mesoporphyrin completely inhibited the occurrence of metastasis. In conclusion, overexpression of HO-1 genes potentiates pancreatic cancer aggressiveness, by increasing tumor growth, angiogenesis and metastasis and that the inhibition of the HO system may be of useful benefit for the future treatment of the disease. PMID:14517400

Sunamura, Makoto; Duda, Dan G; Ghattas, Maivel H; Lozonschi, Lucian; Motoi, Fuyuhiko; Yamauchi, Jun-Ichiro; Matsuno, Seiki; Shibahara, Shigeki; Abraham, Nader G

2003-01-01

34

Malignant mammary tumor in female dogs: environmental contaminants  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Mammary tumors of female dogs have greatly increased in recent years, thus demanding rapid diagnosis and effective treatment in order to determine the animal survival. There is considerable scientific interest in the possible role of environmental contaminants in the etiology of mammary tumors, specifically in relation to synthetic chemical substances released into the environment to which living beings are either directly or indirectly exposed. In this study, the presence of pyrethroid insecticide was observed in adjacent adipose tissue of canine mammary tumor. High Precision Liquid Chromatography - HPLC was adapted to detect and identify environmental contaminants in adipose tissue adjacent to malignant mammary tumor in nine female dogs, without predilection for breed or age. After surgery, masses were carefully examined for malignant neoplastic lesions. Five grams of adipose tissue adjacent to the tumor were collected to detect of environmental contaminants. The identified pyrethroids were allethrin, cyhalothrin, cypermethrin, deltamethrin and tetramethrin, with a contamination level of 33.3%. Histopathology demonstrated six female dogs (66.7% as having complex carcinoma and three (33.3% with simple carcinoma. From these tumors, seven (77.8% presented aggressiveness degree III and two (22.2% degree I. Five tumors were positive for estrogen receptors in immunohistochemical analysis. The contamination level was observed in more aggressive tumors. This was the first report in which the level of environmental contaminants could be detected in adipose tissue of female dogs with malignant mammary tumor, by HPLC. Results suggest the possible involvement of pyrethroid in the canine mammary tumor carcinogenesis. Hence, the dog may be used as a sentinel animal for human breast cancer, since human beings share the same environment and basically have the same eating habits.

Bissacot Denise Z

2010-06-01

35

HORMONAL INFLUENCES ON MAMMARY TUMORS OF THE RAT  

Science.gov (United States)

Many members of the androstane series profoundly retarded the growth of a transplanted benign mammary fibroadenoma of the rat; the restraint of tumor growth was in direct proportion to the amount of the administered compound until its maximal effect was achieved. Certain steroids closely related to the androstane inhibitors accelerated the growth of the tumor. These effects of divergent sort depend on the molecular structure of the steroid. The molecular structure of androstane derivatives, which is of high significance in modifying the rate of growth of the benign mammary tumor, consists of multiple components. These include (a) the presence and number of ketone and hydroxyl groups in special orientation at specific sites, (b) the sites of dehydrogenation in the molecule, and (c) the presence, number, and state of hydrogenation of alkyl groups at designated molecular positions. These multiple factors determine whether androstane compounds will inhibit growth of the tumor, enhance it, or fail to influence its growth. The androstane compounds which caused either the restraint or the promotion of tumor growth had the common property of inducing proliferation of the normal mammary epithelium. Two mechanisms are involved in the restraint of growth of mammary fibroadenoma by androstane inhibitors. The primary effect is the abolition of action of phenolic estrogens and progesterone when dihydrotestosterone is administered concurrently, presumably through direct action at the tumor cell level A secondary contributory suppressive effect is the depression of ovarian activity, and consequently of the production of phenolic estrogens and progesterone, by these compounds. Transplanted mammary fibroadenoma in the rat possesses neoplastic traits and also some growth properties of normal mammary epithelium; inhibition of these latter by hormonal methods commonly retarded the growth of the tumor. But in hypophysectomized rats dihydrotestosterone failed to inhibit the growth of a mammary fibroadenoma with unusually low hormonal dependence as determined by functional tests of its growth. PMID:13428917

Huggins, Charles; Mainzer, Klaus

1957-01-01

36

Collagen density promotes mammary tumor initiation and progression  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background Mammographically dense breast tissue is one of the greatest risk factors for developing breast carcinoma. Despite the strong clinical correlation, breast density has not been causally linked to tumorigenesis, largely because no animal model has existed for studying breast tissue density. Importantly, regions of high breast density are associated with increased stromal collagen. Thus, the influence of the extracellular matrix on breast carcinoma development and the underlying molecular mechanisms are not understood. Methods To study the effects of collagen density on mammary tumor formation and progression, we utilized a bi-transgenic tumor model with increased stromal collagen in mouse mammary tissue. Imaging of the tumors and tumor-stromal interface in live tumor tissue was performed with multiphoton laser-scanning microscopy to generate multiphoton excitation and spectrally resolved fluorescent lifetimes of endogenous fluorophores. Second harmonic generation was utilized to image stromal collagen. Results Herein we demonstrate that increased stromal collagen in mouse mammary tissue significantly increases tumor formation approximately three-fold (p p Conclusion This study provides the first data causally linking increased stromal collagen to mammary tumor formation and metastasis, and demonstrates that fundamental differences arise and persist in epithelial tumor cells that progressed within collagen-dense microenvironments. Furthermore, the imaging techniques and signature identified in this work may provide useful diagnostic tools to rapidly assess fresh tissue biopsies.

Knittel Justin G

2008-04-01

37

Chemokines as mediators of tumor angiogenesis and neovascularization.  

Science.gov (United States)

Chemokines are a superfamily of structurally homologous heparin-binding proteins that influence tumor growth and metastasis. Several members of the CXC and CC chemokine families are potent inducers of neovascularization, whereas a subset of the CXC chemokines are potent inhibitors. In this paper, we review the current literature regarding the role of chemokines as mediators of tumor angiogenesis and neovascularization. PMID:21040721

Keeley, Ellen C; Mehrad, Borna; Strieter, Robert M

2011-03-10

38

Chemokines as mediators of tumor angiogenesis and neovascularization  

OpenAIRE

Chemokines are a superfamily of structurally homologous heparin-binding proteins that influence tumor growth and metastasis. Several members of the CXC and CC chemokine families are potent inducers of neovascularization, whereas a subset of the CXC chemokines are potent inhibitors. In this paper, we review the current literature regarding the role of chemokines as mediators of tumor angiogenesis and neovascularization.

Keeley, Ellen C.; Mehrad, Borna; Strieter, Robert M.

2010-01-01

39

Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer  

Energy Technology Data Exchange (ETDEWEB)

Cytochrome P450 (CYP) 4Z1, a novel CYP4 family member, is over-expressed in human mammary carcinoma and associated with high-grade tumors and poor prognosis. However, the precise role of CYP4Z1 in tumor progression is unknown. Here, we demonstrate that CYP4Z1 overexpression promotes tumor angiogenesis and growth in breast cancer. Stable expression of CYP4Z1 in T47D and BT-474 human breast cancer cells significantly increased mRNA expression and production of vascular endothelial growth factor (VEGF)-A, and decreased mRNA levels and secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2), without affecting cell proliferation and anchorage-independent cell growth in vitro. Notably, the conditioned medium from CYP4Z1-expressing cells enhanced proliferation, migration and tube formation of human umbilical vein endothelial cells, and promoted angiogenesis in the zebrafish embryo and chorioallantoic membrane of the chick embryo. In addition, there were lower levels of myristic acid and lauric acid, and higher contents of 20-hydroxyeicosatetraenoic acid (20-HETE) in CYP4Z1-expressing T47D cells compared with vector control. CYP4Z1 overexpression significantly increased tumor weight and microvessel density by 2.6-fold and 1.9-fold in human tumor xenograft models, respectively. Moreover, CYP4Z1 transfection increased the phosphorylation of ERK1/2 and PI3K/Akt, while PI3K or ERK inhibitors and siRNA silencing reversed CYP4Z1-mediated changes in VEGF-A and TIMP-2 expression. Conversely, HET0016, an inhibitor of the CYP4 family, potently inhibited the tumor-induced angiogenesis with associated changes in the intracellular levels of myristic acid, lauric acid and 20-HETE. Collectively, these data suggest that increased CYP4Z1 expression promotes tumor angiogenesis and growth in breast cancer partly via PI3K/Akt and ERK1/2 activation. -- Highlights: ? CYP4Z1 overexpression promotes human breast cancer growth and angiogenesis. ? The pro-angiogenic effects of CYP4Z1 have been studied in vitro and in vivo. ? CYP4Z1 regulates expression and production of VEGF-A and TIMP-2. ? CYP4Z1-induced angiogenesis is associated with PI3K and ERK1/2 activation. ? CYP4Z1 may be an attractive target for anti-cancer therapy.

Yu, Wei [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Chai, Hongyan [Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Li, Ying; Zhao, Haixia; Xie, Xianfei; Zheng, Hao; Wang, Chenlong; Wang, Xue [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Yang, Guifang [Department of Pathology, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Cai, Xiaojun [Department of Ophthalmology, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Falck, John R. [Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390 (United States); Yang, Jing, E-mail: yangjingliu@yahoo.com.cn [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China)

2012-10-01

40

Prognostic value of vascular endothelial growth factor and hypoxia-inducible factor 1? in canine malignant mammary tumors.  

Science.gov (United States)

Mammary tumors are the most common type of tumor in dogs, with approximately half of these tumors being malignant. Hypoxia, characterized by oxygen levels below normal, is a known adverse factor to cancer treatment. The hypoxia-inducible factor 1? (HIF-1?) is a central regulator of the pathophysiological response of mammalian cells to low oxygen levels. HIF-1? activates the transcription of vascular endothelial growth factor (VEGF), which in turn promotes angiogenesis through its ability to stimulate the growth, migration and invasion of endothelial cells to form new blood vessels, contributing to tumor progression. In this study, we evaluated the serum concentration and gene expression of VEGF and HIF-1? linking them with clinicopathological parameters and survival of dogs with mammary tumors in order to infer the possible prognostic value of these factors. We collected blood and tumor fragments of 24 female dogs with malignant mammary tumors (study group) and 26 non-affected female dogs (control group) to verify the gene expression of VEGF and HIF-1? by quantitative real-time PCR (qPCR) and the serum levels by ELISA (enzyme-linked immunosorbent). The results showed high serum levels of VEGF in the study group and its correlation between abundant vascularization, lymph node involvement, metastasis, death rate and low survival (p<0.05). The serum percentage of HIF-1? in female dogs with mammary neoplasia was lower than that in the control group and higher in female dogs with tumor metastasis and history of tumor recurrence (p<0.05). Regarding gene expression, there was a gene overexpression of VEGFA in female dogs with poor outcome, in contrast to the gene underexpression of HIF-1A. Taken together, these results suggested that VEGF is important in tumor progression and can be used as a potential prognostic marker in the clinic and may be useful in predicting tumor progression in dogs with mammary neoplasia. PMID:25779537

Moschetta, Marina Gobbe; Maschio, Larissa Bazela; Jardim-Perassi, Bruna Victorasso; Gelaleti, Gabriela Bottaro; Lopes, Juliana Ramos; Leonel, Camila; Gonçalves, Naiane Do Nascimento; Ferreira, Lívia Carvalho; Martins, Gustavo Rodrigues; Borin, Thaiz Ferraz; Zuccari, Debora Aparecida Pires De Campos

2015-05-01

41

The role of neutralizing antibodies for mouse mammary tumor virus transmission and mammary cancer development  

Science.gov (United States)

Mouse mammary tumor virus (MMTV) infection establishes chronic germinal centers and a lifelong neutralizing Ab response. We show that removal of the draining lymph node after establishment of the germinal center reaction led to complete loss of neutralizing Abs despite comparable infection levels in peripheral lymphocytes. Importantly, in the absence of neutralization, only the exocrine organs mammary gland, salivary gland, pancreas, and skin showed strikingly increased infection, resulting in accelerated mammary tumor development. Induction of stronger neutralization did not influence chronic infection levels of peripheral lymphoid organs but strongly inhibited mammary gland infection and virus transmission to the next generation. Taken together, we provide evidence that a tight equilibrium in virus neutralization allows limited infection of exocrine organs and controls cancer development in susceptible mouse strains. These experiments show that a strong neutralizing Ab response induced after infection is not able to control lymphoid MMTV infection. Strong neutralization, however, is capable of blocking amplification of mammary gland infection, tumor development, and virus transmission to the next generation. The results also indicate a role of neutralization in natural resistance to MMTV infection.

Finke, Daniela; Luther, Sanjiv A.; Acha-Orbea, Hans

2003-01-01

42

MRI monitoring of tumor response following angiogenesis inhibition in an experimental human breast cancer model  

International Nuclear Information System (INIS)

The aim of this study was to evaluate the potential of dynamic magnetic resonance imaging (MRI) enhanced by macromolecular contrast agents to monitor noninvasively the therapeutic effect of an anti-angiogenesis VEGF receptor kinase inhibitor in an experimental cancer model. MDA-MB-435, a poorly differentiated human breast cancer cell line, was implanted into the mammary fat pad in 20 female homozygous athymic rats. Animals were assigned randomly to a control (n=10) or drug treatment group (n=10). Baseline dynamic MRI was performed on sequential days using albumin-(GdDTPA)30 (6.0 nm diameter) and ultrasmall superparamagnetic iron oxide (USPIO) particles (30 nm diameter). Subjects were treated either with PTK787/ZK 222584, a VEGF receptor tyrosine kinase inhibitor, or saline given orally twice daily for 1 week followed by repeat MRI examinations serially using each contrast agent. Employing a unidirectional kinetic model comprising the plasma and interstitial water compartments, tumor microvessel characteristics including fractional plasma volume and transendothelial permeability (KPS) were estimated for each contrast medium. Tumor growth and the microvascular density, a histologic surrogate of angiogenesis, were also measured. Control tumors significantly increased (PPS) based on MRI assays using both macromolecular contrast media. In contrast, tumor growth was significantly reduced (PPS values declined slightly. Estimated values for the fractional plasma volume did not differ significantly between treatment groups or contrast agents. Microvascular density counts correlated fairly with the tumor growth rate (r=0.64) and were statistically significant higher (PPS), using either of two macromolecular contrast media, were able to detect effects of treatment with a VEGF receptor tyrosine kinase inhibitor on tumor vascular permeability. In a clinical setting such quantitative MRI measurements could be used to monitor tumor anti-angiogenesis therapy. (orig.)

43

Ceramide kinase promotes tumor cell survival and mammary tumor recurrence.  

Science.gov (United States)

Recurrent breast cancer is typically an incurable disease and, as such, is disproportionately responsible for deaths from this disease. Recurrent breast cancers arise from the pool of disseminated tumor cells (DTC) that survive adjuvant or neoadjuvant therapy, and patients with detectable DTCs following therapy are at substantially increased risk for recurrence. Consequently, the identification of pathways that contribute to the survival of breast cancer cells following therapy could aid in the development of more effective therapies that decrease the burden of residual disease and thereby reduce the risk of breast cancer recurrence. We now report that ceramide kinase (Cerk) is required for mammary tumor recurrence following HER2/neu pathway inhibition and is spontaneously upregulated during tumor recurrence in multiple genetically engineered mouse models for breast cancer. We find that Cerk is rapidly upregulated in tumor cells following HER2/neu downregulation or treatment with Adriamycin and that Cerk is required for tumor cell survival following HER2/neu downregulation. Consistent with our observations in mouse models, analysis of gene expression profiles from more than 2,200 patients revealed that elevated CERK expression is associated with an increased risk of recurrence in women with breast cancer. In addition, although CERK expression is associated with aggressive subtypes of breast cancer, including those that are estrogen receptor-negative, HER2(+), basal-like, or high grade, its association with poor clinical outcome is independent of these clinicopathologic variables. Together, our findings identify a functional role for Cerk in breast cancer recurrence and suggest the clinical utility of agents targeted against this prosurvival pathway. PMID:25164007

Payne, Ania W; Pant, Dhruv K; Pan, Tien-Chi; Chodosh, Lewis A

2014-11-01

44

Phyllodes malignant mammary tumors:communication of three cases  

International Nuclear Information System (INIS)

Three cases of phyllode malignant mammary tumors were studied in the Anatomo-Pathology Chair of the Montevideo, Uruguay.The discussion covered epidemiology, morphologic staging and biological significance of phyllode tumor within the broader spectrum of libro-epithelial breast tumors.An overview of literature shows that histo-pathological criteria recommended by world Health Organization(WHO) are the ones which determine the behaviour of phyllode mammary tumors, wheter bening, malignant of borderline.Prognostic factors of metastases are those involved in stroma overgrowth, anaplasia high mitotic index and infiltrative edge of tumor.None of the clinical aspects,including tumor size, are significant from the viewpoint of prognosis.Efective treatment is broad extended surgical excision (adequate margins),mastectomy being reserved for large tummors that are borderline, malignant or recurrent

45

Liposomal targeting of glucocorticoids to inhibit tumor angiogenesis  

OpenAIRE

Glucocorticoids (GC) have inhibitory actions on solid tumor growth due to suppressive effects on tumor angiogenesis and inflammation. When evaluating the preclinical studies on solid tumor growth inhibition, it appears that GC-induced antitumor effects are achieved by using substantially higher doses than the minimal doses needed to achieve inhibition of inflammatory disease processes. The high doses of GC used in these antitumor studies resulted in death of some of the animals due to opportu...

Banciu, M.

2007-01-01

46

Semaphorin7A promotes tumor growth and exerts a pro-angiogenic effect in macrophages of mammary tumor-bearing mice  

Directory of Open Access Journals (Sweden)

Full Text Available Semaphorins, a large family of molecules involved in the axonal guidance and development of the nervous system, have been recently shown to have both angiogenic and anti-angiogenic properties. Specifically, semaphorin 7A (SEMA7A has been reported to have a chemotactic activity in neurogenesis, and to be an immune modulator via it binding to ?1?1integrins. Additionally, SEMA7A has been shown to promote chemotaxis of monocytes, inducing them to produce proinflammatory mediators. In this study we explored the role of SEMA7A in the tumoral context. We show that SEMA7A is highly expressed by DA-3 murine mammary tumor cells in comparison to normal mammary cells (EpH4, and that peritoneal macrophages from mammary tumor-bearing mice also express SEMA7A at higher levels compared to peritoneal macrophages derived from normal control mice. We also show that murine macrophages treated with recombinant murine SEMA7A significantly increased their expression of proangiogenic molecules, such as CXCL2/MIP-2. Gene silencing of SEMA7A in peritoneal elicited macrophages from DA-3 tumor-bearing mice resulted in decreased CXCL2 expression. Mice implanted with SEMA7A silenced tumor cells showed decreased angiogenesis in the tumors compared to the wild type tumors. Furthermore, peritoneal elicited macrophages from mice bearing SEMA7A-silenced tumors produce significantly (p< 0.01 lower levels of angiogenic proteins, such as MIP-2, CXCL1 and MMP-9, compared to macrophages from control DA-3 mammary tumors. We postulate that SEMA7A derived from mammary carcinomas may serve as a monocyte chemoattractant and skew monocytes into a pro-tumorigenic phenotype. A putative relationship between tumor-derived SEMA7A and monocytes could prove valuable in establishing new research avenues towards unraveling important tumor-host immune interactions in breast cancer patients.

VijayaIragavarapu-Charyulu

2014-02-01

47

Induction of mouse mammary tumor virus RNA in mammary tumors of BALB/c mice treated with urethane, x-irradiation, and hormones  

Energy Technology Data Exchange (ETDEWEB)

The involvement of mouse mammary tumor virus (MTV) in the development of mammary tumors of nonviral etiology in BALB/c mice was studied by measuring the levels of MTV RNA, MTV DNA, and MTV proteins in spontaneously arising and hormally, chemically, and/or physically induced mammary tumors of BALB/c females. The following results were obtained: (1) spontaneous mammary tumors contained very low levels of MTV RNA; 4 x 10/sup -6/% of the cytoplasmic RNA was MTV RNA. No MTV proteins could be demonstrated by using sensitive radioimmunoassays for MTV proteins p27 and gp52. (2) Mammary tumors induced by treatments with urethane or x-irradiation alone contained higher levels of MTV RNA; these tumors contained 3- and 19-fold more MTV RNA, respectively, compared with spontaneous mammary tumors. (3) Mammary tumors induced by combined treatment with urethane and x-irradiation expressed high levels of MTV RNA in the mammary tumors; a 1,724-fold increase in MTV RNA content compared with spontaneous mammary tumors was observed. However, very low levels of MTV proteins gp52 and p27 were detected, suggesting some kind of impairment at the translation of MTV RNA. MTV RNA was also induced by this treatment in mammary glands and spleens, but not in the livers of tumor-bearing animals. (4) BALB/c females continuously exposed to prolactin contained high levels of MTV RNA and MTV proteins in stimulated mammary glands and in the hormonally induced mammary tumors. These findings suggest that MTV is not responsible for the maintenance and probably also not for the development of all murine mammary cancers.

Michalides, R.; van Deemter, L.; Nusse, R.; Hageman, P.

1979-07-01

48

Initiation of DNA synthesis in mammary epithelium and mammary tumors by lithium ions.  

Science.gov (United States)

The growth promoting effects of lithium and insulin on cultures of mammary gland epithelium and CZF mouse mammary tumor cells were investigated. Lithium chloride exerts a 450-fold increase in the rate of DNA synthesis in mammary epithelium from mid-pregnant mice in organ culture or monolayer culture. There is an increase in both the percentage of cells initiating DNA synthesis and the net accumulation of DNA. The most effective lithium concentration is 10 mM, and the maximally effective rate of stimulation is reached 48 hours after addition. The magnitude of response to lithium varies with the physiological state of the mammary epithelial cell donor: epithelium from non-pregnant or lactating mice is less responsive than that from mid-pregnant mice. In combination, insulin and lithium produce either a synergistic or an additive effect on the growth of epithelium dependent upon the physiological state of the donor animal. Lithium also promotes the growth of mammary tumor cells in the absence or serum or other mitogens. The action of lithium on DNA synthesis appears to be a direct effect on the epithelial cells. PMID:7000799

Ptashne, K; Stockdale, F E; Conlon, S

1980-04-01

49

Imaging of tumor angiogenesis: current approaches and future prospects.  

Science.gov (United States)

Tumor angiogenesis imaging should provide non-invasive assays of tumor vascular characteristics to supplement the now conventional diagnostic imaging goals of depicting tumor location, size, and morphology. This article will review the current status of angiogenesis imaging approaches, considering ultrasound, CT, MR, SPECT, PET and optical techniques with attention to their respective capabilities and limitations. As a group, these imaging methods have some potential to depict and quantify tumor microvascular features, including those considered to be functionally associated with tumor angiogenesis. Additionally, new molecule-specific imaging techniques may serve to depict those biochemical pathways and regulatory events that control blood vessel growth and proliferation. Non-invasive monitoring of anti-angiogenic therapies has great appeal and should find wide application for defining tumor microvascular and metabolic changes, because treatment-related changes in tumor morphology tend to occur rather late and are non-specific. Future developments are likely to include "fusion" or "hybrid" imaging methods. Superimposed data from MR imaging with spectroscopy, PET with CT, and PET with MR should be able to integrate advantages of different modalities yielding comprehensive information about tumor structure, function and microenvironment. PMID:16842165

Daldrup-Link, Heike E; Simon, Gerhard H; Brasch, Robert C

2006-01-01

50

Survivin and related proteins in canine mammary tumors: immunohistochemical expression.  

Science.gov (United States)

Survivin is reexpressed in most human breast cancers, where its expression has been associated with tumor aggressiveness, poor prognosis, and poor response to therapy. Survivin expression was evaluated in 41 malignant canine mammary tumors (CMTs) by immunohistochemistry, in relation to histological grade and stage, and correlated with that of some related molecules (?-catenin, caspase 3, heat shock proteins) to understand their possible role in canine mammary tumorigenesis. An increase in nuclear survivin expression, compared with healthy mammary glands, was observed in CMTs, where nuclear immunolabeling was related to the presence of necrosis. No statistically significant relation was found between the expression of the investigated molecules and the histological grade or stage. The present study may suggest an important involvement of survivin in CMT tumorigenesis. Its overexpression in most of the cases evaluated might suggest that targeting survivin in CMTs may be a valid anticancer therapy. PMID:24686389

Bongiovanni, L; Romanucci, M; Malatesta, D; D'Andrea, A; Ciccarelli, A; Della Salda, L

2015-03-01

51

Angiogenesis impairment in Id-deficient mice cooperates with an Hsp90 inhibitor to completely suppress HER2/neu-dependent breast tumors  

OpenAIRE

Id proteins bind basic helix–loop–helix transcription factors and function as dominant negative inhibitors of gene expression. Id1 and Id3 are required for the recruitment of bone marrow-derived endothelial cell precursors and tumors transplanted into Id-deficient mice demonstrate impaired angiogenesis. Mouse mammary tumor virus–neu mice were bred with Id1–/–Id3+/– mice to ascertain the role of Id1 and Id3 in mammary tumorigenesis in a more physiologically relevant model. In mamma...

Candia, Paola; Solit, David B.; Giri, Dilip; Brogi, Edi; Siegel, Peter M.; Olshen, Adam B.; Muller, William J.; Rosen, Neal; Benezra, Robert

2003-01-01

52

Radiation response of autochthonous mammary tumors in SHN mice  

International Nuclear Information System (INIS)

The radiation response of spontaneously induced autochthonous mammary tumors was studies in SHN mice, a strain developed at the National Cancer Center. Tumors were mostly adenocarcinomas and grew with an average volume-doubling time of 3.0 days. When tumors reached a size of 8 -- 10 mm in diameter, they were given a single, local irradiation with 6 MVp X-rays generated by a medical linear accelerator. With radiation doses lower than 2 krad, the tumors regrew after a temporary interruption. Surviving fractions of tumor cells in situ were estimated from the tumor regrowth times, yielding a survival curve with D0 = 480 rad for n = 2. With 6.5 krad, tumor regression was very rapid: the volume-halving time was 1.7 days, and temporary tumor control was achieved. This rapid radiation response was not necessarily correlated with the radiosensitivity of tumor cells and is thought to be related to the structure of the mammary tumor mass. A disadvantage of this mouse strain was its high multiple tumor incidence which interfered with the observation of tumor control for adequate periods after irradiation. (author)

53

Comparative expression pathway analysis of human and canine mammary tumors  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background Spontaneous tumors in dog have been demonstrated to share many features with their human counterparts, including relevant molecular targets, histological appearance, genetics, biological behavior and response to conventional treatments. Mammary tumors in dog therefore provide an attractive alternative to more classical mouse models, such as transgenics or xenografts, where the tumour is artificially induced. To assess the extent to which dog tumors represent clinically significant human phenotypes, we performed the first genome-wide comparative analysis of transcriptional changes occurring in mammary tumors of the two species, with particular focus on the molecular pathways involved. Results We analyzed human and dog gene expression data derived from both tumor and normal mammary samples. By analyzing the expression levels of about ten thousand dog/human orthologous genes we observed a significant overlap of genes deregulated in the mammary tumor samples, as compared to their normal counterparts. Pathway analysis of gene expression data revealed a great degree of similarity in the perturbation of many cancer-related pathways, including the 'PI3K/AKT', 'KRAS', 'PTEN', 'WNT-beta catenin' and 'MAPK cascade'. Moreover, we show that the transcriptional relationships between different gene signatures observed in human breast cancer are largely maintained in the canine model, suggesting a close interspecies similarity in the network of cancer signalling circuitries. Conclusion Our data confirm and further strengthen the value of the canine mammary cancer model and open up new perspectives for the evaluation of novel cancer therapeutics and the development of prognostic and diagnostic biomarkers to be used in clinical studies.

Marconato Laura

2009-03-01

54

Murine mammary tumor cells with a claudin-low genotype  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background Molecular classification of human breast cancers has identified at least 5 distinct tumor subtypes; luminal A, luminal B, Her2-enriched, basal-like and claudin-low. The claudin-low subtype was identified in 2007 and is characterized by low expression of luminal differentiation markers and claudins 3, 4 and 7 and high levels of mesenchymal markers. Claudin-low tumors have a reported prevalence of 7-14% and these tumors have a poor prognosis. Results In this study we report the characterization of several cell lines established from mammary tumors that develop in MTB-IGFIR transgenic mice. Two lines, RM11A and RJ348 present with histological features and gene expression patterns that resemble claudin-low breast tumors. Specifically, RM11A and RJ348 cells express high levels of the mesenchymal genes Zeb1, Zeb2, Twist1 and Twist2 and very low levels of E-cadherin and claudins 3, 4 and 7. The RM11A and RJ348 cells are also highly tumorigenic when re-introduced into the mammary fat pad of mice. Conclusions Mammary tumor cells established from MTB-IGFIR transgenic mice can be used as in vitro and in vivo model systems to further our understanding of the poorly characterized, claudin-low, breast cancer subtype.

Siwicky Megan D

2011-08-01

55

Mammary tumorigenesis in feral mice: identification of a new int locus in mouse mammary tumor virus (Czech II)-induced mammary tumors.  

OpenAIRE

A population of Mus musculus subsp. musculus (Czech II), recently isolated from the wild, lack endogenous mouse mammary tumor virus (MMTV) proviral genomes. Some of these mice carry an infectious MMTV [designated MMTV (Czech II)] that is transmitted in the milk and is associated with mammary tumor development. This virus is distinct from laboratory strains of MMTV present in inbred mice. An MMTV (Czech II) genome was found within a 0.5-kilobase region of the cellular genome in five of 16 Czec...

Gallahan, D.; Callahan, R.

1987-01-01

56

Identification of Radiation Specific Gene Signatures in Rat Mammary Tumors  

International Nuclear Information System (INIS)

It is well accepted that cancer arises in a multi-step fashion and that environmental exposures to physical and chemical agents are major etiological factors. Exposure to carcinogens plays a major and probably in etiological role in the initiation of this human disease. In experimental animal models, ionizing radiation induces mammary carcinomas both in vivo and in vitro, however, the cellular and molecular mechanisms of radiation induced carcinogenesis are not known. In this paper, we compare to gene expression patterns by cDNA microarray in gamma-radiation or DMBA induced rat mammary tumors and found that radiation specific gene expression signature was present in radiation induced breast cancer

57

Inoculated mammary carcinoma-associated fibroblasts: contribution to hormone independent tumor growth  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background Increasing evidence has underscored the role of carcinoma associated fibroblasts (CAF in tumor growth. However, there are controversial data regarding the persistence of inoculated CAF within the tumors. We have developed a model in which murine metastatic ductal mammary carcinomas expressing estrogen and progesterone receptors transit through different stages of hormone dependency. Hormone dependent (HD tumors grow only in the presence of progestins, whereas hormone independent (HI variants grow without hormone supply. We demonstrated previously that CAF from HI tumors (CAF-HI express high levels of FGF-2 and that FGF-2 induced HD tumor growth in vivo. Our main goal was to investigate whether inoculated CAF-HI combined with purified epithelial (EPI HD cells can induce HD tumor growth. Methods Purified EPI cells of HD and HI tumors were inoculated alone, or together with CAF-HI, into female BALB/c mice and tumor growth was evaluated. In another set of experiments, purified EPI-HI alone or combined with CAF-HI or CAF-HI-GFP were inoculated into BALB/c or BALB/c-GFP mice. We assessed whether inoculated CAF-HI persisted within the tumors by analyzing inoculated or host CAF in frozen sections of tumors growing in BALB/c or BALB/c-GFP mice. The same model was used to evaluate early stages of tumor development and animals were euthanized at 2, 7, 12 and 17 days after EPI-HI or EPI-HI+CAF-HI inoculation. In angiogenesis studies, tumor vessels were quantified 5 days after intradermal inoculation. Results We found that admixed CAF-HI failed to induce epithelial HD tumor growth, but instead, enhanced HI tumor growth (p Conclusions Inoculated CAF-HI do not persist within the tumor mass although they play a role during the first stages of tumor formation promoting angiogenesis. This angiogenic environment is unable to replace the hormone requirement of HD tumors that still need the hormone to recruit the stroma from the host.

Lanari Claudia

2010-06-01

58

BMP4/Thrombospondin-1 loop paracrinically inhibits tumor angiogenesis and suppresses the growth of solid tumors.  

Science.gov (United States)

Bone morphogenetic protein 4 (BMP4) has potential as an anticancer agent. Recent studies have suggested that BMP4 inhibits the survival of cancer stem cells (CSCs) of neural and colon cancers. Here, we showed that BMP4 paracrinically inhibited tumor angiogenesis via the induction of Thrombospondin-1 (TSP1), and consequently suppressed tumor growth in vivo. Although HeLa (human cervical cancer), HCI-H460-LNM35 (highly metastatic human lung cancer) and B16 (murine melanoma) cells did not respond to the BMP4 treatment in vitro, the growth of xeno- and allografts of these cells was suppressed via reductions in tumor angiogenesis after intraperitoneal treatment with BMP4. When we assessed the mRNA expression of major angiogenesis-related factors in grafted tumors, we found that the expression of TSP1 was significantly upregulated by BMP4 administration. We then confirmed that BMP4 was less effective in suppressing the tumor growth of TSP1-knockdown cancer cells. Furthermore, we found that BMP4 reduced vascular endothelial growth factor (VEGF) expression in vivo in a TSP1-dependent manner, which indicates that BMP4 interfered with the stabilization of tumor angiogenesis. In conclusion, the BMP4/TSP1 loop paracrinically suppressed tumor angiogenesis in the tumor microenvironment, which subsequently reduced the growth of tumors. BMP4 may become an antitumor agent and open a new field of antiangiogenic therapy. PMID:24013228

Tsuchida, R; Osawa, T; Wang, F; Nishii, R; Das, B; Tsuchida, S; Muramatsu, M; Takahashi, T; Inoue, T; Wada, Y; Minami, T; Yuasa, Y; Shibuya, M

2014-07-17

59

Celecoxib decreases growth and angiogenesis and promotes apoptosis in a tumor cell line resistant to chemotherapy  

Scientific Electronic Library Online (English)

Full Text Available SciELO Chile | Language: English Abstract in english BACKGROUND: During the last few years it has been shown in several laboratories that Celecoxib (Cx), a non-steroidal anti-inflammatory agent (NSAID) normally used for pain and arthritis, mediates antitumor and antiangiogenic effects. However, the effects of this drug on a tumor cell line resistant t [...] o chemotherapeutical drugs used in cancer have not been described. Herein we evaluate the angiogenic and antitumor effects of Cx in the development of a drug-resistant mammary adenocarcinoma tumor (TA3-MTXR). RESULTS: Cx reduces angiogenesis in the chick embryonic chorioallantoic membrane assay (CAM), inhibits the growth and microvascular density of the murine TA3-MTXR tumor, reduces microvascular density of tumor metastases, promotes apoptosis and reduces vascular endothelial growth factor (VEGF) production and cell proliferation in the tumor. CONCLUSION: The antiangiogenic and antitumor Cx effects correlate with its activity on other tumor cell lines, suggesting that Prostaglandins (PGs) and VEGF production are involved. These results open the possibility of using Celecoxib combined with other experimental therapies, ideally aiming to get synergic effects.

Carlos, Rosas; Mariana, Sinning; Arturo, Ferreira; Marcela, Fuenzalida; David, Lemus.

60

Prenatal exposure to bisphenol A promotes angiogenesis and alters steroid-mediated responses in the mammary glands of cycling rats.  

Science.gov (United States)

Prenatal exposure to BPA disturbs mammary gland histoarchitecture and increases the carcinogenic susceptibility to chemical challenges administered long after BPA exposure. Our aim was to assess the effect of prenatal BPA exposure on mammary gland angiogenesis and steroid hormone pathways in virgin cycling rats. Pregnant Wistar rats were exposed to either 25 or 250 g/kg/day (25 and 250 BPA, respectively) or to vehicle. Female offspring were autopsied on postnatal day (PND) 50 or 110. Ovarian steroid serum levels, the expression of steroid receptors and their co-regulators SRC-3 and SMRT in the mammary gland, and angiogenesis were evaluated. At PND 50, all BPA-treated animals had lower serum levels of progesterone, while estradiol levels remained unchanged. The higher dose of BPA increased mammary ER? and decreased SRC-3 expression at PND 50 and PND 110. SMRT protein levels were similar among groups at PND 50, whereas at PND 110, animals exposed to 250 BPA showed a lower SMRT expression. Interestingly, in the control and 25 BPA groups, SMRT increased from PND 50 to PND 110. At PND 50, an increased vascular area associated with higher VEGF expression was observed in the 250 BPA-treated rats. At PND 110, the vascular area was still increased, but VEGF expression was similar to that of control rats. The present results demonstrate that prenatal exposure to BPA alters the endocrine environment of the mammary gland and its angiogenic process. Increased angiogenesis and altered steroid hormone signals could explain the higher frequency of pre-neoplastic lesions found later in life. This article is part of a Special Issue entitled 'Endocrine disruptors'. PMID:21513798

Durando, Milena; Kass, Laura; Perdomo, Virginia; Bosquiazzo, Verónica L; Luque, Enrique H; Muñoz-de-Toro, Mónica

2011-10-01

61

Plants as useful agents for angiogenesis and tumor growth prevention  

Directory of Open Access Journals (Sweden)

Full Text Available Introduction: Angiogenesis, the process of new blood vessel formation from pre-existing vessels, has important physiological roles in embryonic development, female reproduction cycle, and wound healing. It is also crucial for pathological processes in several diseases especially tumor growth and metastasis. Thereby, inhibition of angiogenesis as an addition to the conventional therapies such as chemotherapy and radiotherapy has attracted the attention of scientists. Results: Different studies have shown that botanical derivatives specifically antagonize new vessel formation in tumors without significant toxicity to normal tissues and without major adverse reactions. Furthermore, many studies have revealed that the active ingredients of these natural products inhibit tumor cell proliferation through interference with other physiological pathways such as intracellular signaling pathways. A number of studies have also demonstrated that many traditional foods especially plant derived foods have preventive potential against around one third of cancers. Therefore, plant rich diet can inhibit the progression of many chronic diseases such as malignant solid tumors which are related to angiogenesis.

Hamid-Reza Mohammadi-Motlagh

2010-10-01

62

Caveolin-1 expression is elevated in claudin-low mammary tumor cells  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background Caveolin-1 is a scaffolding protein found in plasma membrane invaginations known as caveolae. Caveolin-1 can regulate a number of intracellular processes such as signal transduction, cholesterol metabolism and vesicular transport. With respect to breast cancer caveolin-1 has been observed in both tumor cells and stromal cells surrounding tumors however most of the recent research has focused on how the loss of caveolin-1 in the stromal cells surrounding the tumor alters the tumor microenvironment. Methods Caveolin-1 expression was evaluated in (1 mammary tumors induced by the transgenic overexpression of the type I insulin-like growth factor receptor (IGF-IR, (2 mammary tumors that became independent of IGF-IR signalling and acquired a claudin-low genotype, (3 two murine mammary epithelial tumor cell lines and (4 two murine mammary claudin-low tumor cell lines. Results We found that mammary tumors induced by IGF-IR overexpression expressed low levels of caveolin-1 while mammary tumors that became independent of IGF-IR signalling expressed considerably higher levels of caveolin-1. Interestingly, pockets of caveolin-1 positive cells could be observed in some of the IGF-IR-induced mammary tumors and these caveolin-1 positive cells were associated with tumor cells that expressed basal cytokeratins (cytokeratins 5 and 14. This caveolin-1 expression pattern was maintained in the murine mammary tumor cell lines in that the epithelial mammary tumor cell lines expressed little or no caveolin-1 while the claudin-low cell lines expressed caveolin-1. Conclusions Our model indicates that mammary tumor cells with epithelial characteristics lack caveolin-1 while mesenchymal tumor cells express caveolin-1 suggesting that caveolin-1 may serve as a marker of mammary tumor cells with mesenchymal characteristics such as claudin-low breast tumors.

Thompson Devan E

2012-02-01

63

Targeting Angiogenesis and the Tumor Microenvironment  

OpenAIRE

The role of the microenvironment during the initiation and progression of malignancy is appreciated to be of critical importance for improved molecular diagnostics and therapeutics. The tumor microenvironment is the product of a crosstalk between different cells types. Critical elements in the microenvironment include tumor associated fibroblasts, which provide an essential communication network via secretion of growth factors and chemokines, inducing an altered extracellular matrix (ECM), th...

Samples, Jennifer; Willis, Monte; Klauber-demore, Nancy

2013-01-01

64

Endogenous mammary tumor viruses in mice. [X radiation  

Energy Technology Data Exchange (ETDEWEB)

The hypothesis of an endogenous mammary tumor virus seems to be substantiated in this paper by: transfer of genetic information for an MTV in vitro by GR sperm cells; segregation of MTV-P and MTV-L markers in the test cross of the F/sub 1/ hybrid between C3Hf, producing MTV-L, and GR, releasing MTV-P; induction of MTV antigens by BrdU in cultures of kidneys from various mouse strains; and induction of MTV-O in BALB/c mice by lethal doses of radiation. The picture that emerges is that different genetic systems control the expression of endogenous mammary tumor viruses. There are those which seem to affect only that germinal provirus with which they are genetically linked, while others have an influence on other germinal proviruses as well as somatic proviruses. Further studies on the genetic regulation of the expression of the germinal MTV proviruses are in progress.

Bentvelzen, P.

1975-01-01

65

Estrogen-induced Ets-1 promotes capillary formation in an in vitro tumor angiogenesis model.  

Science.gov (United States)

We employed an in vitro angiogenesis model that simulates the in vivo milieu for tumor capillary formation to study the direct effects of estrogen. 17beta-estradiol (E2) treatment significantly stimulated capillary sprouting within 8 h in co-cultures of rat aortic endothelial cells (RAECs) and mouse mammary tumor cells. Co-cultures treated with either progesterone (P4) or E2+P4 showed minimal endothelial cell (EC) sprouting when compared to E2 treated cultures. Treatment with the E2 agonist ICI 182,780 dramatically inhibited capillary formation, demonstrating E2-specificity. Within hours, of E2 treatment ECs isolated from tumor cell/EC co-cultures demonstrated a statistically significant increase in both mRNA and protein levels of the transcription factor Ets-1. We observed increased matrix metalloproteinase (MMP) and decreased tissue inhibitor of metalloproteinase (TIMP) mRNA levels in these ECs following E2 treatment. Ets-1 upregulates expression of the vascular endothelial growth factor (VEGF) receptor, Flt-1 and we detected increased Flt-1 mRNA levels in ECs co-cultured with tumor cells following E2 treatment. Expression of Ets-1 contributes to destabilization of a quiescent EC phenotype in favor of an invasive angiogenic one, in part, by increasing expression of MMPs and integrin molecules that favor migration and invasion. Transfection of ECs with Ets-1 antisense prior to co-culture with E2 resulted in a 95% inhibition in capillary formation. We demonstrate here, for the first time that nanomolar concentrations of E2 directly and rapidly induced new capillary formation in a mammary tumor/EC co-culture system and suggest that this response may be mediated, in part, by an E2-induced increase in Ets-1 expression. PMID:12725417

Lincoln, David W; Phillips, Patricia G; Bove, Kathleen

2003-03-01

66

Dynamic MRI and tumor angiogenesis of breast cancer  

Energy Technology Data Exchange (ETDEWEB)

The purpose of this study was to clarify the mechanism underlying early enhanced MR images of breast cancer by dynamic MR imaging from the aspect of tumor angiogenesis. The images depicted by dynamic MR imaging of breast cancer were divided into the following two groups: a marginal strong enhancement (MSE) pattern and a variable pattern without marginal strong enhancement (non-MSE). Twenty patients with invasive ductal carcinoma (maximum diameter <2 cm) were examined by dynamic MR imaging, and the histological materials were submitted to two-dimensional computer image analysis with immunohistochemistry and histochemistry; morphological microvessel characteristics and microvessel density were examined; and the expression of vascular endothelial growth factor (VEGF) was investigated. In the MSE cases, vessel wall irregularity of capillaries and venules in the peripheral area adjacent to the tumor correlated (p<0.0001) with the enhancement pattern, and the total microvessel density (especially of arterioles with a maximum diameter less than 50 {mu}m) of the peripheral area adjacent to the tumor was significantly higher than that of the tumor area. However, in the non-MSE cases, total microvessel density showed no significant difference between the peripheral area adjacent to the tumor and the tumor area, whereas the capillary density of the tumor area was four times greater than that of the peripheral area adjacent to the tumor. The expression of VEGF was strongly positive for the tumor nest adjacent to the capillaries. These results suggest that the enhanced images of the MSE pattern depend on abundant blood supply from arterioles and that the images of the non-MSE pattern might be reflective of angiogenic activity including variable VEGF expression of tumor cells. Thus the mechanism underlying early dynamic MR images of breast cancer was a complex result of tumor angiogenesis and the microcirculatory environment. (author)

Yasumura, Kazuhiko; Ogawa, Kenji [Nippon Kokan Hospital, Kawasaki, Kanagawa (Japan); Yuasa, Yuji; Hiramatsu, Hideko; Hiramatsu, Kyoichi; Kitajima, Masaki

2000-06-01

67

Dynamic MRI and tumor angiogenesis of breast cancer  

International Nuclear Information System (INIS)

The purpose of this study was to clarify the mechanism underlying early enhanced MR images of breast cancer by dynamic MR imaging from the aspect of tumor angiogenesis. The images depicted by dynamic MR imaging of breast cancer were divided into the following two groups: a marginal strong enhancement (MSE) pattern and a variable pattern without marginal strong enhancement (non-MSE). Twenty patients with invasive ductal carcinoma (maximum diameter <2 cm) were examined by dynamic MR imaging, and the histological materials were submitted to two-dimensional computer image analysis with immunohistochemistry and histochemistry; morphological microvessel characteristics and microvessel density were examined; and the expression of vascular endothelial growth factor (VEGF) was investigated. In the MSE cases, vessel wall irregularity of capillaries and venules in the peripheral area adjacent to the tumor correlated (p<0.0001) with the enhancement pattern, and the total microvessel density (especially of arterioles with a maximum diameter less than 50 ?m) of the peripheral area adjacent to the tumor was significantly higher than that of the tumor area. However, in the non-MSE cases, total microvessel density showed no significant difference between the peripheral area adjacent to the tumor and the tumor area, whereas the capillary density of the tumor area was four times greater than that of the peripheral area adjacent to the tumor. The expression of VEGF was strongly positive expression of VEGF was strongly positive for the tumor nest adjacent to the capillaries. These results suggest that the enhanced images of the MSE pattern depend on abundant blood supply from arterioles and that the images of the non-MSE pattern might be reflective of angiogenic activity including variable VEGF expression of tumor cells. Thus the mechanism underlying early dynamic MR images of breast cancer was a complex result of tumor angiogenesis and the microcirculatory environment. (author)

68

Inhibition of tumor angiogenesis by globotriaosylceramide immunotargeting  

OpenAIRE

Current antiangiogenic immunotherapeutic strategies mainly focus on the blockade of circulating cytokines or receptors that are overexpressed by endothelial cells. We proposed globotriaosylceramide (Gb3) as a viable alternative target for antiangiogenic therapies. In this setting, we developed an anti-Gb3 antibody and validated its therapeutic efficacy in metastatic tumor models.

Birkle?, Ste?phane; Desselle, Ariane; Chaumette, Tanguy; Gaugler, Marie-he?le?ne; Cochonneau, Denis; Fleurence, Julien; Dubois, Nolwenn; Hulin, Philippe; Aubry, Jacques; Paris, Franc?ois

2013-01-01

69

Host deficiency in caveolin-2 inhibits lung carcinoma tumor growth by impairing tumor angiogenesis.  

Science.gov (United States)

Caveolin-2 (Cav-2), a member of caveolin protein family, is largely different from better known caveolin-1 (Cav-1) and thus might play distinct functions. Here, we provide the first genetic evidence suggesting that host-expressed Cav-2 promotes subcutaneous tumor growth and tumor-induced neovascularization using two independent syngeneic mouse models. Host deficiency in Cav-2 resulted in defective and reduced growth of subcutaneously implanted Lewis lung carcinoma (LLC) and B16-F10 melanoma tumors, respectively. Consistent with the defective growth, LLC and B16-F10 melanoma tumors implanted into Cav-2 KO mice displayed reduced microvascular density (MVD) determined by IHC with anti-CD31 antibodies, suggesting impaired pathologic angiogenesis. Additional studies involving LLC tumors extracted from Cav-2 KO mice just 10 days after implantation determined reduced cell proliferation, massive necrotic cell death, and fibrosis. In contrast with day 10, only MVD but not cell proliferation and survival was reduced in the earliest palpable LLC tumors extracted 6 days after implantation into Cav-2 KO mice, suggesting that impaired angiogenesis is the causative factor. Mechanistically, impaired LLC tumor growth and angiogenesis in Cav-2 KO mice was associated with increased expression levels of antiangiogenic thrombospondin-1 and inhibited S1177 phosphorylation of endothelial nitric oxide synthase. Taken together, our data suggest that host deficiency in Cav-2 impairs tumor-induced angiogenesis, leading to compromised tumor cell survival/proliferation manifested by the defective tumor growth. In conclusion, host-expressed Cav-2 may promote tumor growth via supporting tumor-induced angiogenesis. Thus, Cav-2 expressed in tumor microenvironment may potentially become a novel target for cancer therapy. PMID:25269481

Liu, Yajun; Jang, Sungchan; Xie, Leike; Sowa, Grzegorz

2014-11-15

70

Longitudinal Studies of Angiogenesis in Hormone-Dependent Shionogi Tumors  

Directory of Open Access Journals (Sweden)

Full Text Available Vessel size imaging was used to assess changes in the average vessel size of Shionogi tumors throughout the tumor growth cycle. Changes in R2 and R2* relaxivities caused by the injection of a superparamagnetic contrast agent (ferumoxtran-10 were measured using a 2.35-T animal magnetic resonance imaging system, and average vessel size index (VSI was calculated for each stage of tumor progression: growth, regression, and relapse. Statistical analysis using Spearman rank correlation test showed no dependence between vessel size and tumor volume at any stage of the tumor growth cycle. Paired Student's t test was used to assess the statistical significance of the differences in average vessel size for the three stages of the tumor growth cycle. The average VSI for regressing tumors (15.1 ± 6.6 wm was significantly lower than that for growing tumors (35.2 ± 25.5 ?m; P < .01. Relapsing tumors also had an average VSI (45.4 ± 41.8 ?m higher than that of regressing tumors, although the difference was not statistically significant (P = .067. This study shows that VSI imaging is a viable method for the noninvasive monitoring of angiogenesis during the progression of a Shionogi tumor from androgen dependence to androgen independence.

Trevor P. Wade

2007-07-01

71

Dll4-Notch signaling as a therapeutic target in tumor angiogenesis  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Tumor angiogenesis is an important target for cancer therapy, with most current therapies designed to block the VEGF signaling pathway. However, clinical resistance to anti-VEGF therapy highlights the need for targeting additional tumor angiogenesis signaling pathways. The endothelial Notch ligand Dll4 (delta-like 4 has recently emerged as a critical regulator of tumor angiogenesis and thus as a promising new therapeutic anti-angiogenesis target. Blockade of Dll4-Notch signaling in tumors results in excessive, non-productive angiogenesis with resultant inhibitory effects on tumor growth, even in some tumors that are resistant to anti-VEGF therapies. As Dll4 inhibitors are entering clinical cancer trials, this review aims to provide current perspectives on the function of the Dll4-Notch signaling axis during tumor angiogenesis and as a target for anti-angiogenic cancer therapy.

Kuhnert Frank

2011-09-01

72

Type-2 pericytes participate in normal and tumoral angiogenesis.  

Science.gov (United States)

Tissue growth and function depend on vascularization, and vascular insufficiency or excess exacerbates many human diseases. Identification of the biological processes involved in angiogenesis will dictate strategies to modulate reduced or excessive vessel formation. We examine the essential role of pericytes. Their heterogeneous morphology, distribution, origins, and physiology have been described. Using double-transgenic Nestin-GFP/NG2-DsRed mice, we identified two pericyte subsets. We found that Nestin-GFP(-)/NG2-DsRed(+) (type-1) and Nestin-GFP(+)/NG2-DsRed(+) (type-2) pericytes attach to the walls of small and large blood vessels in vivo; in vitro, type-2, but not type-1, pericytes spark endothelial cells to form new vessels. Matrigel assay showed that only type-2 pericytes participate in normal angiogenesis. Moreover, when cancer cells were transplanted into Nestin-GFP/NG2-DsRed mice, type-1 pericytes did not penetrate the tumor, while type-2 pericytes were recruited during its angiogenesis. As inhibition of angiogenesis is a promising strategy in cancer therapy, type-2 pericytes may provide a cellular target susceptible to signaling and pharmacological manipulation in treating malignancy. This work also reports the potential of type-2 pericytes to improve blood perfusion in ischemic hindlimbs, indicating their potential for treating ischemic illnesses. PMID:24788248

Birbrair, Alexander; Zhang, Tan; Wang, Zhong-Min; Messi, Maria Laura; Olson, John D; Mintz, Akiva; Delbono, Osvaldo

2014-07-01

73

Effect of Hedyotis Diffusa Willd extract on tumor angiogenesis.  

Science.gov (United States)

Inhibition of tumor angiogenesis has become an attractive target of anticancer chemotherapy. However, drug resistance and cytotoxicity against non-tumor associated endothelial cells limit the long-term use and the therapeutic effectiveness of angiogenesis inhibitors, thus increasing the necessity for the development of multi-target agents with minimal side effects. Traditional Chinese medicine (TCM) formulas, which have relatively fewer side effects and have been used clinically to treat various types of diseases, including cancer, for thousands of years, are considered to be multi-component and multi-target agents exerting their therapeutic function in a more holistic way. Hedyotis Diffusa Willd (EEHDW) has long been used as an important component in several TCM formulas to treat various types of cancer. Although recently we reported that EEHDW promotes cancer cell apoptosis via activation of the mitochondrial-dependent pathway, the precise mechanism of its tumoricidalactivity still remains to be clarified. In the present study, we investigated the angiogenic effects of the ethanol extract of EEHDW. Cell cycle analysis was perfomed using flow cytometry. Cell viability was analyzed using MTT assay. We found that EEHDW inhibited angiogenesis in vivo in chick embryo chorioallantoic membrane (CAM). In addition, we observed that EEHDW dose- and time-dependently inhibited the prolife-ration of human umbilical vein endothelial cells (HUVEC) by blocking the cell cycle G1 to S progression. Moreover, EEHDW inhibited the migration and tube formation of HUVECs. Furthermore, EEHDW treatment down-regulated the mRNA and protein expression levels of VEGF-A in HT-29 human colon carcinoma cells and HUVECs. Our findings suggest that inhibiting tumor angiogenesis is one of the mechanisms by which EEHDW is involved in cancer therapy. PMID:21887465

Lin, Jiumao; Wei, Lihui; Xu, Wei; Hong, Zhenfeng; Liu, Xianxiang; Peng, Jun

2011-01-01

74

Common Integration Sites for MMTV in Viral Induced Mouse Mammary Tumors  

OpenAIRE

The paradigm of mammary cancer induction by the mouse mammary tumor virus (MMTV) is used to illustrate the body of evidence that supports the hypothesis that mammary epithelial stem/progenitor cells represent targets for oncogenic transformation. It is argued that this is not a special case applicable only to MMTV-induced mammary cancer, because MMTV acts as an environmental mutagen producing random interruptions in the somatic DNA of infected cells by insertion of proviral DNA copies. In add...

Callahan, Robert; Smith, Gilbert H.

2008-01-01

75

Heterogeneity of angiogenesis and blood vessel maturation in cartilage tumors.  

Science.gov (United States)

Cartilage tumors have a special angiogenic phenotype, with blood vessels arranged predominantly in pericartilage fibrous septa and relatively low microvessel density (MVD), except in dedifferentiated chondrosarcomas. To further elucidate angiogenesis in cartilage tumors, we used double-labeling immunohistochemistry to determine microvessel pericyte coverage index (MPI) and proliferating capillary index (PCI), referring to blood vessel maturation and angiogenic activity in enchondromas, conventional chondrosarcomas, and dedifferentiated chondrosarcomas. Altogether, we found high MPIs (>70%) especially in dedifferentiated chondrosarcomas but without a correlation to the grade of malignancy. PCI was significantly higher in conventional chondrosarcomas grades II and III than in enchondromas, chondrosarcomas grade I, and dedifferentiated chondrosarcomas. Thus, PCI positively correlated with the previously reported differential expression of vascular endothelial growth factor (VEGF)-A in cartilage tumors. Altogether, cartilage tumors exhibit a heterogeneous but predominantly mature angiogenic phenotype with differential proliferative activity. PMID:19157720

Kalinski, Thomas; Sel, Saadettin; Kouznetsova, Irina; Röpke, Martin; Roessner, Albert

2009-01-01

76

Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2  

OpenAIRE

Recent findings indicate that tumor-associated macrophages are important drivers of tumor angiogenesis. Here, we review the essential role played by Tie2-expressing monocytes (TEM) in this phenomenon. TEMs are present in human blood and tumors and their elimination in various tumor models suppresses tumor angiogenesis. A ligand for Tie2, angiopoietin-2 (Ang-2), is produced by angiogenic tumor vessels and is a chemoattractant for TEMs. Hypoxia up-regulates Tie2 expression on TEMs and, together...

Lewis, Claire E.; Palma, Michele; Naldini, Luigi

2007-01-01

77

Mammary gland tumor formation in transgenic mice overexpressing stromelysin-1  

Energy Technology Data Exchange (ETDEWEB)

An intact basement membrane (BM) is essential for the proper function, differentiation and morphology of many epithelial cells. The disruption or loss of this BM occurs during normal development as well as in the disease state. To examine the importance of BM during mammary gland development in vivo, we generated transgenic mice that inappropriately express autoactivating isoforms of the matrix metalloproteinase stromelysin-1. The mammary glands from these mice are both functionally and morphologically altered throughout development. We have now documented a dramatic incidence of breast tumors in several independent lines of these mice. These data suggest that overexpression of stromelysin-1 and disruption of the BM may be a key step in the multi-step process of breast cancer.

Sympson, Carolyn J; Bissell, Mina J; Werb, Zena

1995-06-01

78

Wogonin inhibits tumor angiogenesis via degradation of HIF-1? protein  

Energy Technology Data Exchange (ETDEWEB)

Wogonin, a plant-derived flavone, has been shown recently to have antitumor effects. However, the mechanisms that wogonin inhibits tumor angiogenesis are not well known. In this study, we investigated the effects of wogonin on expression of hypoxia-inducible factor-1? (HIF-1?) and secretion of vascular endothelial growth factor (VEGF) in tumor cells. We found that wogonin decreased the expression of HIF-1? by affecting its stability and reduced the secretion of VEGF, which suppressed angiogenesis in cancer. Wogonin promoted the degradation of HIF-1? by increasing its prolyl hydroxylation, which depended on prolyl hydroxylase (PHD) and the von Hippel–Lindau tumor suppressor (VHL). Intriguingly, wogonin impeded the binding between heat-shock protein 90 (Hsp90) and HIF-1?. In addition, wogonin down-regulated the Hsp90 client proteins EGFR, Cdk4 and survivin, but did not affect the level of Hsp90. Wogonin also increased ubiquitination of HIF-1? and promoted its degradation in proteasome. We also found that wogonin could inhibit nuclear translocation of HIF-1?. Electrophoresis mobility shift assay (EMSA) showed that wogonin decreased the binding activity of exogenous consensus DNA oligonucleotide with HIF-1? in nuclear extracts from MCF-7 cells. Chromatin immunoprecipitation (ChIP) assay also revealed that HIF-1? directly binded to endogenous hypoxia-responsive element (HRE) and this binding was significantly decreased in MCF-7 cells treated with wogonin. Preliminary results indicated in vivo activity of wogonin against xenograft-induced angiogenesis in nude mice. Taken together, the results suggested that wogonin was a potent inhibitor of HIF-1? and provided a new insight into the mechanisms of wogonin against cancers. - Highlights: • Wogonin is an all around inhibitor of VEGF signaling. • We firstly demonstrate that wogonin inhibits secretion of VEGF by decreasing HIF-1?. • Wogonin enhances PDH and VHL expression and inhibits Hsp90 function. • Wogonin decreases HIF-1? nuclear import and binding to DNA. • Wogonin may be a potent HIF-1? inhibitor for cancer therapeutics in the future.

Song, Xiuming; Yao, Jing; Wang, Fei; Zhou, Mi; Zhou, Yuxin; Wang, Hu; Wei, Libin; Zhao, Li; Li, Zhiyu; Lu, Na, E-mail: luna555@163.com; Guo, Qinglong, E-mail: anticancer_drug@yahoo.com.cn

2013-09-01

79

Immunohistochemical characterization and morphometric analysis of macrophages in rat mammary tumors.  

Science.gov (United States)

Macrophages are an important leukocyte component of the microenvironment of neoplasms. Macrophages have classically been subdivided into M1 and M2, depending on their roles in immune response, wound healing, and promotion or inhibition of tumor growth. In human breast cancer, increased presence of M2 macrophages has been associated with poor prognosis. The authors hypothesized that rat mammary carcinomas have increased macrophage influx compared to benign mammary proliferative lesions and normal mammary glands as well. In humans, both M1 and M2 macrophages express CD68, while CD163 is expressed primarily by M2 macrophages. Based on a single immunolabeling protocol with anti-CD68 and anti-CD163 antibodies, the extent of macrophage influx was investigated by morphometry to quantitate the immunopositive cells in normal rat mammary glands, benign mammary proliferative lesions, and mammary carcinomas. In mammary carcinomas, there was significantly higher percentage of CD68+ cells compared to benign mammary proliferative lesions and normal mammary glands. There was also higher percentage of CD163+ cells in mammary carcinomas compared to benign mammary proliferative lesions. Thus, increase in CD68+ and CD163+ macrophages corresponded to increased malignancy of rat mammary tumors in this study. PMID:24842486

Ong, C B; Brandenberger, C; Kiupel, M; Kariagina, A; Langohr, I M

2015-03-01

80

Endothelial cell pseudopods and angiogenesis of breast cancer tumors  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background A neoplastic tumor cannot grow beyond a millimeter or so in diameter without recruitment of endothelial cells and new blood vessels to supply nutrition and oxygen for tumor cell survival. This study was designed to investigate formation of new blood vessels within a human growing breast cancer tumor model (MDA MB231 in mammary fat pad of nude female mouse. Once the tumor grew to 35 mm3, it developed a well-vascularized capsule. Histological sections of tumors greater than 35 mm3 were stained with PAS, with CD-31 antibody (an endothelial cell maker, or with hypoxia inducible factor 1? antibody (HIF. The extent of blood vessel and endothelial cell pseudopod volume density was measured by ocular grid intercept counting in the PAS stained slides. Results The tumor area within 100–150 ?m of the well-vascularized capsule had few blood vessels and only occasional endothelial cell pseudopods, whereas the area greater than 150 ?m from the capsule had more blood vessels, capillaries, and a three-fold increase in volume density of pseudopods sprouting from the capillary endothelial cells. This subcortical region, rich in pseudopods, some of which were observed to have vacuoles/lumens, was strongly positive for presence of HIF. In some larger tumors, pseudopods were observed to insinuate for mm distances through hypoxic regions of the tumor. Conclusion The positive correlation between presence of HIF and the increased extent of pseudopods suggests volume density measure of the latter as a quantifiable marker of tumor hypoxia. Apparently, hypoxic regions of the tumor produce HIF leading to production of vascular endothelial growth factors that stimulate sprouting of capillary endothelial cells and formation of endothelial cell pseudopods.

Sun LuZhe

2005-05-01

81

Mouse mammary tumor virus derived from wild mice does not target Notch-4 protooncogene for the development of mammary tumors in inbred mice.  

Science.gov (United States)

The colony of wild mice, named Jyg, has been shown to express an exogenous mouse mammary tumor virus (Jyg-MMTV). This virus induces mammary tumors in its natural host at a high incidence ( approximately 80%) resulting from insertion mutations in Notch-4 (43%), Wnt-1 (26%), and Fgf-3 (13%). Since the activation of Notch-4 is not common in mammary tumors of standard laboratory strains of mice infected with various MMTV strains, we examined the consequences of Jyg-MMTV infection in BALB/c and C57BL/6 mice. The results show that Jyg-MMTV induces mammary tumors in both mouse strains, but the incidence of mammary tumors in BALB/c mice is greater than in C57BL/6 mice. Surprisingly, however, none of the 75 mammary tumors, analyzed both by Southern and Northern hybridizations, showed insertion mutations in or expression of Notch-4. In contrast, both Wnt-1 and Fgf-3 were found to be involved in these tumors. Our findings may suggest, among other possibilities, the existence of a structural difference(s) between laboratory and wild mice at the Notch-4 locus that regulates the integration of Jyg-MMTV proviral DNA. PMID:19329137

Sarkar, Nurul H

2009-05-25

82

Natural history of tumor growth and immune modulation in common spontaneous murine mammary tumor models.  

Science.gov (United States)

Recent studies in patients with breast cancer suggest the immune microenvironment influences response to therapy. We aimed to evaluate the relationship between growth rates of tumors in common spontaneous mammary tumor models and immune biomarkers evaluated in the tumor and blood. TgMMTV-neu and C3(1)-Tag transgenic mice were followed longitudinally from birth, and MPA-DMBA-treated mice from the time of carcinogen administration, for the development of mammary tumors. Tumor-infiltrating CD4(+) and CD8(+) T-cells, FOXP3(+) T-regulatory cells, and myeloid-derived suppressor cells were assessed by flow cytometry. Serum cytokines were evaluated in subsets of mice. Fine needle aspirates of tumors were collected and RNA was isolated to determine levels of immune and proliferation markers. Age of tumor onset and kinetics of tumor growth were significantly different among the models. Mammary tumors from TgMMTV-neu contained a lower CD8/CD4 ratio than that of other models (p MDSC (p < 0.001) compared with the other models. Individuals with significantly slower tumor growth demonstrated higher levels of Type I serum cytokines prior to the development of lesions compared to those with rapid tumor growth. Moreover, the tumors of animals with more rapid tumor growth demonstrated a significant increase in the expression of genes associated with Type II immunity than those with slower-progressing tumors. These data provide a foundation for the development of in vivo models to explore the relationship between endogenous immunity and response to standard therapies for breast cancer. PMID:25395320

Gad, Ekram; Rastetter, Lauren; Slota, Meredith; Koehnlein, Marlese; Treuting, Piper M; Dang, Yushe; Stanton, Sasha; Disis, Mary L

2014-12-01

83

Polymer-peptide conjugates for angiogenesis targeted tumor radiotherapy  

International Nuclear Information System (INIS)

Introduction: New methods of delivering radiotherapy to sites of occult or disseminated cancer are needed to control the disease and address the failure of conventional therapy. Because tumor cells rely on angiogenesis for survival, we assessed the effectiveness of ?-emitter radiotherapy delivered by polymer-peptide conjugates that target tumor neovasculature. This molecularly targeted radiation is intended to damage both the endothelial bed and surrounding neoplastic cells. Methods: N-(2-Hydroxypropyl) methacrylamide (HPMA), a biocompatible and water-soluble copolymer, was derivatized to incorporate side chains for 99mTc and 9Y chelation and was further conjugated to a ?V?3 integrin-targeting peptide (RGD4C). The HPMA copolymer-RGD4C conjugate was characterized by its side-chain contents, in vitro endothelial cell adhesion assay and its biodistribution and antitumor effectiveness in a SCID mouse xenograft model of human prostate carcinoma. Results: The conjugate contained about 16 RGD4C moieties per polymer backbone. Tumor accumulation significantly increased (P9Y treat100- and 250-?Ci 9Y treatment groups, respectively. Histopathological examination revealed increased apoptosis in the treated tumors with no acute signs of radiation-induced toxicity to other organs. Conclusion: This copolymer-peptide conjugate targets tumor angiogenic vessels and delivers sufficient radiotherapy to arrest tumor growth

84

Quantitative protein profiling of tumor angiogenesis and metastasis biomarkers in mouse and human models  

Science.gov (United States)

Tumor and stromal cells secrete a variety of proteins acting as extracellular signals and creating a supportive microenvironment for tumor development, angiogenesis, and metastasis. We used the Luminex immunoassay platform (including MILLIPLEX® MAP cytokine/chemokine, bone metabolism, adipocyte, M...

85

Geminin overexpression induces mammary tumors via suppressing cytokinesis.  

Science.gov (United States)

Aneuploidy plays an important role in the development of cancer. Here, we uncovered an oncogenic role for geminin in mitotic cells. In addition to chromatin, tyrosine phosphorylated geminin also localizes to centrosome, spindle, cleavage furrow and midbody during mitosis. Geminin binding to Aurora B prevents its binding to INCENP, and thus activation leading to lack of histone H3-(serine 10) phosphorylation, chromosome condensation failure, aborted cytokinesis and the formation of aneuploid, drug resistance cells. Geminin overexpressing human mammary epithelial cells form aneuploid, aggressive tumors in SCID mice. Geminin is overexpressed in more than half of all breast cancers analyzed. The current study reveals that geminin is a genuine oncogene that promotes cytokinesis failure and production of aneuploid, aggressive breast tumors when overexpressed and thus a worthy therapeutic target (oncotarget) for aggressive breast cancer. PMID:22184288

Blanchard, Zannel; Malik, Rohit; Mullins, Nicole; Maric, Christine; Luk, Hugh; Horio, David; Hernandez, Brenda; Killeen, Jeffrey; Elshamy, Wael M

2011-12-01

86

Mouse mammary tumor virus infection accelerates mammary carcinogenesis in Wnt-1 transgenic mice by insertional activation of int-2/Fgf-3 and hst/Fgf-4.  

OpenAIRE

Transgenic mice carrying the Wnt-1 protooncogene modified for expression in mammary epithelial cells exhibit hyperplastic mammary glands and stochastically develop mammary carcinomas, suggesting that additional events are necessary for tumorigenesis. To induce such events and to identify the genes involved, we have infected Wnt-1 transgenic mice with mouse mammary tumor virus (MMTV), intending to insertionally activate, and thereby molecularly tag, cooperating protooncogenes. Infection of bre...

Shackleford, G. M.; Macarthur, C. A.; Kwan, H. C.; Varmus, H. E.

1993-01-01

87

Amino Acid Deprivation Promotes Tumor Angiogenesis through the GCN2/ATF4 Pathway1  

OpenAIRE

As tumors continue to grow and exceed their blood supply, nutrients become limited leading to deficiencies in amino acids (AAD), glucose (GD), and oxygen (hypoxia). These alterations result in significant changes in gene expression. While tumors have been shown to overcome the stress associated with GD or hypoxia by stimulating vascular endothelial growth factor (VEGF)-mediated angiogenesis, the role of AAD in tumor angiogenesis remains to be elucidated. We found that in human tumors, the exp...

Wang, Yugang; Ning, Yu; Alam, Goleeta N.; Jankowski, Brandon M.; Dong, Zhihong; No?r, Jacques E.; Polverini, Peter J.

2013-01-01

88

Induction of vascular endothelial tubular morphogenesis by human glioma cells. A model system for tumor angiogenesis.  

OpenAIRE

We have developed two different models of tumor angiogenesis by human brain tumors: one being tube formation by bovine aortic endothelial (BAE) cells cocultured with tumor cells in vitro, and other being in vivo angiogenesis in mice when tumor cells are transplanted into the dorsal sac. We investigated whether tube formation could be induced in BAE cells in type I collagen gel when these cells were cocultured with seven human glioma cell lines. Four of the seven glioma cell lines, which had h...

Abe, T.; Okamura, K.; Ono, M.; Kohno, K.; Mori, T.; Hori, S.; Kuwano, M.

1993-01-01

89

Dietary linoleate-enhanced metastasis of 4526 murine mammary tumors  

International Nuclear Information System (INIS)

The influence of quantitative differences in dietary linoleic acid (18:2) and of the cyclooxygenase inhibitor, indomethacin (IM), on the metastasis of line 4526 mammary tumors was investigated. All mice were fed high fat (20%, w/w), semipurified diets that were prepared using different mixtures of coconut (primarily saturated) and safflower (mostly 18:2) oil and thus contained either 1, 2, 4, 8, or 12% 18:2 (w/w). The spontaneous metastasis of 4526 tumor cells from primary sites, was increased 2-4 fold in mice that were fed diets containing higher levels of 18:2 (8 and 12%). Chronic treatment of mice with a relatively low dosage of IM reduced the growth rate of primary 4526 tumors, slightly reduced metastasis in mice fed 1 and 4% 18:2, and completely inhibited the increased metastasis observed in mice fed 12% 18:2. Treatment with a higher dosage of IM reduced metastasis even further compared to controls, but did not decrease growth rate compared to the low dosage of IM. The level of 18:2 in the diet did not appear to affect the incorporation of 3H-thymidine into tumor cells of metastatic lung nodules. The effect of 18:2 may be through a modulation of arachidonic acid metabolism. This modulation, in turn, may affect particular steps in the metastatic cascade such as lodgement and survival of tumor cells

90

Amplification of tumor inducing putative cancer stem cells (CSCs) by vitamin A/retinol from mammary tumors  

International Nuclear Information System (INIS)

Highlights: •Vitamin A supports self renewal of putative CSCs from mammary tumors. •These cells exhibit impaired retinol metabolism into retinoic acid. •CSCs from mammary tumors differentiate into mammary specific cell lineages. •The cells express mammary stem cell specific CD29 and CD49f markers. •Putative CSCs form highly metastatic tumors in NOD SCID mouse. -- Abstract: Solid tumors contain a rare population of cancer stem cells (CSCs) that are responsible for relapse and metastasis. The existence of CSC however, remains highly controversial issue. Here we present the evidence for putative CSCs from mammary tumors amplified by vitamin A/retinol signaling. The cells exhibit mammary stem cell specific CD29hi/CD49fhi/CD24hi markers, resistance to radiation and chemo therapeutic agents and form highly metastatic tumors in NOD/SCID mice. The cells exhibit indefinite self renewal as cell lines. Furthermore, the cells exhibit impaired retinol metabolism and do not express enzymes that metabolize retinol into retinoic acid. Vitamin A/retinol also amplified putative CSCs from breast cancer cell lines that form highly aggressive tumors in NOD SCID mice. The studies suggest that high purity putative CSCs can be isolated from solid tumors to establish patient specific cell lines for personalized therapeutics for pre-clinical translational applications. Characterization of CSCs will allow understanding of basic cellular and molecular pathways that are deregulated, mechanisms of tumor metastasis and evasion of therapies that has direct clinical relevance

91

Tumor suppressor XAF1 induces apoptosis, inhibits angiogenesis and inhibits tumor growth in hepatocellular carcinoma  

OpenAIRE

X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1), a XIAP-binding protein, is a tumor suppressor gene. XAF1 was silent or expressed lowly in most human malignant tumors. However, the role of XAF1 in hepatocellular carcinoma (HCC) remains unknown. In this study, we investigated the effect of XAF1 on tumor growth and angiogenesis in hepatocellular cancer cells. Our results showed that XAF1 expression was lower in HCC cell lines SMMC-7721, Hep G2 and BEL-7404 and liver cancer tis...

Zhu, Li Ming; Shi, Dong Mei; Dai, Qiang; Cheng, Xiao Jiao; Yao, Wei Yan; Sun, Ping Hu; Ding, Yan Fei; Qiao, Min Min; Wu, Yun Lin; Jiang, Shi Hu; Tu, Shui Ping

2014-01-01

92

Tumor angiogenesis and anti-angiogenic therapy in malignant gliomas revisited  

OpenAIRE

The cellular and molecular mechanisms of tumor angiogenesis and its prospects for anti-angiogenic cancer therapy are major issues in almost all current concepts of both cancer biology and targeted cancer therapy. Currently, (1) sprouting angiogenesis, (2) vascular co-option, (3) vascular intussusception, (4) vasculogenic mimicry, (5) bone marrow-derived vasculogenesis, (6) cancer stem-like cell-derived vasculogenesis and (7) myeloid cell-driven angiogenesis are all considered to contribute to...

Plate, Karl H.; Scholz, Alexander; Dumont, Daniel J.

2012-01-01

93

Tumor angiogenesis in rabbit VX2 brain tumor: model establishment, pathologic study and preliminary imaging observation  

International Nuclear Information System (INIS)

Objective: To establish a stable implanted model of VX2 rabbit brain tumor, and to evaluate the pathological and imaging features and tumor angiogenesis. Methods: Thirty New Zealand white rabbits were implanted with 100 ?l viable VX2 tumor cells (107/ml) through a hole 5 mm to the right of the sagittal suture and 5 mm posterior to the coronal suture bored by a dental drill. MRI was performed every 2 days after 7 days of implantation to evaluate the growth of the tumor, and perfusion CT studies were performed in different days of tumor growth. After that the animals were sacrificed on days 14, 18, 22, 26, and 30 of tumor implantation. 2% Evans blue (2 ml/kg) was given intravenously in 16 of these animals 1 hour prior to sacrifice to detect the breakdown of the blood-brain barrier (BBB). The specimens of the rabbit brains were examined pathologically and histologically. VEGF and MVD were evaluated in immunohistochemical examination. Results: Of the 22 animals included into the study, the tumor grew in 20 animals, which could be seen clearly on MR imaging. Pathologic examination showed characteristics of squamous carcinoma. VEGF was expressed in all tumors with the mean rate of positive cells of (52.51 ± 19.15)% (19.5%-92.9%). Mean MVD was (51.30 ± 14.42) pice piece/microscope (25-81 pice piece/microscope). Using Pearson's linear correlation analysis, positive correlation was found between tumor growth time and volume (r=0.791, P=0.000), between MVD and tum(r=0.791, P=0.000), between MVD and tumor growth time (r=0.875, P=0.000), and between MVD and tumor volume (r=0.901, P=0.000), respectively. Spearman's rank correlation analysis showed positive correlation between VEGF grade and blue stain of the tumor (rs=0.594, P=0.015). Conclusion: A stable model of VX2 rabbit brain tumor has been established with the method of skull drilling. The method was simple and easy to use, with a high tumor growth rate and remarkable angiogenesis. The model is helpful for the pathological and radiological study of tumor angiogenesis. (authors)

94

Acetyl-11-Keto-?-Boswellic Acid Inhibits Prostate Tumor Growth by Suppressing Vascular Endothelial Growth Factor Receptor 2-Mediated Angiogenesis  

OpenAIRE

The role of angiogenesis in tumor growth and metastasis is well established. Identification of small molecule that blocks tumor angiogenesis and is safe and affordable has been a challenge in drug development. In this study, we demonstrated that acetyl-11-keto-?-boswellic acid (AKBA), an active component from an Ayurvedic medicinal plant (Boswellia serrata), could strongly inhibit tumor angiogenesis. AKBA suppressed tumor growth in the human prostate tumor xenograft mice treated daily (10 mg...

Pang, Xiufeng; Yi, Zhengfang; Zhang, Xiaoli; Sung, Bokyung; Qu, Weijing; Lian, Xiaoyuan; Aggarwal, Bharat B.; Liu, Mingyao

2009-01-01

95

Hyperoxia retards growth and induces apoptosis and loss of glands and blood vessels in DMBA-induced rat mammary tumors  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background This study investigated the effects of hyperoxic treatment on growth, angiogenesis, apoptosis, general morphology and gene expression in DMBA-induced rat mammary tumors. Methods One group of animals was exposed to normobaric hyperoxia (1 bar, pO2 = 1.0 bar and another group was exposed to hyperbaric hyperoxia (1.5 bar, pO2 = 1.5 bar. A third group was treated with the commonly used chemotherapeutic drug 5- Fluorouracil (5-FU, whereas animals housed under normal atmosphere (1 bar, pO2 = 0.2 bar served as controls. All treatments were performed on day 1, 4, 7 and 10 for 90 min. Tumor growth was calculated from caliper measurements. Biological effects of the treatment, was determined by assessment of vascular morphology (immunostaining for von Willebrandt factor and apoptosis (TUNEL staining. Detailed gene expression profiles were obtained and verified by quantitative rtPCR. Results Tumor growth was significantly reduced (~57–66 % after hyperoxic treatment compared to control and even more than 5-FU (~36 %. Light microscopic observations of the tumor tissue showed large empty spaces within the tissue after hyperoxic treatment, probably due to loss of glands as indicated by a strong down-regulation of glandular secretory proteins. A significant reduction in mean vascular density (30–50% was found after hyperoxic treatment. Furthermore, increased apoptosis (18–21% was found after hyperoxic treatment. Conclusion Thus, by increasing the pO2 in mammary tumor tissue using normobaric and moderate hyperbaric oxygen therapy, a significant retardation in tumor growth is achieved, by loss of glands, reduction in vascular density and enhanced cell death. Hyperbaric oxygen should therefore be further evaluated as a tumor treatment.

Steen Vidar M

2007-01-01

96

Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and ERK signaling pathways  

OpenAIRE

Thymoquinone, a component derived from the medial plant Nigella sativa, has been used for medical purposes for more than two thousands of years. Recent studies reported that thymoquinone exhibited inhibitory effects on cell proliferation of many cancer cell lines and hormone-refractory prostate cancer by suppressing androgen receptor and E2F-1. Whether thymoquinone inhibits angiogenesis, the critical step of tumor growth and metastasis, is still unknown. In this study, we found that thymoquin...

Yi, Tingfang; Cho, Sung-gook; Yi, Zhengfang; Pang, Xiufeng; Rodriguez, Melissa; Wang, Ying; Sethi, Gautam; Aggarwal, Bharat B.; Liu, Mingyao

2008-01-01

97

Benign and malignant mammary tumors induced by DMBA in female Wistar rats  

OpenAIRE

This study pretends to characterize 7, 12-dimetylbenz[a]anthracene-induced benign and malignant tumors. One hundred and twenty female Wistar rats were randomly allocated to two groups: Control Group and Induction Group; IG animals were given a single dose of DMBA and killed 24 weeks after. Other tumors besides breast tumors were diagnosed, mainly tumors of the salivary glands and ovarian benign epithelial tumors. Incidence of breast disorders was about 60%. Macroscopic mammary tumors varied i...

Dias, M.; Cabrita, S.; Sousa, E.; Franc?a, B.; Patri?cio, J.; Oliveira, Cf

1999-01-01

98

Calcitriol reduces thrombospondin-1 and increases vascular endothelial growth factor in breast cancer cells: implications for tumor angiogenesis.  

Science.gov (United States)

Calcitriol, a potent antineoplastic vitamin D metabolite, inhibits proliferation, induces apoptosis and slows the growth of tumors. Calcitriol also may exert either antiangiogenic or proangiogenic effects depending on the tissue. Vascular endothelial growth factor (VEGF) and thrombospondin-1 (Tsp-1) are key factors involved in promoting and inhibiting angiogenesis, respectively. The effects of calcitriol on Tsp-1 have not been studied in the mammary gland, while VEGF regulation is not clear, since opposite outcomes have been demonstrated. Therefore, the present study was undertaken to investigate the effects of calcitriol on VEGF and Tsp-1 expression in primary breast tumor-derived cells and a panel of established breast cancer cell lines. In vivo studies in athymic mice were also performed in order to gain further insight into the biological effects of calcitriol on angiogenesis. Real time-PCR and ELISA analyses showed that calcitriol stimulated VEGF mRNA expression and protein secretion while elicited the opposite effect on Tsp-1 in 7 out of 8 cell lines studied, independently of the cell phenotype (P<0.05 in n=5). In vivo, calcitriol significantly inhibited the relative tumoral volume after 4 weeks of treatment; however, serum VEGF was higher in calcitriol-treated animals compared to controls (P<0.05). The integrated fluorescence intensity analysis of CD31, a vessel marker, showed that xenografted breast cancer cells developed tumors with similar vascular density regardless of the treatment. Nevertheless, larger necrotic areas were observed in the tumors of calcitriol-treated mice compared to controls. Since the antineoplastic activity of calcitriol has been consistently demonstrated in several studies including this one, our results suggest that the antitumoral effect of calcitriol in vivo involve different mechanisms not necessarily related to the inhibition of tumor vascularization. Overall, our findings indicate that calcitriol can impact the angiogenic process in breast cancer by regulating VEGF and Tsp-1 expression. This article is part of a Special Issue entitled '16th Vitamin D Workshop'. PMID:24120914

García-Quiroz, Janice; Rivas-Suárez, Mariana; García-Becerra, Rocío; Barrera, David; Martínez-Reza, Isela; Ordaz-Rosado, David; Santos-Martinez, Nancy; Villanueva, Octavio; Santos-Cuevas, Clara L; Avila, Euclides; Gamboa-Domínguez, Armando; Halhali, Ali; Larrea, Fernando; Díaz, Lorenza

2014-10-01

99

Tumor growth and angiogenesis is impaired in CIB1 knockout mice  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background Pathological angiogenesis contributes to various ocular, malignant, and inflammatory disorders, emphasizing the need to understand this process more precisely on a molecular level. Previously we found that CIB1, a 22 kDa regulatory protein, plays a critical role in endothelial cell function, angiogenic growth factor-mediated cellular functions, PAK1 activation, MMP-2 expression, and in vivo ischemia-induced angiogenesis. Since pathological angiogenesis is highly dependent on many of these same processes, we hypothesized that CIB1 may also regulate tumor-induced angiogenesis. Methods To test this hypothesis, we allografted either murine B16 melanoma or Lewis lung carcinoma cells into WT and CIB1-KO mice, and monitored tumor growth, morphology, histology, and intra-tumoral microvessel density. Results Allografted melanoma tumors that developed in CIB1-KO mice were smaller in volume, had a distinct necrotic appearance, and had significantly less intra-tumoral microvessel density. Similarly, allografted Lewis lung carcinoma tumors in CIB1-KO mice were smaller in volume and mass, and appeared to have decreased perfusion. Intra-tumoral hemorrhage, necrosis, and perivascular fibrosis were also increased in tumors that developed in CIB1-KO mice. Conclusions These findings suggest that, in addition to its other functions, CIB1 plays a critical role in facilitating tumor growth and tumor-induced angiogenesis.

Zayed Mohamed A

2010-08-01

100

Cell kinetics of tumors of the mammary gland  

International Nuclear Information System (INIS)

In vitro double cell labelling with 3H, 14C-thymidine in the S-phase of the cell cycle was used in a study of the proliferative activity of some dysplasias and malignant tumors of the mammary gland: 2 cases of mastopathy, 1 fibroadenoma and 22 nondifferentiated carcinoma (medullary type 8 and scirrhous type 14). Patients from whom specimens were obtained were largely in I and II stage of the disease, had not been irradiated, nor treated with cytostatic drugs before operation. Labelling index (LI) duration of S-phase (Tsub(s)) and potential time for cell population doubling (Tsub(p)) was determined. Using the data of Kusama et al., the authors determined also the actual tumor volume doubling time (Tsub(d)) and cell loss (F). It was shown that the proliferative activity of medullary breast cancer is higher than that of scirrhous cancer. With advancing age LI decreased and the duration of the cell cycle S-phase (Tsub(s)) was increased. There were major differences in LI and Tsub(s) between individual cases. Tsub(p) showed no statistically significant differences in scirrhous and medullary carcinomas. In younger patients predominated higher Tsub(p) values. Cell loss (F) was greater in medullary carcinoma, which has higher proliferative activity. (A.B.)

101

The impact of the immune system on tumor angiogenesis and vascular remodeling  

Directory of Open Access Journals (Sweden)

Full Text Available Angiogenesis, the formation of new blood vessels, as well as inflammation with massive infiltration of leukocytes are hallmarks of various tumor entities. Various epidemiological, clinical and experimental studies have not only demonstrated a link between chronic inflammation and cancer onset but also shown that immune cells from the bone marrow such as tumor-infiltrating macrophages significantly influence tumor progression. Tumor angiogenesis is a crucial step in tumor development as tumors have to establish a blood supply in order to grow and metastasize. Although tumor cells were first thought to drive the cellular events underpinning tumor angiogenesis, the use of transgenic mouse models and analysis of human tumor biopsies have shown that the tumor microenvironment with infiltrating immune cell subsets are important for regulating the process of tumor angiogenesis. These infiltrates involve the adaptive immune system including several types of lymphocytes as well as cells of the innate immunity such as macrophages, neutrophils, eosinophils, mast cells, dendritic cells and natural killer cells. Besides their known immune function, these cells are now recognized for their important role in regulating the formation and the remodeling of blood vessels in the tumor. In this review we will discuss for each cell type the mechanisms that regulate the vascular phenotype and its impact on tumor growth and metastasis.

ChristianStockmann

2014-04-01

102

Tumor Markers for Potentially Predicting Outcome of Anti-angiogenesis Therapy  

Science.gov (United States)

Researchers at the National Cancer Institute have identified tumor cell apoptosis, p53, and HER2 as having potential predictive significance for treatment outcome in breast cancer patients who received anti-angiogenesis therapy in combination with chemotherapy. The researchers have developed a quantitative antibody-based testing method for correlating expression of p53 and HER2 and tumor apoptosis with clinical outcome. These markers can be potentially applied to predict which patients should receive anti-angiogenesis therapy plus chemotherapy.

103

Depletion of Ascorbic Acid Restricts Angiogenesis and Retards Tumor Growth in a Mouse Model  

OpenAIRE

Angiogenesis requires the deposition of type IV collagen by endothelial cells into the basement membrane of new blood vessels. Stabilization of type IV collagen triple helix depends on the hydroxylation of proline, which is catalyzed by the iron-containing enzyme prolyl hydroxylase. This enzyme, in turn, requires ascorbic acid to maintain the enzyme-bound iron in its reduced state. We hypothesized that dietary ascorbic acid might be required for tumor angiogenesis and, therefore, tumor growth...

Telang, Sucheta; Clem, Amy L.; Eaton, John W.; Chesney, Jason

2007-01-01

104

The role of the Delta-like 4 Notch ligand in tumor angiogenesis  

OpenAIRE

Clinically significant tumors induce their own vascularization using molecular mechanisms involved in the regulation of physiological angiogenesis. One of these mechanisms is mediated by Delta-like 4 (Dll4)/Notch signaling, which is known to play a fundamental role in the regulation of embryonic angiogenesis and arterial specification. Up-regulated in animal and human tumors, Dll4 represents the focus of the work presented in this thesis, which aimed to characterize its function(s) in the reg...

Djokovic, Dusan

2011-01-01

105

Evolution of somatic mutations in mammary tumors in transgenic mice is influenced by the inherited genotype  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background MMTV-Wnt1 transgenic mice develop mammary hyperplasia early in development, followed by the appearance of solitary mammary tumors with a high proportion of cells expressing early lineage markers and many myoepithelial cells. The occurrence of tumors is accelerated in experiments that activate FGF proto-oncogenes or remove the tumor suppressor genes Pten or P53, implying that secondary oncogenic events are required for progression from mammary hyperplasia to carcinoma. It is not known, however, which oncogenic pathways contribute to Wnt1-induced tumorigenesis – further experimental manipulation of these mice is needed. Secondary events also appear to be required for mammary tumorigenesis in MMTV-Neu transgenic mice because the transgene in the tumors usually contains an acquired mutation that activates the Neu protein-tyrosine kinase. Methods cDNA or DNA from the mammary glands and mammary tumors from MMTV-Wnt1, MMTV-Wnt1/p53-/-, MMTV-Neu transgenic mice, and newly generated MMTV-Wnt1/MMTV-Neu bitransgenic mice, was sequenced to seek activating mutations in H-Ras, K-Ras, and N-Ras genes, or in the MMTV-Neu transgene. In addition, tumors from bitransgenic animals were examined to determine the cellular phenotype. Results We found activating mutations at codons 12, 13, and 61 of H-Ras in just over half of the mammary tumors in MMTV-Wnt1 transgenic mice, and we confirmed the high frequency of activating mutations of Neu in tumors in MMTV-Neu transgenic mice. Tumors appeared earlier in bitransgenic MMTV-Wnt1/MMTV-Neu mice, but no Ras or MMTV-Neu mutations were found in these tumors, which were phenotypically similar to those arising in MMTV-Wnt1 mice. In addition, no Ras mutations were found in the mammary tumors that arise in MMTV-Wnt1 transgenic mice lacking an intact P53 gene. Conclusions Tumorigenic properties of cells undergoing functionally significant secondary mutations in H-Ras or the MMTV-Neu transgene allow selection of those cells in MMTV-Wnt1 and MMTV-Neu transgenic mice, respectively. Alternative sources of oncogenic potential, such as a second transgenic oncogene or deficiency of a tumor suppressor gene, can obviate the selective power of those secondary mutations. These observations are consistent with the notion that somatic evolution of mouse mammary tumors is influenced by the specific nature of the inherited cancer-promoting genotype.

Li Yi

2004-06-01

106

Lack of effect of indomethacin on the growth of N-nitrosomethylurea-induced rat mammary tumors.  

Science.gov (United States)

Elevated prostaglandin levels have been previously reported in mammary tumors. This study was designed to determine if treatment with indomethacin, a prostaglandin synthesis inhibitor, influenced the growth of N-nitrosomethylurea-induced mammary tumors in Wistar rats. Indomethacin was given in drinking water to tumor-bearing rats, and rats consumed between 2.5 and 3.0 mg/kg body weight/day. Continuous p.o. administration of indomethacin during 4 weeks did not affect the rate of tumor growth as compared to the control group of untreated rats. It can be concluded that indomethacin lack of effect on N-nitrosomethylurea-induced mammary tumors, and this may be due to a specific prostaglandin profile as compared with previous results using other experimental models. PMID:3843001

Pérez-López, F R; Lorenzo, H K; Urcia, M A; Hergueta, J; Lafarga, L; Guillen, V

1985-01-01

107

Modulation of prostaglandin biosynthesis in murine mammary adenocarcinoma tumor cells  

International Nuclear Information System (INIS)

In efforts to exploit the differential oxygen levels within the subcompartments of solid neoplasms, this project has focused on modulating prostaglandin (PG) biosynthesis under aerobic and hypoxic conditions. Mammary adenocarcinoma tumor cells (Line 4526), either intact or sonicated, were incubated with either 2.0 uM 14C-arachidonic acid (AA) or 20.0 uM 14C-PGH2, respectively. Following metabolism, products were extracted, separated by thin layer chromatography and analyzed by radiochromatographic scan. PGE2 was predominantly formed with minimal amounts of PGF2a or PGD2. Indomethacin and ibuprofen inhibited the PGE2 formation from AA with an IC50 value of 6.3 x 10-8 and 9.6 x 10-5M, respectively. Suspended cells in glass vials were made hypoxic by flushing with N2 for varying time intervals to study AA metabolism. A time-dependent inhibition of PG biosynthesis was observed under hypoxia, and by 30 min, the PGE2 synthesis was reduced by 50% which was further inhibited by indomethacin. Misonidazole, a 2-nitroimidazole analogue, partially reversed the inhibition of PGE2 synthesis under hypoxia by 49% at 100 uM. However, misonidazole did not affect PG biosynthesis under aerobic conditions. The stimulation of PGE2 biosynthesis by misonidazole under hypoxia was blocked by indomethacin, suggesting that misonidazole can not cin, suggesting that misonidazole can not act independently of the cyclooxygenase

108

Oridonin inhibits tumor growth and metastasis through anti-angiogenesis by blocking the Notch signaling.  

Science.gov (United States)

While significant progress has been made in understanding the anti-inflammatory and anti-proliferative effects of the natural diterpenoid component Oridonin on tumor cells, little is known about its effect on tumor angiogenesis or metastasis and on the underlying molecular mechanisms. In this study, Oridonin significantly suppressed human umbilical vascular endothelial cells (HUVECs) proliferation, migration, and apillary-like structure formation in vitro. Using aortic ring assay and mouse corneal angiogenesis model, we found that Oridonin inhibited angiogenesis ex vivo and in vivo. In our animal experiments, Oridonin impeded tumor growth and metastasis. Immunohistochemistry analysis further revealed that the expression of CD31 and vWF protein in xenografts was remarkably decreased by the Oridonin. Furthermore, Oridonin reinforced endothelial cell-cell junction and impaired breast cancer cell transendothelial migration. Mechanistically, Oridonin not only down-regulated Jagged2 expression and Notch1 activity but also decreased the expression of their target genes. In conclusion, our results demonstrated an original role of Oridonin in inhibiting tumor angiogenesis and propose a mechanism. This study also provides new evidence supporting the central role of Notch in tumor angiogenesis and suggests that Oridonin could be a potential drug candidate for angiogenesis related diseases. PMID:25485753

Dong, Yanmin; Zhang, Tao; Li, Jingjie; Deng, Huayun; Song, Yajuan; Zhai, Dong; Peng, Yi; Lu, Xiaoling; Liu, Mingyao; Zhao, Yongxiang; Yi, Zhengfang

2014-01-01

109

SCA-1 Identifies the Tumor-Initiating Cells in Mammary Tumors of BALB-neuT Transgenic Mice  

Directory of Open Access Journals (Sweden)

Full Text Available Cancer stem cells, initiating and sustaining the tumor process, have been isolated in human and murine breast cancer using different cell markers. In the present study, we aimed to evaluate the presence and characteristics of stem/tumor-initiating cells in the model of the mouse mammary neoplasia driven by the activated form of rat Her-2/neu oncogene (BALB-neuT mice. For this purpose, we generated tumor spheres from primary spontaneous BALB-neuT tumors. Tumor sphere cultures were characterized for clonogenicity, self-renewal, and ability to differentiate in epithelial/myoepithelial cells of the mammary gland expressing basal and luminal cytokeratins and alpha-smooth muscle actin. In addition, tumor spheres were more resistant to doxorubicin compared with parental tumor cells. In the attempt to identify a selected marker for the sphere-generating cells, we found that Sca-1+ cells, present in tumors or enriched in mammospheres, and not CD24+ or CD29+ cells, were responsible for the sphere generation in vitro. Moreover, cells from the tumor spheres showed an increased tumor-generating ability in respect to the epithelial tumor cells. Sca-1+ sorted cells or clonal mammospheres derived from a Sca-1+ cell showed a superimposable tumor-initiating ability. The data of the present study indicate that a Sca-1+ population derived from mammary BALB-neuT tumors is responsible for sphere generation in culture and for initiating tumors in vivo.

Cristina Grange

2008-12-01

110

Localization of mammary tumors in vivo with 131I-labeled Fab fragments of antibodies against mouse mammary epithelial (MME) antigens  

International Nuclear Information System (INIS)

The Fab fragments of antibodies against cell-type-specific surface antigens of mouse mammary epithelial cells (MME-antigens) were used to localize mammary tumors successfully. The radioiodine-labeled anti-MME (Fab) was injected into mice carrying simulated mammary metastases, and after 24 hours the amount of label per gram of excised tissue was several times greater in the tumor than in liver, brain, lung, or muscle. Kidney showed considerable accumulation of label but this appeared to be nonspecific. Kinetic studies revealed a rapid elimination of labeled Fab in the urine with only 1% of the injected dose remaining in the entire blood pool after 24 hours. Wit a high-purity germanium camera, mammary tumors were clearly located ty the 131I-labeled anti-MME (Fab), and normalization to /sup 99m/Tc-pertechnetate distribution in the animal increased the specificity. The density of 131I-label was fourfold greater over the mammary tumor than over comparable areas of the mouse. No accumulation of 131I-anti-MME (Fab) was observed in nonmammary tumors nor in mammary tumors when labeled nonspecific Fab was used. An analogous system using an antihuman mammary epithelial antiserum is being developed for localization of breast metastases in humans

111

Tumor Angiogenesis Phenotyping by Nanoparticle-facilitated Magnetic Resonance and Near-infrared Fluorescence Molecular Imaging  

Directory of Open Access Journals (Sweden)

Full Text Available One of the challenges of tailored antiangiogenic therapy is the ability to adequately monitor the angiogenic activity of a malignancy in response to treatment. The ?v?3 integrin, highly overexpressed on newly formed tumor vessels, has been successfully used as a target for Arg-Gly-Asp (RGD-functionalized nanoparticle contrast agents. In the present study, an RGD-functionalized nanocarrier was used to image ongoing angiogenesis in two different xenograft tumor models with varying intensities of angiogenesis (LS174T > EW7. To that end, iron oxide nanocrystals were included in the core of the nanoparticles to provide contrast for T2*-weighted magnetic resonance imaging (MRI, whereas the fluorophore Cy7 was attached to the surface to enable near-infrared fluorescence (NIRF imaging. The mouse tumor models were used to test the potential of the nanoparticle probe in combination with dual modality imaging for in vivo detection of tumor angiogenesis. Pre-contrast and post-contrast images (4 hours were acquired at a 9.4-T MRI system and revealed significant differences in the nanoparticle accumulation patterns between the two tumor models. In the case of the highly vascularized LS174T tumors, the accumulation was more confined to the periphery of the tumors, where angiogenesis is predominantly occurring. NIRF imaging revealed significant differences in accumulation kinetics between the models. In conclusion, this technology can serve as an in vivo biomarker for antiangiogenesis treatment and angiogenesis phenotyping.

Peter A Jarzyna

2012-10-01

112

Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment  

Science.gov (United States)

The interplay between host genetics, tumor microenvironment and environmental exposure in cancer susceptibility remains poorly understood. Here we assessed the genetic control of stromal mediation of mammary tumor susceptibility to low dose ionizing radiation (LDIR) using backcrossed F1 into BALB/c (F1Bx) between cancer susceptible (BALB/c) and resistant (SPRET/EiJ) mouse strains. Tumor formation was evaluated after transplantation of non-irradiated Trp53-/- BALB/c mammary gland fragments into cleared fat pads of F1Bx hosts. Genome-wide linkage analysis revealed 2 genetic loci that constitute the baseline susceptibility via host microenvironment. However, once challenged with LDIR, we discovered 13 additional loci that were enriched for genes involved in cytokines, including TGF?1 signaling. Surprisingly, LDIR-treated F1Bx cohort significantly reduced incidence of mammary tumors from Trp53-/- fragments as well as prolonged tumor latency, compared to sham-treated controls. We demonstrated further that plasma levels of specific cytokines were significantly correlated with tumor latency. Using an ex vivo 3-D assay, we confirmed TGF?1 as a strong candidate for reduced mammary invasion in SPRET/EiJ, which could explain resistance of this strain to mammary cancer risk following LDIR. Our results open possible new avenues to understand mechanisms of genes operating via the stroma that affect cancer risk from external environmental exposures. PMID:25747469

Zhang, Pengju; Lo, Alvin; Huang, Yurong; Huang, Ge; Liang, Guozhou; Mott, Joni; Karpen, Gary H.; Blakely, Eleanor A.; Bissell, Mina J.; Barcellos-Hoff, Mary Helen; Snijders, Antoine M.; Mao, Jian-Hua

2015-01-01

113

Delphinidin is a novel inhibitor of lymphangiogenesis but promotes mammary tumor growth and metastasis formation in syngeneic experimental rats.  

Science.gov (United States)

We have recently demonstrated that the anthocyanidin delphinidin (DEL), one of the most abundant dietary flavonoids, inhibits activation of ErbB and vascular endothelial growth factor receptor family members. These receptors play crucial roles in the context of tumor progression and the outgrowth of blood and lymphatic vessels. Here, we have developed an improved chemical synthesis for DEL in order to study the effects of the aglycon and its degradation product gallic acid (GA) on endothelial and tumor cells in vitro and in vivo. We found that DEL blocked the proliferation in vitro of primary human blood and lymphatic endothelial cells as well as human HT29 colon and rat MT-450 mammary carcinoma cells in a dose-dependent manner. In contrast, its degradation product GA had little effect. At higher concentrations, DEL induced apoptosis of endothelial and tumor cells. Furthermore, DEL potently blocked the outgrowth of lymphatic capillaries in ex vivo lymphangiogenesis assays. In the MT-450 rat syngeneic breast tumor model, it also significantly reduced angiogenesis and tumor-induced lymphangiogenesis when administered in vivo. These data reveal DEL to be a novel antilymphangiogenesis reagent. Surprisingly, however, the application of DEL unexpectedly promoted tumor growth and metastasis in the MT-450 tumor model, suggesting that the antiproliferative effect of DEL on cultured cells does not necessarily reflect the response of tumors to this anthocyanidin in vivo. Furthermore, while DEL may have utility as a cancer chemopreventative agent, its ability to promote tumor growth once a neoplasm develops also needs to be taken into consideration. PMID:23975834

Thiele, Wilko; Rothley, Melanie; Teller, Nicole; Jung, Nicole; Bulat, Bekir; Plaumann, Diana; Vanderheiden, Sylvia; Schmaus, Anja; Cremers, Natascha; Göppert, Bettina; Dimmler, Arno; Eschbach, Verena; Quagliata, Luca; Thaler, Sonja; Marko, Doris; Bräse, Stefan; Sleeman, Jonathan P

2013-12-01

114

Clonal variations among multiple primary mammary tumors and within a tumor of individual mice: insertion mutations of int oncogenes.  

Science.gov (United States)

Laboratory mice infected with the mouse mammary tumor virus (MMTV) often develop multiple mammary tumors. However, no comprehensive studies have been done addressing the question of whether or not different primary tumors of individual mice are related ontogenetically to each other. Further, it is not known to what extent individual tumors vary in their cellular composition. We, therefore, examined intertumor and intratumor patterns of the rearrangements in int-1 (Wnt-1), int-2 (Fgf-3), and int-3 protooncogenes, since mutations in ints caused by MMTV result in the development of mammary tumors in mice and thus provide the most suitable genetic markers for the tumor cells. Our results show that, irrespective of the genetic background of the mice and/or the strain of MMTV, the pattern of MMTV integration in the different tumors of individual mice varies as widely as is found with the tumors of different mice. Of the 79 tumors obtained from 25 mice of different genetic backgrounds, 31 showed insertional mutations in int-1 (39%). By contrast only 9 of the 65 tumors tested had mutations in int-2 (14%). None of the tumors showed mutations in int-3. Interestingly, tumors from individual mice also showed variations in their pattern of int gene mutation, indicating that multiple tumors that develop in a mouse bear no ontogenetical link. The analysis of the pattern of intratumor MMTV integration, int mutation, and int expression revealed that several int mutational events as well as variations in int expression may occur in the same tumor. The diversity of int activation within individual tumors may suggest that the initiation and progression of most mammary tumors, if not all, occur through the concerted action of different mutational events in the same cell or through interactions of different cell populations, each of which acquired different int mutations. PMID:7571419

Sarkar, N H

1995-10-01

115

An approach to malignant mammary phyllodes tumors detection  

Directory of Open Access Journals (Sweden)

Full Text Available Background/Aim. Mammary phyllodes tumors (MPT are uncommon fibroepithelial (biphasic neoplasms whose clinical behavior is difficult to predict on the basis of histological criteria only. They are divided into benign, borderline malignant and malignant groups. Sometimes it appears difficult to distinguish these tumors from other types of soft tissue sarcomas. Because of the relatively scant data on the role of biological markers in MPT histogenesis, we have decided to undertake the following study, trying to shed more light on the issue by investigating the following elements that make up MPT: their histological patterns, biological behavior, enzymohistochemical, histochemical and immunohistochemical characteristics (ICH together with the mast cell analysis. Methods. We examined the biopsy material of 35 MPT in our laboratory. Enzymohistochemistry was performed on frozen sections (method of Crowford, Nachlas and Seligman. The used methods were classical hematoxylin-eosin (H&E; histochemical Massontrichrome, Alcian-blue, Periodic acid Schiff and immunohistochemical LSAB2 method (DacoCytomation. Ki-67, ckit, vimentin, estrogen receptor (ER, progesterone receptor (PR and Her-2 oncoprotein immunohistochemistry was performed on all tumors. Results. The patients were ranged per age from 30-62 years (mean 43.3 years, median 39 years. A total of 35 cases of MPT were included: 20 benign (57%, 6 borderline malignant (17% and 9 malignant (26%. Twenty-two patients (62.8 % underwent segmental mastectomy, while 13 (37.2% had total mastectomies. Twenty-eight patients had negative surgical margins at original resection. The mean size of malignant MPT (7.8 cm was larger than that of benign MPT (4.5 cm. Significant features of the malignant MPT were: stromal cellularity, stromal cellular atypism, high mitotic activity, atypic mitoses, stromal overgrowth, infiltrative tumor contour and heterologous stromal elements. Benign MPT showed strong enzymohistochemical Leucine Amino Peptidase (LAP activity in both epithelial and stromal components while it was weak or absent in the epithelial parts of the malignant tumors. Acid mucopolysacharides were present in the stromal component of all types of these tumors. Benign MPT had a lower Ki-67 than did borderline malignant MPT (4 versus 28. Malignant MPT had a greater than 8-fold higher Ki-67 activity than did benign tumors (35 versus 4. Intracytoplasmatic c-kit expression was associated with a pathological diagnosis of malignant MPT, correlating with increasing grade (p < 0.05. In hypercellular stroma of borderline malignant and especially malignant forms of MPT, high activity of ER in mast cells was confirmed. Oncoprotein Her-2 activity, mostly in epithelial components, correlated with the degree of malignant progression of MPT (p < 0.05. Conclusion. Besides the well-known malignant features additional parameters have been found to be high Ki-67 and ckit stromal expressions, and weak LAP activity in the epithelial part of malignant MPT, as well as mast cells with a high expression of ER.

Ili? Ivan

2009-01-01

116

Sequential imaging of indium-111-labeled monoclonal antibody in human mammary tumors hosted in nude mice  

International Nuclear Information System (INIS)

Using a bifunctional chelating agent, indium-111 was attached to a monoclonal antibody 10-3D2, specific for a 126-kilodalton phosphoglycoprotein antigen associated with human mammary carcinoma, and was then used to localize and visualize human mammary tumors hosted in nude mice. Simultaneous tumor concentration of In-111-10-3D2 was eight times greater than that of control I-125-MOPC-21. Uptake of F(ab')2 and Fab of 10-3D2 was also compared. The scintigrams demonstrated that intact antibody provided the best images. Control In-111-labeled MOPC-21 and plasma did not show specific localization in the tumor. Uptake of In-111-labeled 10-3D2 was also compared in two lines of human mammary tumors, BT-20 and HS-578T. Imaging with 10-3D2 was better for BT-20 than for HS-578T

117

Dendra2 Photoswitching through the Mammary Imaging Window  

OpenAIRE

In the last decade, intravital microscopy of breast tumors in mice and rats at single-cell resolution1-4 has resulted in important insights into mechanisms of metastatic behavior such as migration, invasion and intravasation of tumor cells5, 6, angiogenesis3 and immune cells response7-9. We have recently reported a technique to image orthotopic mammary carcinomas over multiple intravital imaging sessions in living mice10. For this, we have developed a Mammary Imaging Window (MIW) and optimiz...

Gligorijevic, Bojana; Kedrin, Dmitriy; Segall, Jeffrey E.; Condeelis, John; Rheenen, Jacco

2009-01-01

118

Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer.  

Science.gov (United States)

As neovascularization is essential for tumor growth and metastasis, controlling angiogenesis is a promising tactic in limiting cancer progression. Melatonin has been studied for their inhibitory properties on angiogenesis in cancer. We performed an in vivo study to evaluate the effects of melatonin treatment on angiogenesis in breast cancer. Cell viability was measured by MTT assay after melatonin treatment in triple-negative breast cancer cells (MDA-MB-231). After, cells were implanted in athymic nude mice and treated with melatonin or vehicle daily, administered intraperitoneally 1 hour before turning the room light off. Volume of the tumors was measured weekly with a digital caliper and at the end of treatments animals underwent single photon emission computed tomography (SPECT) with Technetium-99m tagged vascular endothelial growth factor (VEGF) C to detect in vivo angiogenesis. In addition, expression of pro-angiogenic/growth factors in the tumor extracts was evaluated by membrane antibody array and collected tumor tissues were analyzed with histochemical staining. Melatonin in vitro treatment (1 mM) decreased cell viability (pbreast cancer xenografts nude mice treated with melatonin showed reduced tumor size and cell proliferation (Ki-67) compared to control animals after 21 days of treatment (p0.05) images. In addition, there was a decrease of micro-vessel density (Von Willebrand Factor) in melatonin treated mice (pmelatonin treatment showed effectiveness in reducing tumor growth and cell proliferation, as well as in the inhibition of angiogenesis. PMID:24416386

Jardim-Perassi, Bruna Victorasso; Arbab, Ali S; Ferreira, Lívia Carvalho; Borin, Thaiz Ferraz; Varma, Nadimpalli R S; Iskander, A S M; Shankar, Adarsh; Ali, Meser M; de Campos Zuccari, Debora Aparecida Pires

2014-01-01

119

Methylation and miRNA effects of resveratrol on mammary tumors vs. normal tissue.  

Science.gov (United States)

We reported that resveratrol decreased DNA methyltransferase (DNMT) 1 and 3b expression in vitro and demethylates tumor suppressor RASSF-1a in women at increased breast cancer risk. We investigated the effects of resveratrol on DNMT and miRNA expression in normal and tumor mammary tissue in a rodent model of estrogen dependent mammary carcinoma. Eighty-nine female ACI rats received estradiol plus: low dose (lo) resveratrol, high dose (hi) resveratrol, 5-aza-2-deoxycytidine (Aza), a known inhibitor of DNMTs, or control (no additional treatment). After 21 wk of treatment, animals were sacrificed and mammary glands harvested. Matched tumor/normal tissues were available from 36 rats. DMNT3b (but not DNMT1) differed in tumor vs. normal tissue after lo (P = .04) and hi (P = .007) resveratrol and Aza treatment. With hi resveratrol, DNMT3b decreased in tumor but increased normal tissue. Hi resveratrol increased miR21, -129, -204, and -489 >twofold in tumor and decreased the same miRs in normal tissue 10-50% compared to control. There was an inverse association between DNMT3b and miR129, -204, and -489 in normal and/or tumor tissue. Treatment with resveratrol differentially influences tumor vs. normal tissue DNMT3b and miRNA expression. This mechanism of action of resveratrol to influence mammary carcinogenesis warrants further investigation. PMID:24447120

Qin, Wenyi; Zhang, Ke; Clarke, Kaitlin; Weiland, Timothy; Sauter, Edward R

2014-01-01

120

Genotype x diet interactions in mice predisposed to mammary cancer: II. Tumors and metastasis  

DEFF Research Database (Denmark)

High dietary fat intake and obesity may increase the risk of susceptibility to certain forms of cancer. To study the interactions of dietary fat, obesity, and metastatic mammary cancer, we created a population of F2 mice cosegregating obesity QTL and the MMTV-PyMT transgene. We fed the F2 mice either a very high-fat or a matched-control-fat diet, and we measured growth, body composition, age at mammary tumor onset, tumor number and severity, and formation of pulmonary metastases. SNP genotyping across the genome facilitated analyses of QTL and QTL × diet interaction effects. Here we describe effects of diet on mammary tumor and metastases phenotypes, mapping of tumor/metastasis modifier genes, and the interaction between dietary fat levels and effects of cancer modifiers. Results demonstrate that animals fed a high-fat diet are not only more likely to experience decreased mammary cancer latency but increased tumor growth and pulmonary metastases occurrence over an equivalent time. We identified 25 modifier loci for mammary cancer and pulmonary metastasis, likely representing 13 unique loci after accounting for pleiotropy, and novel QTL × diet interactions at a majority of these loci. These findings highlight the importance of accurately modeling not only the human cancer characteristics in mice but also the environmental exposures of human populations Udgivelsesdato: March

Gordon, Ryan R; Hunter, Kent W

2008-01-01

121

The Role of Histidine-rich Glycoprotein in Angiogenesis and Tumor Growth  

OpenAIRE

Histidine-rich glycoprotein (HRG) is a heparin-binding plasma protein modulating immune, hemostatic and vascular functions. I have studied the antiangiogenic functions of HRG in vitro and in vivo in order to understand the molecular mechanisms of action of HRG as an angiogenesis inhibitor. Angiogenesis is the formation of new blood vessels from the pre-existing vasculature. It is a central rate-limiting step of tumor development and thus a possible target for cancer therapeutics. Previous stu...

Thulin, A?sa

2009-01-01

122

Human BCAS3 expression in embryonic stem cells and vascular precursors suggests a role in human embryogenesis and tumor angiogenesis.  

Science.gov (United States)

Cancer is often associated with multiple and progressive genetic alterations in genes that are important for normal development. BCAS3 (Breast Cancer Amplified Sequence 3) is a gene of unknown function on human chromosome 17q23, a region associated with breakpoints of several neoplasms. The normal expression pattern of BCAS3 has not been studied, though it is implicated in breast cancer progression. Rudhira, a murine WD40 domain protein that is 98% identical to BCAS3 is expressed in embryonic stem (ES) cells, erythropoiesis and angiogenesis. This suggests that BCAS3 expression also may not be restricted to mammary tissue and may have important roles in other normal as well as malignant tissues. We show that BCAS3 is also expressed in human ES cells and during their differentiation into blood vascular precursors. We find that BCAS3 is aberrantly expressed in malignant human brain lesions. In glioblastoma, hemangiopericytoma and brain abscess we note high levels of BCAS3 expression in tumor cells and some blood vessels. BCAS3 may be associated with multiple cancerous and rapidly proliferating cells and hence the expression, function and regulation of this gene merits further investigation. We suggest that BCAS3 is mis-expressed in brain tumors and could serve as a human ES cell and tumor marker. PMID:18030336

Siva, Kavitha; Venu, Parvathy; Mahadevan, Anita; S K, Shankar; Inamdar, Maneesha S

2007-01-01

123

Molecular analysis reveals heterogeneity of mouse mammary tumors conditionally mutant for Brca1  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background Development of therapies for patients with BRCA1 mutations has been hampered by lack of readily available in vitro and in vivo models. We recently showed that transplantation of transgenic mammary tumors as cell suspensions into naïve recipients generates reproducible tumors with remarkable stability of gene expression profile. We examined the expression profiles of original and serially transplanted mammary tumors from Brca1 deficient mice, and tumor derived cell lines to validate their use for preclinical testing and studies of tumor biology. Methods Original tumors, serially transplanted and multiple cell lines derived from Brca1 mammary tumors were characterized by morphology, gene and protein expression, and cell surface markers. Results Gene expression among Brca1 tumors showed more heterogeneity than among previously characterized tumors from MMTV-PyMT and -Wnt1 models. Gene expression data segregated Brca1 tumors into 3 distinct types: basal, mixed luminal, and tumors with epithelial-to-mesenchymal transition (EMT. Serial transplantation of individual tumors and multiple cell lines derived from the original tumors recapitulated the molecular characteristics of each tumor of origin. One tumor had distinct features of EMT and gave rise to cell lines that contained a distinct CD44+/CD24-/low population that may correlate with human breast cancer stem cells. Conclusion Although individual tumors expanded by transplantation maintain the genomic profile of the original tumors, the heterogeneity among Brca1 tumors limits the extent of their use for preclinical testing. However, cell lines offer a robust material for understanding tumor biology and response to therapies driven by BRCA1 deficiency.

Anver Miriam R

2008-04-01

124

Effects of tamoxifen and interferon-beta or the combination on tumor-induced angiogenesis.  

Science.gov (United States)

Inhibition of angiogenesis by anti-tumor agents may play a role in tumor growth arrest. Tamoxifen and interferon-alpha/beta (IFN-alpha/beta) exhibit potentiated anti-proliferative activity against tumor cells. However, additional host-mediated effects such as modulation of angiogenesis may also inhibit tumor growth in vivo. The effect of tamoxifen and IFN-beta on angiogenesis induced by 2 human tumors, MCF-7 breast carcinoma (estradiol dependent) and NIH-OVCAR-3 ovarian carcinoma (estradiol independent), was assessed. Treatment of nude mice bearing MCF-7 tumors with tamoxifen resulted in a 68% decrease in the number of vessels at the tumor periphery. Treatment with IFN-beta yielded a 33% reduction. Treatment of nude mice bearing NIH-OVCAR-3 tumors with tamoxifen resulted in a 73% decrease in the number of vessels. Treatment with IFN-beta yielded a 57% reduction. Combination treatment resulted in augmented anti-angiogenic effects. As single agents, both tamoxifen and IFN-beta inhibited xenograft tumor growth. Ten weeks of tamoxifen treatment resulted in growth inhibition of MCF-7 and NIH-OVCAR-3 carcinomas by 85% and 66%, respectively. Ten weeks of IFN-beta treatment resulted in inhibition of growth of MCF-7 and NIH-OVCAR-3 carcinomas by 67% and 88%, respectively. The combination of tamoxifen and IFN-beta completely prevented growth of MCF-7 and NIH-OVCAR-3 carcinomas. The anti-angiogenic effects of tamoxifen and IFN-beta were additive. Inhibition of angiogenesis was detectable before measurable effects on tumor volume in both MCF-7 and NIH-OVCAR-3 tumors. Potentiation of anti-angiogenic effects by tamoxifen and IFN-beta, possibly resulting from enhanced IFN-induced gene expression, may contribute to anti-tumor activity in both estradiol-dependent and estradiol-independent tumors in vivo. PMID:9139884

Lindner, D J; Borden, E C

1997-05-01

125

Distinct biological roles for the Akt family in mammary tumor progression  

OpenAIRE

The phosphatidylinositol 3' kinase/Akt pathway is frequently dysregulated in cancer which can have unfavorable consequences in terms of cell proliferation, survival, metabolism and migration. Increasing evidence suggests that Akt1, Akt2 and Akt3 play unique roles in breast cancer initiation and progression. We have recently shown that in contrast to Akt1 which accelerates mammary tumor induction in transgenic mice, Akt2 promotes metastasis of tumor cells without affecting the latency of tumor...

Dillon, Rachelle L.; Muller, William J.

2010-01-01

126

Pristimerin, a Triterpenoid, Inhibits Tumor Angiogenesis by Targeting VEGFR2 Activation  

Directory of Open Access Journals (Sweden)

Full Text Available Pristimerin is a triterpenoid isolated from Celastrus and Maytenus spp. that has been shown to possess a variety of biological activities, including anti-cancer activity. However, little is known about pristimerin’s effects on tumor angiogenesis. In this study, we examined the function and the mechanism of this compound in tumor angiogenesis using multiple angiogenesis assays. We found that pristimerin significantly reduced both the volume and weight of solid tumors and decreased angiogenesis in a xenograft mouse tumor model in vivo. Pristimerin significantly inhibited the neovascularization of chicken chorioallantoic membrane (CAM in vivo and abrogated vascular endothelial growth factor (VEGF-induced microvessel sprouting in an ex vivo rat aortic ring assay. Furthermore, pristimerin inhibited the VEGF-induced proliferation, migration and capillary-like structure formation of human umbilical vascular endothelial cells (HUVECs in a concentration-dependent manner. Mechanistic studies revealed that pristimerin suppressed the VEGF-induced phosphorylation of VEGF receptor 2 kinase (KDR/Flk-1 and the activity of AKT, ERK1/2, mTOR, and ribosomal protein S6 kinase. Taken together, our results provide evidence for the first time that pristimerin potently suppresses angiogenesis by targeting VEGFR2 activation. These results provide a novel mechanism of action for pristimerin which may be important in the treatment of cancer.

Luyong Zhang

2012-06-01

127

A new common integration region (int-3) for mouse mammary tumor virus on mouse chromosome 17.  

OpenAIRE

Mus musculus subsp. musculus (Czech II) mammary tumor DNA frequently contains an integrated proviral genome of the mouse mammary tumor virus (MMTV) within a specific 0.5-kilobase-pair region of the cellular genome (designated int-3). Viral integration at this site results in activation of expression of an adjacent cellular gene. We mapped int-3 to mouse chromosome 17 by analysis of PstI-restricted cellular DNAs from mouse-hamster somatic cell hybrids. Restriction analysis of cellular DNA from...

Gallahan, D.; Kozak, C.; Callahan, R.

1987-01-01

128

Alterations of a mouse mammary tumor virus glycoprotein with interferon treatment.  

OpenAIRE

The effects of exogenous mouse interferon on the MJY-alpha mammary tumor cell line chronically infected with mouse mammary tumor virus (MMTV) were examined. Interferon at concentrations of 25 to 2,000 IU/ml in culture medium did not alter the growth rate or morphology of the cell layers. Electron microscopic examination of interferon-treated cells indicated a decrease in the numbers of A-type and budding B-type particles of MMTV. However, the levels of extracellular MMTV virions in the cultur...

Yagi, M. J.; King, N. W.; Bekesi, J. G.

1980-01-01

129

Flor-Essence? Herbal Tonic Promotes Mammary Tumor Development in Sprague Dawley Rats  

Energy Technology Data Exchange (ETDEWEB)

Background: Women who are diagnosed with breast cancer often self-administer complementary and alternative medicines to augment their conventional treatments, improve health, or prevent recurrence. Flor-Essence{reg_sign} Tonic is a complex mixture of herbal extracts used by cancer patients because of anecdotal evidence that it can treat or prevent disease. Methods: Female Sprague Dawley rats were given water or exposed to 3% or 6% Flor-Essence{reg_sign} beginning at one day of age. Mammary tumors were induced with a single oral 40 mg/kg/bw dose of dimethylbenz(a)anthracene at 50 days of age and sacrificed at 23 weeks. Rats were maintained on AIN-76A diet. Results: Control rats had palpable mammary tumor incidence of 51.0% at 19 weeks of age compared to 65.0% and 59.4% for the 3% and 6% Flor-Essence{reg_sign} groups respectively. Overall, no significant difference in time until first palpable tumor was detected among any of the groups. At necropsy, mammary tumor incidence was 82.5% for controls compared to 90.0% and 97.3% for rats consuming 3% and 6% Flor-Essence{reg_sign}, respectively. Mean mammary tumor multiplicity ({+-}SES) for the controls was 2.8 ({+-} 0.5) and statistically different from the 3% or 6% Flor- Essence{reg_sign} groups with 5.2 ({+-} 0.7), and 4.8 ({+-} 0.6), respectively (p{<=}0.01). As expected, the majority of isolated tumors were diagnosed as adenocarcinomas. Conclusions: Flor-Essence{reg_sign} can promote mammary tumor development in the Sprague Dawley rat model. This observation is contrary to widely available anecdotal evidence as well as the desire of the consumer that this commercially available herbal tonic will suppress and/or inhibit tumor growth.

Bennett, L; Montgomery, J; Steinberg, S; Kulp, K

2004-01-28

130

Correlation Between PSMA and VEGF Expression as Markers for LNCaP Tumor Angiogenesis  

OpenAIRE

Our aim is the identification and correlation of changes in tumor-associated protein expression which results from therapy. LNCaP tumors, excised from nude mice treated either by orchiectomy or with the chemotherapeutic agent paclitaxel, were evaluated for the expression of proteins and receptors associated with growth, differentiation, and angiogenesis using immunohistologic procedures. Compared to untreated control tumors, both treatments reduced the expression of vascular endothelial growt...

Tsui Paulus; Rubenstein Marvin; Guinan Patrick

2005-01-01

131

A Cell-Based Model Exhibiting Branching and Anastomosis during Tumor-Induced Angiogenesis  

OpenAIRE

This work describes the first cell-based model of tumor-induced angiogenesis. At the extracellular level, the model describes diffusion, uptake, and decay of tumor-secreted pro-angiogenic factor. At the cellular level, the model uses the cellular Potts model based on system-energy reduction to describe endothelial cell migration, growth, division, cellular adhesion, and the evolving structure of the stroma. Numerical simulations show: 1), different tumor-secreted pro-angiogenic factor gradien...

Bauer, Amy L.; Jackson, Trachette L.; Jiang, Yi

2007-01-01

132

Key Roles for the Lipid Signaling Enzyme Phospholipase D1 in the Tumor Microenvironment During Tumor Angiogenesis and Metastasis  

OpenAIRE

Angiogenesis inhibitors confer only short-term benefits on tumor growth. We report that ablation of the lipid signaling enzyme phospholipase D1 (PLD1) in the tumor environment compromises neovascularization and growth of tumors. PLD1 deficiency suppressed activation of AKT and mitogen-activated protein kinase signaling pathways by vascular endothelial growth factor (VEGF) in vascular endothelial cells, resulting in decreased integrin-dependent cell adhesion to and migration on extracellular m...

Chen, Qin; Sato, Takanobu; Hongu, Tsunaki; Zhang, Yi; Ali, Wahida; Cavallo, Julie-ann; Velden, Adrianus; Tian, Huasong; Di Paolo, Gilbert; Nieswandt, Bernhard; Kanaho, Yasunori; Frohman, Michael A.

2012-01-01

133

Wound healing-like immune program facilitates postpartum mammary gland involution and tumor progression.  

Science.gov (United States)

Women diagnosed with breast cancer within 5 years postpartum have poor survival rates. The process of postpartum mammary gland involution, whereby the lactating gland remodels to its prepregnant state, promotes breast cancer progression in xenograft models. Macrophage influx occurs during mammary gland involution, implicating immune modulation in the promotion of postpartum breast cancer. Herein, we characterize the postpartum murine mammary gland and find an orchestrated influx of immune cells similar to that which occurs during wound healing. Further, the normal involuting gland may be in an immunosuppressed state as discerned by the transient presence of Foxp3(+) regulatory T cells and IL-10(+) macrophages with T cell suppressive function. To determine the influence of the postpartum immune microenvironment on mammary tumor promotion, we developed an immune-competent model. In this model, mammary tumors in the involution group are sixfold larger than nulliparous group tumors, have decreased CD4(+) and CD8(+) T cell infiltrates and contain a greater number of macrophages with the ability to inhibit T cell activation. Targeting involution with a neutralizing antibody against the immunosuppressive cytokine IL-10 reduces tumor growth in involution group mice but not in nulliparous mice, implicating the involution microenvironment as the primary target of ?IL-10 treatment. Relevance to women is implicated, as we find postlactational human breast tissue has transient high IL-10(+) and Foxp3(+) immune cell infiltrate. These data show an immune modulated microenvironment within the normal involuting mammary gland suggestive of immunosuppression, that when targeted reduces tumor promotion, revealing possible immune-based strategies for postpartum breast cancer. PMID:25187059

Martinson, Holly A; Jindal, Sonali; Durand-Rougely, Clarissa; Borges, Virginia F; Schedin, Pepper

2015-04-15

134

Autophagy regulates keratin 8 homeostasis in mammary epithelial cells and in breast tumors  

Science.gov (United States)

Autophagy is activated in response to cellular stressors and mediates lysosomal degradation and recycling of cytoplasmic material and organelles as a temporary cell survival mechanism. Defective autophagy is implicated in human pathology, as disruption of protein and organelle homeostasis enables disease-promoting mechanisms such as toxic protein aggregation, oxidative stress, genomic damage and inflammation. We previously showed that autophagy-defective immortalized mouse mammary epithelial cells (iMMECs) are susceptible to metabolic stress, DNA damage and genomic instability. We now report that autophagy deficiency was associated with ER and oxidative stress, and deregulation of p62-mediated keratin homeostasis in mammary cells and allograft tumors and in mammary tissues from genetically engineered mice. In human breast tumors, high phospho(Ser73)-K8 levels inversely correlated with Beclin 1 expression. Thus, autophagy preserves cellular fitness by limiting ER and oxidative stress, a function potentially important in autophagy-mediated suppression of mammary tumorigenesis. Furthermore, autophagy regulates keratin homeostasis in the mammary gland via a p62-dependent mechanism. High phospho(Ser73)-K8 expression may be a marker of autophagy functional status in breast tumors and, as such, could have therapeutic implications for breast cancer patients. PMID:20530580

Kongara, Sameera; Kravchuk, Olga; Teplova, Irina; Lozy, Fred; Schulte, Jennifer; Moore, Dirk; Barnard, Nicola; Neumann, Carola A.; White, Eileen; Karantza, Vassiliki

2010-01-01

135

Radiolabeled RGD peptides as tumor angiogenesis markers: from molecular imaging to targeted therapy  

International Nuclear Information System (INIS)

Integrin ???3 plays a significant role in tumor angiogenesis which is one of the key requirements for cancer growth. During the past two decades, a number of radiolabeled linear and cyclic RGD peptide derivatives have been evaluated as integrin ???3-targeting radiotracers for detection and prognosis of cancer by SPECT and PET imaging. However, there is a continuing need for more efficient integrin ???3 -targeted radiotracers that could be readily prepared from a kit formulation without further post-labeling purification. The present article gives a brief overview of the fundamental aspects in the design and development of ideal radiotracers for targeting tumor angiogenesis based on RGD peptides. (author)

136

Genetic heterogeneity of Myc-induced mammary tumors reflecting diverse phenotypes including metastatic potential.  

Science.gov (United States)

Human cancers result from a complex series of genetic alterations, resulting in heterogeneous disease states. Dissecting this heterogeneity is critical for understanding underlying mechanisms and providing opportunities for therapeutics matching the complexity. Mouse models of cancer have generally been used to reduce this complexity and focus on the role of single genes. Nevertheless, our analysis of tumors arising in the MMTV-Myc model of mammary carcinogenesis reveals substantial heterogeneity, seen in both histological and expression phenotypes. One contribution to this heterogeneity is the substantial frequency of activating Ras mutations. Additionally, we show that these Myc-induced mammary tumors exhibit even greater heterogeneity, revealed by distinct histological subtypes as well as distinct patterns of gene expression, than many other mouse models of tumorigenesis. Two of the major histological subtypes are characterized by differential patterns of cellular signaling pathways, including beta-catenin and Stat3 activities. We also demonstrate that one of the MMTV-Myc mammary tumor subgroups exhibits metastatic capacity and that the signature derived from the subgroup can predict metastatic potential of human breast cancer. Together, these data reveal that a combination of histological and genomic analyses can uncover substantial heterogeneity in mammary tumor formation and therefore highlight aspects of tumor phenotype not evident in the population as a whole. PMID:19805309

Andrechek, Eran R; Cardiff, Robert D; Chang, Jeffrey T; Gatza, Michael L; Acharya, Chaitanya R; Potti, Anil; Nevins, Joseph R

2009-09-22

137

Gene expression array analyses predict increased proto-oncogene expression in MMTV induced mammary tumors.  

Science.gov (United States)

Exogenous infection by milk-borne mouse mammary tumor viruses (MMTV) typically induce mouse mammary tumors in genetically susceptible mice at a rate of 90-95% by 1 year of age. In contrast to other transforming retroviruses, MMTV acts as an insertional mutagen and under the influence of steroid hormones induces oncogenic transformation after insertion into the host genome. As these events correspond with increases in adjacent proto-oncogene transcription, we used expression array profiling to determine which commonly associated MMTV insertion site proto-oncogenes were transcriptionally active in MMTV induced mouse mammary tumors. To verify our gene expression array results we developed real-time quantitative RT-PCR assays for the common MMTV insertion site genes found in RIII/Sa mice (int-1/wnt-1, int-2/fgf-3, int-3/Notch 4, and fgf8/AIGF) as well as two genes that were consistently up regulated (CCND1, and MAT-8) and two genes that were consistently down regulated (FN1 and MAT-8) in the MMTV induced tumors as compared to normal mammary gland. Finally, each tumor was also examined histopathologically. Our expression array findings support a model whereby just one or a few common MMTV insertions into the host genome sets up a dominant cascade of events that leave a characteristic molecular signature. PMID:16469401

Popken-Harris, Pamela; Kirchhof, Nicole; Harrison, Ben; Harris, Lester F

2006-08-01

138

Activation of int-1 and int-2 loci in GRf mammary tumors.  

Science.gov (United States)

The Mtv-2 locus is known to be associated with a high mammary tumor incidence (97%) and early development of mammary tumors (3-13 months) in GR mice. However, it was not previously known whether the provirus which resides at the Mtv-2 locus is tumorigenic in and of itself or whether reintegration of proviruses generated from Mtv-2 is required for tumorigenesis. Foster-nursing GR mice on C57/BL mice eliminates the milk-borne source of GR virus, and allows the study of Mtv-2 derived proviruses alone. Using this approach, we have tested predictions which follow from the "positional" versus "reintegrational" models of tumorigenesis. Specifically, we have examined tumors from primary foster-nursed (GRf) mice to determine if MMTV proviruses derived from Mtv-2 were scattered randomly throughout the genome or were clustered in the vicinity of the int-1 and int-2 loci, which are thought to be associated with mammary tumorigenesis. It was found that the majority of spontaneous GRf mammary tumors that were tested have MMTV proviral integrations in either or both of the int-1 and int-2 loci and have transcription of either or both of the int loci. Tumors induced by Mtv-2, therefore, appear to have arisen via a mechanism similar to the activation of the int loci by exogenous (milk-borne) MMTV proviruses. PMID:3020781

Gray, D A; Jackson, D P; Percy, D H; Morris, V L

1986-10-30

139

?-Tocotrienol Oxazine Derivative Antagonizes Mammary Tumor Cell Compensatory Response to CoCl2-Induced Hypoxia  

Science.gov (United States)

In response to low oxygen supply, cancer cells elevate production of HIF-1?, a hypoxia-inducible transcription factor that subsequently acts to stimulate blood vessel formation and promote survival. Studies were conducted to determine the role of ?-tocotrienol and a semisynthetic ?-tocotrienol oxazine derivative, compound 44, on +SA mammary tumor cell hypoxic response. Treatment with 150?µM CoCl2 induced a hypoxic response in +SA mammary tumor cells as evidenced by a large increase in HIF-1? levels, and combined treatment with compound 44 attenuated this response. CoCl2-induced hypoxia was also associated with a large increase in Akt/mTOR signaling, activation of downstream targets p70S6K and eIF-4E1, and a significant increase in VEGF production, and combined treatment with compound 44 blocked this response. Additional in vivo studies showed that intralesional treatment with compound 44 in BALB/c mice bearing +SA mammary tumors significantly decreased the levels of HIF-1?, and this effect was associated with a corresponding decrease in Akt/mTOR signaling and activation of downstream targets p70S6kinase and eIF-4E1. These findings demonstrate that treatment with the ?-tocotrienol oxazine derivative, compound 44, significantly attenuates +SA mammary tumor cell compensatory responses to hypoxia and suggests that this compound may provide benefit in the treatment of rapidly growing solid breast tumors. PMID:25140303

Ananthula, Suryatheja; Parajuli, Parash; Behery, Fathy A.; Alayoubi, Alaadin Y.; Nazzal, Sami; El Sayed, Khalid; Sylvester, Paul W.

2014-01-01

140

Analysis of tumor heterogeneity and cancer gene networks using deep sequencing of MMTV-induced mouse mammary tumors.  

Science.gov (United States)

Cancer develops through a multistep process in which normal cells progress to malignant tumors via the evolution of their genomes as a result of the acquisition of mutations in cancer driver genes. The number, identity and mode of action of cancer driver genes, and how they contribute to tumor evolution is largely unknown. This study deployed the Mouse Mammary Tumor Virus (MMTV) as an insertional mutagen to find both the driver genes and the networks in which they function. Using deep insertion site sequencing we identified around 31000 retroviral integration sites in 604 MMTV-induced mammary tumors from mice with mammary gland-specific deletion of Trp53, Pten heterozygous knockout mice, or wildtype strains. We identified 18 known common integration sites (CISs) and 12 previously unknown CISs marking new candidate cancer genes. Members of the Wnt, Fgf, Fgfr, Rspo and Pdgfr gene families were commonly mutated in a mutually exclusive fashion. The sequence data we generated yielded also information on the clonality of insertions in individual tumors, allowing us to develop a data-driven model of MMTV-induced tumor development. Insertional mutations near Wnt and Fgf genes mark the earliest "initiating" events in MMTV induced tumorigenesis, whereas Fgfr genes are targeted later during tumor progression. Our data shows that insertional mutagenesis can be used to discover the mutational networks, the timing of mutations, and the genes that initiate and drive tumor evolution. PMID:23690930

Klijn, Christiaan; Koudijs, Marco J; Kool, Jaap; ten Hoeve, Jelle; Boer, Mandy; de Moes, Joost; Akhtar, Waseem; van Miltenburg, Martine; Vendel-Zwaagstra, Annabel; Reinders, Marcel J T; Adams, David J; van Lohuizen, Maarten; Hilkens, John; Wessels, Lodewyk F A; Jonkers, Jos

2013-01-01

141

Raloxifene inhibits tumor growth and lymph node metastasis in a xenograft model of metastatic mammary cancer  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background The effects of raloxifene, a novel selective estrogen receptor modulator, were studied in a mouse metastatic mammary cancer model expressing cytoplasmic ER?. Methods Mammary tumors, induced by inoculation of syngeneic BALB/c mice with BJMC3879luc2 cells, were subsequently treated with raloxifene at 0, 18 and 27 mg/kg/day using mini-osmotic pumps. Results In vitro study demonstrated that the ER? in BJMC3879luc2 cells was smaller (between 50 and 64 kDa than the normal-sized ER? (66 kDa and showed cytoplasmic localization. A statistically significant but weak estradiol response was observed in this cell line. When BJMC3879luc2 tumors were implanted into mice, the ER? mRNA levels were significantly higher in females than in males. In vitro studies showed that raloxifene induced mitochondria-mediated apoptosis and cell-cycle arrest in the G1-phase and a decrease in the cell population in the S-phase. In animal experiments, tumor volumes were significantly suppressed in the raloxifene-treated groups. The multiplicity of lymph node metastasis was significantly decreased in the 27 mg/kg group. Levels of apoptosis were significantly increased in the raloxifene-treated groups, whereas the levels of DNA synthesis were significantly decreased in these groups. No differences in microvessel density in tumors were observed between the control and raloxifene-treated groups. The numbers of dilated lymphatic vessels containing intraluminal tumor cells were significantly reduced in mammary tumors in the raloxifene-treated groups. The levels of ER? mRNA in mammary tumors tended to be decreased in the raloxifene-treated groups. Conclusion These results suggest that the antimetastatic activity of raloxifene in mammary cancer expressing cytoplasmic ER? may be a crucial finding with clinical applications and that raloxifene may be useful as an adjuvant therapy and for the chemoprevention of breast cancer development.

Li Zhong-Lian

2010-10-01

142

Immunohistochemical Study Effects of Spirulina Algae on the Induced Mammary Tumor in Rats  

International Nuclear Information System (INIS)

This work aimed at investigating the protective effects of Spirulina platensis on the induced mammary tumor in rats by dimethylbenz(a)anthracene (DMBA) and the proliferation of the tumor cells by using immunohistochemical staining for proliferating cell nuclear antigen (PCNA). At 50 days of age, group 1 remained untreated, group 2 treated with 2% Spirulina platenesis in food, group 3 received 50 mg/kg DMBA i.p. groupe 4 received 50 mg/kg DMBA i.p and fed on 2% spirulina. Rats were killed when the largest mammary tumor reached 1-2 cm in diameter or after 6 months of animal>s age. All the tumors produced by DMBA were ductal carcinoma in 100% of group 3, but in group 4 two rats had mammary tumor. The groups 1 and 2 had no tumor and have the same histological and immunostaining features, but in group 4, 13/15 rats had no tumor except formation of some cysts and hyperplasia in epithelial cells. The conclusion of this work suggests that Spirulina platnesis could be considered as a chemotherapeutic agent that causes apoptosis to tumor cells by reducing the number of malignant cells and resists cancer formation. (author)

143

CD13-positive bone marrow-derived myeloid cells promote angiogenesis, tumor growth, and metastasis  

Science.gov (United States)

Angiogenesis is fundamental to tumorigenesis and an attractive target for therapeutic intervention against cancer. We have recently demonstrated that CD13 (aminopeptidase N) expressed by nonmalignant host cells of unspecified types regulate tumor blood vessel development. Here, we compare CD13 wild-type and null bone marrow-transplanted tumor-bearing mice to show that host CD13+ bone marrow-derived cells promote cancer progression via their effect on angiogenesis. Furthermore, we have identified CD11b+CD13+ myeloid cells as the immune subpopulation directly regulating tumor blood vessel development. Finally, we show that these cells are specifically localized within the tumor microenvironment and produce proangiogenic soluble factors. Thus, CD11b+CD13+ myeloid cells constitute a population of bone marrow-derived cells that promote tumor progression and metastasis and are potential candidates for the development of targeted antiangiogenic drugs. PMID:24297924

Dondossola, Eleonora; Rangel, Roberto; Guzman-Rojas, Liliana; Barbu, Elena M.; Hosoya, Hitomi; St. John, Lisa S.; Molldrem, Jeffrey J.; Corti, Angelo; Sidman, Richard L.; Arap, Wadih; Pasqualini, Renata

2013-01-01

144

Matrix-degrading proteases and angiogenesis during development and tumor formation.  

Science.gov (United States)

Embryonic development and tumor progression both require the exquisite coordination of programs for extracellular matrix (ECM) formation and remodeling, and those for angiogenesis and vascular development. Without a vascular supply the normal tissue or tumor is limited in size and organization. Without ECM remodeling the alteration of tissue and tumor boundaries and cellular migrations are limited. Recent insights into the molecular mechanisms regulating the extracellular environment of the growing embryonic tissue or tumors have implicated proteases, the matrix metalloproteinases (MMPs) in particular, in both the process of ECM remodeling and angiogenesis, and in a potential causal relationship between these processes. This review focuses on the roles that MMPs play in regulating three processes in which both proteolysis and vascular development are tightly coordinated: embryo implantation, bone development and tumor progression. PMID:10190275

Werb, Z; Vu, T H; Rinkenberger, J L; Coussens, L M

1999-01-01

145

Halofuginone Inhibits Angiogenesis and Growth in Implanted Metastatic Rat Brain Tumor Model-an MRI Study  

Directory of Open Access Journals (Sweden)

Full Text Available Tumor growth and metastasis depend on angiogenesis; therefore, efforts are made to develop specific angiogenic inhibitors. Halofuginone (HF is a potent inhibitor of collagen type ?1(I. In solid tumor models, HF has a potent antitumor and antiangiogenic effect in vivo, but its effect on brain tumors has not yet been evaluated. By employing magnetic resonance imaging (MRI, we monitored the effect of HF on tumor progression and vascularization by utilizing an implanted malignant fibrous histiocytoma metastatic rat brain tumor model. Here we demonstrate that treatment with HF effectively and dose-dependently reduced tumor growth and angiogenesis. On day 13, HF-treated tumors were fivefold smaller than control (P < .001. Treatment with HF significantly prolonged survival of treated animals (142%; P = .001. In HF-treated rats, tumor vascularization was inhibited by 30% on day 13 and by 37% on day 19 (P < .05. Additionally, HF treatment inhibited vessel maturation (P = .03. Finally, in HF-treated rats, we noticed the appearance of a few clusters of satellite tumors, which were distinct from the primary tumor and usually contained vessel cores. This phenomenon was relatively moderate when compared to previous reports of other antiangiogenic agents used to treat brain tumors. We therefore conclude that HF is effective for treatment of metastatic brain tumors.

Rinat Abramovitch

2004-09-01

146

Lysyl Oxidase Plays a Critical Role in Endothelial Cell Stimulation to Drive Tumor Angiogenesis  

DEFF Research Database (Denmark)

Identification of key molecules that drive angiogenesis is critical for the development of new modalities for the prevention of solid tumor progression. Using multiple models of colorectal cancer, we show that activity of the extracellular matrix-modifying enzyme lysyl oxidase (LOX) is essential for stimulating endothelial cells in vitro and angiogenesis in vivo. We show that LOX activates Akt through platelet-derived growth factor receptor ß (PDGFRß) stimulation, resulting in increased VEGF expression. LOX-driven angiogenesis can be abrogated through targeting LOX directly or using inhibitors of PDGFRß, Akt, and VEGF signaling. Furthermore, we show that LOX is clinically correlated with VEGF expression and blood vessel formation in 515 colorectal cancer patient samples. Finally, we validate our findings in a breast cancer model, showing the universality of these observations. Taken together, our findings have broad clinical and therapeutic implications for a wide variety of solid tumor types. Cancer Res; 73(2); 1-12. ©2012 AACR.

Baker, Ann-Marie; Bird, Demelza

2013-01-01

147

Morinda citrifolia (Noni) Juice Augments Mammary Gland Differentiation and Reduces Mammary Tumor Growth in Mice Expressing the Unactivated c-erbB2 Transgene  

OpenAIRE

Morinda citrifolia (noni) is reported to have many beneficial properties, including on immune, inflammatory, quality of life, and cancer endpoints, but little is known about its ability to prevent or treat breast cancer. To test its anticancer potential, the effects of Tahitian Noni Juice (TNJ) on mammary carcinogenesis were examined in MMTV-neu transgenic mice. Mammary tumor latency, incidence, multiplicity, and metastatic incidence were unaffected by TNJ treatment, which suggests that it wo...

Witt-enderby, Paula A.; Davis, Vicki L.; Foster, Warren G.; King, Tracy L.; Kotlarczyk, Mary P.; Mark Cline, J.; Clafshenkel, William P.

2012-01-01

148

Obesity decreases serum selenium levels in DMBA-induced mammary tumor using Obese Zucker Rat Model  

Science.gov (United States)

Recently, we reported that obese Zucker rats had increased susceptibility to DMBA-induced mammary tumors compared to lean Zucker rats. Several studies suggest that lower serum selenium may play an important role in increasing the risk of several types of cancers (e.g, colon, breast and prostate canc...

149

Proteoglycans in Cancer Biology, Tumor Microenvironment and Angiogenesis  

OpenAIRE

Proteoglycans, key molecular effectors of cell surface and pericellular microenvironments, perform multiple functions in cancer and angiogenesis by virtue of their polyhedric nature and their ability to interact with both ligands and receptors that regulate neoplastic growth and neovascularization. Some proteoglycans such as perlecan, have pro- and anti-angiogenic activities, whereas other proteoglycans, such as syndecan and glypican, can also directly affect cancer growth by modulating key s...

Iozzo, Renato V.; Sanderson, Ralph D.

2011-01-01

150

Amino acid deprivation promotes tumor angiogenesis through the GCN2/ATF4 pathway.  

Science.gov (United States)

As tumors continue to grow and exceed their blood supply, nutrients become limited leading to deficiencies in amino acids (AAD), glucose (GD), and oxygen (hypoxia). These alterations result in significant changes in gene expression. While tumors have been shown to overcome the stress associated with GD or hypoxia by stimulating vascular endothelial growth factor (VEGF)-mediated angiogenesis, the role of AAD in tumor angiogenesis remains to be elucidated. We found that in human tumors, the expression of the general control non-derepressible 2 (GCN2, an AAD sensor) kinase is elevated at both protein and mRNA levels. In vitro studies revealed that VEGF expression is universally induced by AAD treatment in all five cell lines tested (five of five). This is in contrast to two other angiogenesis mediators interleukin-6 (two of five) and fibroblast growth factor 2 (two of five) that have a more restricted expression. Suppressing GCN2 expression significantly decreased AAD-induced VEGF expression. Silencing activating transcription factor 4 (ATF4), a downstream transcription factor of the GCN2 signaling pathway, is also associated with strong inhibition of AAD-induced VEGF expression. PKR-like kinase, the key player in GD-induced unfolded protein response is not involved in this process. In vivo xenograft tumor studies in nonobese diabetic/severe combined immunodeficient mice confirmed that knockdown of GCN2 in tumor cells retards tumor growth and decreases tumor blood vessel density. Our results reveal that the GCN2/ATF4 pathway promotes tumor growth and angiogenesis through AAD-mediated VEGF expression and, thus, is a potential target in cancer therapy. PMID:23908598

Wang, Yugang; Ning, Yu; Alam, Goleeta N; Jankowski, Brandon M; Dong, Zhihong; Nör, Jacques E; Polverini, Peter J

2013-08-01

151

Amino Acid Deprivation Promotes Tumor Angiogenesis through the GCN2/ATF4 Pathway  

Directory of Open Access Journals (Sweden)

Full Text Available As tumors continue to grow and exceed their blood supply, nutrients become limited leading to deficiencies in amino acids (AAD, glucose (GD, and oxygen (hypoxia. These alterations result in significant changes in gene expression. While tumors have been shown to overcome the stress associated with GD or hypoxia by stimulating vascular endothelial growth factor (VEGF-mediated angiogenesis, the role of AAD in tumor angiogenesis remains to be elucidated. We found that in human tumors, the expression of the general control non-derepressible 2 (GCN2, an AAD sensor kinase is elevated at both protein and mRNA levels. In vitro studies revealed that VEGF expression is universally induced by AAD treatment in all five cell lines tested (five of five. This is in contrast to two other angiogenesis mediators interleukin-6 (two of five and fibroblast growth factor 2 (two of five that have a more restricted expression. Suppressing GCN2 expression significantly decreased AAD-induced VEGF expression. Silencing activating transcription factor 4 (ATF4, a downstream transcription factor of the GCN2 signaling pathway, is also associated with strong inhibition of AAD-induced VEGF expression. PKR-like kinase, the key player in GD-induced unfolded protein response is not involved in this process. In vivo xenograft tumor studies in nonobese diabetic/severe combined immunodeficient mice confirmed that knockdown of GCN2 in tumor cells retards tumor growth and decreases tumor blood vessel density. Our results reveal that the GCN2/ATF4 pathway promotes tumor growth and angiogenesis through AAD-mediated VEGF expression and, thus, is a potential target in cancer therapy.

Yugang Wang

2013-08-01

152

Tie2-dependent deletion of ?6 integrin subunit in mice reduces tumor growth and angiogenesis.  

Science.gov (United States)

The ?6 integrin subunit (?6) has been implicated in cancer cell migration and in the progression of several malignancies, but its role in tumor angiogenesis is unclear. In mice, anti-?6 blocking antibodies reduce tumor angiogenesis, whereas Tie1-dependent ?6 gene deletion enhances neovessel formation in melanoma and lung carcinoma. To clarify the discrepancy in these results we used the cre-lox system to generate a mouse line, ?6fl/fl?Tie2Cre(+), with ?6 gene deletion specifically in Tie2-lineage cells: endothelial cells, pericytes, subsets of hematopoietic stem cells, and Tie2-expressing monocytes/macrophages (TEMs), known for their proangiogenic properties. Loss of ?6 expression in ?6fl/fl?Tie2Cre(+) mice reduced tumor growth in a murine B16F10 melanoma model. Immunohistological analysis of the tumors showed that Tie2-dependent ?6 gene deletion was associated with reduced tumor vascularization and with reduced infiltration of proangiogenic Tie2-expressing macrophages. These findings demonstrate that ?6 integrin subunit plays a major role in tumor angiogenesis and TEM infiltration. Targeting ?6 could be used as a strategy to reduce tumor growth. PMID:25176420

Bouvard, Claire; Segaoula, Zacharie; De Arcangelis, Adèle; Galy-Fauroux, Isabelle; Mauge, Laetitia; Fischer, Anne-Marie; Georges-Labouesse, Elisabeth; Helley, Dominique

2014-11-01

153

Mouse mammary tumor virus (MMTV)-like DNA sequences in the breast tumors of father, mother, and daughter  

OpenAIRE

Abstract Background The diagnosis of late onset breast cancer in a father, mother, and daughter living in the same house for decades suggested the possibility of an environmental agent as a common etiological factor. Both molecular and epidemiological data have indicated a possible role for the mouse mammary tumor virus (MMTV), the etiological agent of breast cancer in mice, in a certain percentage of human breast tumors. The aim of this study was to determine if MMTV might be involved in the...

Wiernik Peter H; Fr, Stewart Alexandre; Etkind Polly R

2008-01-01

154

A model of spontaneous mouse mammary tumor for human estrogen receptor- and progesterone receptor-negative breast cancer  

OpenAIRE

Breast cancer (BC) is the most frequently malignancy in women. Therefore, establishment of an animal model for the development of preventative measures and effective treatment for tumors is required. A novel heterogeneous spontaneous mammary tumor animal model of Kunming mice was generated. The purpose of this study was to characterize the spontaneous mammary tumor model. Histopathologically, invasive nodular masses of pleomorphic tubular neoplastic epithelial cells invaded fibro-vascular str...

Zheng, Lixiang; Zhou, Bugao; Meng, Xianming; Zhu, Weifeng; Zuo, Airen; Wang, Xiaomin; Jiang, Runde; Yu, Shiping

2014-01-01

155

Control of Tumor Growth in Animals by Infusion of an Angiogenesis Inhibitor  

Science.gov (United States)

Angiogenesis and tumor growth were inhibited in two different animal models by regional infusion of a partially purified cartilage extract. In rabbits bearing corneal implants of V2 carcinoma and receiving the inhibitor, vascular growth rates were animals receiving either Ringer's solution or bovine trypsin inhibitor (Trasylol). Subconjunctival B16 melanoma implants in mice receiving the inhibitor weighed tests revealed no toxic effects in any of the animals. The inhibitor did not retard the growth of either tumor cell type in tissue culture at concentrations as high as 1 mg/ml. These results suggest that the cartilage factor does not interfere with the growth of the tumor cell population directly but that it prevents tumor growth by inhibiting angiogenesis.

Langer, Robert; Conn, Howard; Vacanti, Joseph; Haudenschild, Christian; Folkman, Judah

1980-07-01

156

Assessment of high-intensity focused ultrasound treatment of rodent mammary tumors using ultrasound backscatter coefficients  

OpenAIRE

Fischer 344 rats with subcutaneous mammary adenocarcinoma tumors were exposed to therapeutic ultrasound at one of three exposure levels (335, 360, and 502?W/cm2 spatial-peak temporal-average intensity). Quantitative ultrasound estimates were generated from ultrasound radio frequency (RF) data from tumors before and after high-intensity focused ultrasound treatment. Treatment outcome was independently assessed by triphenyl tetrazolium chloride (TTC) staining, histological analysis by a patho...

Kemmerer, Jeremy P.; Ghoshal, Goutam; Karunakaran, Chandra; Oelze, Michael L.

2013-01-01

157

Transcriptional profiling of human mammary carcinoma cell lines reveals PKW, a new tumor-specific gene.  

Science.gov (United States)

In order to identify genes associated with distinct stages of mammary carcinoma we have investigated the transcriptional profile of normal mammary gland epithelial cells, cell lines derived from primary tumors, from bone marrow micrometastases and from ascites fluid. mRNA's for ribosomal protein L41 and URIM (Up-Regulated In Metastasis) were consistently increased in all cells derived from metastatic lesions. mRNA for human secreted frizzled-related protein (hsFRP) was found to be dramatically down-regulated in all mammary tumor cells compared to non-transformed mammary gland epithelial cells. mRNA for Human Hypoxia Related Factor--2 (HRF-2) and a transcript including the human mitochondrial control region were significantly overexpressed in the cell lines derived from primary tumors and ascites fluid. A new gene, referred to as PKW, was only expressed in one of the primary tumor cell lines, the one derived from a medullary carcinoma. The small and the large transcript which are derived by differential splicing encode potential proteins comprising 95 aa and 130 aa, sharing 88 aa at the N-terminus. The IEP's suggest a nuclear localization of the proteins. Surprisingly mRNA for the new gene was detected only in the salivary gland, but not in other adult human tissues and a restricted panel of embryonic tissues. The same holds true for a panel of human tumor cell lines and cell lines derived from ductal mammary carcinoma. RT-PCR revealed expression of PKW in 4 out of 11 breast carcinomas. PMID:10953283

Preiherr, J; Hildebrandt, T; Klostermann, S; Eberhardt, S; Kaul, S; Weidle, U H

2000-01-01

158

Upregulation of HYAL1 Expression in Breast Cancer Promoted Tumor Cell Proliferation, Migration, Invasion and Angiogenesis  

OpenAIRE

Hyaluronic acid (HA) is a component of the Extra-cellular matrix (ECM), it is closely correlated with tumor cell growth, proliferation, metastasis and angiogenesis, etc. Hyaluronidase (HAase) is a HA-degrading endoglycosidase, levels of HAase are elevated in many cancers. Hyaluronidase-1 (HYAL1) is the major tumor-derived HAase. We previously demonstrated that HYAL1 were overexpression in human breast cancer. Breast cancer cells with higher HAase expression, exhibited significantly higher inv...

Tan, Jin-xiang; Wang, Xiao-yi; Su, Xin-liang; Li, Hong-yuan; Shi, Yuan; Wang, Liang; Ren, Guo-sheng

2011-01-01

159

Morphine Suppresses Tumor Angiogenesis through a HIF-1?/p38MAPK Pathway  

OpenAIRE

Morphine, a highly potent analgesic agent, is frequently prescribed for moderate to severe cancer pain. In this study, morphine was administered at a clinically relevant analgesic dose to assess tumor cell-induced angiogenesis and subcutaneous tumor growth in nude mice using mouse Lewis lung carcinoma cells (LLCs). Implantation of mice with a continuous slow-release morphine pellet achieved morphine plasma levels within 250–400 ng/ml (measured using a radioimmunoassay, Coat-A-Count Serum Mo...

Koodie, Lisa; Ramakrishnan, Sundaram; Roy, Sabita

2010-01-01

160

Inhibition of telomerase in the endothelial cells disrupts tumor angiogenesis in glioblastoma xenografts.  

Science.gov (United States)

Tumor angiogenesis is a complex process that involves a series of interactions between tumor cells and endothelial cells (ECs). In vitro, glioblastoma multiforme (GBM) cells are known to induce an increase in proliferation, migration and tube formation by the ECs. We have previously shown that in human GBM specimens the proliferating ECs of the tumor vasculature express the catalytic component of telomerase, hTERT, and that telomerase can be upregulated in human ECs by exposing these cells to GBM in vitro. Here, we developed a controlled in vivo assay of tumor angiogenesis in which primary human umbilical vascular endothelial cells (HUVECs) were subcutaneously grafted with or without human GBM cells in immunocompromised mice as Matrigel implants. We found that primary HUVECs did not survive in Matrigel implants, and that telomerase upregulation had little effect on HUVEC survival. In the presence of GBM cells, however, the grafted HUVECs not only survived in Matrigel implants but developed tubule structures that integrated with murine microvessels. Telomerase upregulation in HUVECs enhanced such effect. More importantly, inhibition of telomerase in HUVECs completely abolished tubule formation and greatly reduced survival of these cells in the tumor xenografts. Our data demonstrate that telomerase upregulation by the ECs is a key requisite for GBM tumor angiogenesis. PMID:18027853

Falchetti, Maria Laura; Mongiardi, Maria Patrizia; Fiorenzo, Paolo; Petrucci, Giovanna; Pierconti, Francesco; D'Agnano, Igea; D'Alessandris, Giorgio; Alessandri, Giulio; Gelati, Maurizio; Ricci-Vitiani, Lucia; Maira, Giulio; Larocca, Luigi Maria; Levi, Andrea; Pallini, Roberto

2008-03-15

161

Interspecies radioimmunoassay for the major internal protein of mammary tumor viruses  

Energy Technology Data Exchange (ETDEWEB)

An interspecies radioimmunoassay was developed which detects antigenic determinants shared by type-B mammary tumor viruses (MTVs). This interspecies assay is specific for antigenic sites which the 28,000-dalton major internal protein of MMTVs of laboratory mice (Mus musculus) has in common with polypeptides of MC-MTV. MC-MTV is a new type-B retrovirus isolated from the Asian rodent. Mus cervicolor. Other retrovirus isolates of Mus cervicolor, i.e., M432, CERV-CI, and CERV-CII, as well as other type-C and type-D retroviruses, do not compete in the interspecies assay. The interspecies assay detected MTV cross-reactive antigenic determinants with equal efficiency in milks, lactating mammary glands, and in spontaneous mammary tumors of three distinct species. Particles morphologically indistinguishable from MMTV and MC-MTV have also been detected in Mus cookii mammary tumor cells. The interspecies MTV p28 radioimmunoassay thus provides a potentially useful tool for the detection of etiologically related viruses or viral translational products in species other than the laboratory mouse.

Hand, P.H.; Teramoto, Y.A.; Callahan, R.; Schlom, J.

1980-02-01

162

Interspecies radioimmunoassay for the major internal protein of mammary tumor viruses  

International Nuclear Information System (INIS)

An interspecies radioimmunoassay was developed which detects antigenic determinants shared by type-B mammary tumor viruses (MTVs). This interspecies assay is specific for antigenic sites which the 28,000-dalton major internal protein of MMTVs of laboratory mice (Mus musculus) has in common with polypeptides of MC-MTV. MC-MTV is a new type-B retrovirus isolated from the Asian rodent. Mus cervicolor. Other retrovirus isolates of Mus cervicolor, i.e., M432, CERV-CI, and CERV-CII, as well as other type-C and type-D retroviruses, do not compete in the interspecies assay. The interspecies assay detected MTV cross-reactive antigenic determinants with equal efficiency in milks, lactating mammary glands, and in spontaneous mammary tumors of three distinct species. Particles morphologically indistinguishable from MMTV and MC-MTV have also been detected in Mus cookii mammary tumor cells. The interspecies MTV p28 radioimmunoassay thus provides a potentially useful tool for the detection of etiologically related viruses or viral translational products in species other than the laboratory mouse

163

c-erbB-2 expression and nuclear pleomorphism in canine mammary tumors  

Directory of Open Access Journals (Sweden)

Full Text Available The objective of the present investigation was to study the expression of c-erbB-2 and MIB-1 and try to associate them with morphological features of the cell such as nuclear pleomorphism, mitotic count and histological grade in a series of 70 canine mammary gland tumors, 22 of them benign and 48 malignant. Tumors were collected at the Veterinary Hospital of UFMG (Brazil and the Veterinary Faculty of Porto University (Portugal. c-erbB-2 expression was determined according to the guidelines provided by the manufacturer of the HercepTest system and nuclear pleomorphism, mitotic count and histological grade according the Elston and Ellis grading system. The HercepTest is the FDA-approved in vitro diagnostic test marketed by Dako. It is a semi-quantitative immunohistochemical assay used to determine overexpression of HER2 protein (human epidermal growth factor receptor in breast cancer tissue. MIB-1 expression was also evaluated in 28 malignant tumors. Seventeen (35.4% of the malignant tumors were positive for c-erbB-2 expression, which was positively associated with nuclear pleomorphism (P < 0.0001, histological grade (P = 0.0017 and mitotic count (P < 0.05. Nuclear pleomorphism also showed a positive association with MIB-1 index (P < 0.0001. These results suggest that some of the biological and morphological characteristics of the tumor are associated in canine mammary gland tumors, as also reported for human breast cancer. It was also possible to show that the immunoexpression of c-erbB-2 can be a factor in mammary carcinogenesis. This fact opens the possibility of using anti-c-erbB-2 antibodies in the treatment of canine mammary tumors.

Dutra A.P.

2004-01-01

164

PET imaging of tumor angiogenesis in mice with VEGF-A targeted 86Y-CHX-A?-DTPA-bevacizumab  

OpenAIRE

Bevacizumab is a humanized monoclonal antibody that binds to tumor-secreted VEGF-A and inhibits tumor angiogenesis. In 2004, the antibody was approved by the United States FDA for the treatment of metastatic colorectal carcinoma in combination with chemotherapy. This report describes the preclinical evaluation of a radioimmunoconjugate, 86Y-CHX-A?-DTPA-bevacizumab, for potential use in PET imaging of VEGF-A tumor angiogenesis and as a surrogate marker for 90Y based radioimmunotherapy. Bevac...

Nayak, Tapan K.; Garmestani, Kayhan; Baidoo, Kwamena E.; Milenic, Diane E.; Brechbiel, Martin W.

2011-01-01

165

Metronomic chemotherapy and anti-angiogenesis: can upgraded pre-clinical assays improve clinical trials aimed at controlling tumor growth?  

OpenAIRE

Metronomic chemotherapy, which is continuously administered systemically at close to non-toxic doses, targets the endothelial cells (ECs) that are proliferating during tumor angiogenesis. This leads to harmful effects of an even greatly increased number contiguous tumor cells. Although pre-clinical studies of angiogenesis-related EC features in vitro and of the anti-angiogenic and anti-tumor effects in vivo of metronomic chemotherapy have provided valuable insights, clinical trials with this ...

Norrby, Klas

2013-01-01

166

Comparative characteristics of mammary glands cancer in humans and animals  

Directory of Open Access Journals (Sweden)

Full Text Available

 

This review is devoted to a comparative analysis of receptor status, immunity, angiogenesis, metastatic mammal glands cancer expression profiling in humans and animals. Angiogenesis has been assessed by quantitative and immunohistochemical characteristics by means of evaluation of microvascular density (MVD using Claudin-5 (CLDN-5 as a marker of vascular endothelium in tumors of mammary glands in dogs.

Vorobyova ?.V.

2012-09-01

167

Mouse mammary-tumor virus activates Fgf-3/Int-2 less frequently in tumors from virgin than from parous mice.  

Science.gov (United States)

Tumorigenesis by mouse mammary-tumor virus (MMTV) involves proviral disruption and transcriptional activation of a number of cellular oncogenes, generically termed Int. The frequencies with which different Int genes are activated in different mouse strains can be quite variable, and previous surveys have suggested that insertions at Int-2/Fgf-3 occur primarily in strains that develop pregnancy-dependent mammary tumors. To address this issue, we have determined the relative contributions of 5 known Int genes (Wnt-1, Wnt-3, Fgf-3, Fgf-4 and Int-3) in mammary tumors from virgin BR6 and multiparous BR6, BALB/cfBR6 and RIII mice. Whereas Fgf-3 was implicated in 66%, 80% and 92% of the tumors from the respective parous animals, only 20% of the tumors from virgin mice expressed Fgf-3. This reduced involvement of Fgf-3 was compensated by proviral insertions in Fgf-4, Int-3 and Wnt-3, but the frequency of Wnt-1 activation was relatively constant. These data strengthen the link between Fgf-3 and a pregnancy-dependent phenotype and suggest that, in the strains analyzed, the frequency of Int-gene activation was influenced more by the hormonal status than by the genetic background. PMID:8393839

Clausse, N; Smith, R; Calberg-Bacq, C M; Peters, G; Dickson, C

1993-08-19

168

RANK Overexpression in Transgenic Mice with Mouse Mammary Tumor Virus Promoter-Controlled RANK Increases Proliferation and Impairs Alveolar Differentiation in the Mammary Epithelia and Disrupts Lumen Formation in Cultured Epithelial Acini? †  

OpenAIRE

RANK and RANKL, the key regulators of osteoclast differentiation and activation, also play an important role in the control of proliferation and differentiation of mammary epithelial cells during pregnancy. Here, we show that RANK protein expression is strictly regulated in a spatial and temporal manner during mammary gland development. RANK overexpression under the control of the mouse mammary tumor virus (MMTV) promoter in a transgenic mouse model results in increased mammary epithelial cel...

Gonzalez-suarez, Eva; Branstetter, Daniel; Armstrong, Allison; Dinh, Huyen; Blumberg, Hal; Dougall, William C.

2006-01-01

169

Depletion of ascorbic acid restricts angiogenesis and retards tumor growth in a mouse model.  

Science.gov (United States)

Angiogenesis requires the deposition of type IV collagen by endothelial cells into the basement membrane of new blood vessels. Stabilization of type IV collagen triple helix depends on the hydroxylation of proline, which is catalyzed by the iron-containing enzyme prolyl hydroxylase. This enzyme, in turn, requires ascorbic acid to maintain the enzyme-bound iron in its reduced state. We hypothesized that dietary ascorbic acid might be required for tumor angiogenesis and, therefore, tumor growth. Here, we show that, not surprisingly, ascorbic acid is necessary for the synthesis of collagen type IV by human endothelial cells and for their effective migration and tube formation on a basement membrane matrix. Furthermore, ascorbic acid depletion in mice incapable of synthesizing ascorbic acid (Gulo(-/-)) dramatically restricts the in vivo growth of implanted Lewis lung carcinoma tumors. Histopathological analyses of these tumors reveal poorly formed blood vessels, extensive hemorrhagic foci, and decreased collagen and von Willebrand factor expression. Our data indicate that ascorbic acid plays an essential role in tumor angiogenesis and growth, and that restriction of ascorbic acid or pharmacological inhibition of prolyl hydroxylase may prove to be novel therapeutic approaches to the treatment of cancer. PMID:17325743

Telang, Sucheta; Clem, Amy L; Eaton, John W; Chesney, Jason

2007-01-01

170

Depletion of Ascorbic Acid Restricts Angiogenesis and Retards Tumor Growth in a Mouse Model  

Directory of Open Access Journals (Sweden)

Full Text Available Angiogenesis requires the deposition of type IV collagen by endothelial cells into the basement membrane of new blood vessels. Stabilization of type IV collagen triple helix depends on the hydroxylation of proline, which is catalyzed by the iron-containing enzyme prolyl hydroxylase. This enzyme, in turn, requires ascorbic acid to maintain the enzyme-bound iron in its reduced state. We hypothesized that dietary ascorbic acid might be required for tumor angiogenesis and, therefore, tumor growth. Here, we show that, not surprisingly, ascorbic acid is necessary for the synthesis of collagen type IV by human endothelial cells and for their effective migration and tube formation on a basement membrane matrix. Furthermore, ascorbic acid depletion in mice incapable of synthesizing ascorbic acid (Gulo-/- dramatically restricts the in vivo growth of implanted Lewis lung carcinoma tumors. Histopathological analyses of these tumors reveal poorly formed blood vessels, extensive hemorrhagic foci, and decreased collagen and von Willebrand factor expression. Our data indicate that ascorbic acid plays an essential role in tumor angiogenesis and growth, and that restriction of ascorbic acid or pharmacological inhibition of prolyl hydroxylase may prove to be novel therapeutic approaches to the treatment of cancer.

Sucheta Telang

2007-01-01

171

Extramedullary hematopoiesis in a case of benign mixed mammary tumor in a female dog: cytological and histopathological assessment  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Backgroud Extramedullary hematopoiesis (EMH is defined as the presence of hematopoietic stem cells such as erythroid and myeloid lineage plus megakaryocytes in extramedullary sites like liver, spleen and lymph nodes and is usually associated with either bone marrow or hematological disorders. Mammary EMH is a rare condition either in human and veterinary medicine and can be associated with benign mixed mammary tumors, similarly to that described in this case. Case presentation Hematopoietic stem cells were found in a benign mixed mammary tumor of a 7-year-old female mongrel dog that presents a nodule in the left inguinal mammary gland. The patient did not have any hematological abnormalities. Cytological evaluation demonstrated two distinct cell populations, composed of either epithelial or mesenchymal cells, sometimes associated with a fibrillar acidophilic matrix, apart from megakaryocytes, osteoclasts, metarubricytes, prorubricytes, rubricytes, rubriblasts, promyelocytes, myeloblasts. Histological examination confirmed the presence of an active hematopoietic bone marrow within the bone tissue of a benign mammary mixed tumor. Conclusions EMH is a rare condition described in veterinary medicine that can be associated with mammary mixed tumors. It's detection can be associated with several neoplastic and non-neoplastic mammary lesions, i.e. osteosarcomas, mixed tumors and bone metaplasia.

Leão João

2010-09-01

172

Enhanced radiosensitivity of rat autochthonous mammary tumors by dietary docosahexaenoic acid.  

Science.gov (United States)

Dietary docosahexaenoic acid (DHA), which integrates into tumor cell membranes, has been reported to enhance the efficacy against tumors of cytotoxic drugs that induce reactive oxygen species (ROS). Because ionizing radiation also generate ROS, we initiated a study to determine whether dietary DHA might sensitize mammary tumors to irradiation. Mammary tumors were induced by N-methylnitrosourea (NMU) in Sprague-Dawley rats. The optimal dose of radiation to examine the effect of DHA on tumor response to irradiation was determined to be 18 grays (Gy) using a 4-6 MeV electron beam (according to the depth of the target volume) delivered in a single fraction from a linear accelerator. Two groups of rats were fed a basal diet containing 7% of a mixture of peanut and rapeseed oils enriched with 8% of an oil containing either a low (palm oil) or high (DHASCO oil containing 40% DHA) DHA content. DHA group was equally subdivided into 2 groups without or with addition of vitamin E (100 IU/kg diet). Irradiation was carried out when the first tumor in each rat reached 1.5 cm2 and subsequent change in tumor size was documented over time. DHA level in adipose tissue, taken as a biomarker, was higher in the DHA supplemented group compared to the control group. Vitamin E level in liver, the best storage for this compound, was higher in the vitamin E supplemented DHA group compared to the DHA group. Tumor size decreased by 60% at 12 days after irradiation in the DHA group vs. 31% in the control group (p = 0.03) and 36% in the DHA plus vitamin E group. Therefore, dietary DHA sensitized mammary tumors to radiation. The addition of vitamin E inhibited the beneficial effect of DHA, suggesting that this effect might be mediated by oxidative damage to the peroxidizable lipids. PMID:14961586

Colas, Séverine; Paon, Lénaic; Denis, Fabrice; Prat, Marie; Louisot, Pascal; Hoinard, Claude; Le Floch, Olivier; Ogilvie, Gregory; Bougnoux, Philippe

2004-04-10

173

The mechanisms of involvement of IL-1 molecules in tumor-mediated angiogenesis  

Directory of Open Access Journals (Sweden)

Full Text Available Progressively growing tumors emerge from a unique inflammatory microenvironment derived from the interaction between tumor cells and the host. Tumor angiogenesis is one of the hallmarks of tumor progression and is required for invasiveness and metastasis. Myeloid inflammatory cells, such as immature myeloid precursor cells, also termed myeloid-derived suppressor cells (MDSCs, neutrophils and monocytes/macrophages, are recruited to the tumor microenvironment by factors released by the malignant cells that are subsequently “educated” in situ to acquire a pro-invasive and pro-angiogenic, as well as an immunosuppressive phenotype. The proximity of myeloid cells to endothelial cells (EC lining blood vessels suggests that they play an important role in the angiogenic response, possibly via secreting a network of cytokines/chemokines and inflammatory mediators. As VEGF is a major angiogenic factor for tumor progression, attempts were made to block the angiogenic response by using anti-VEGF antibodies, or receptor tyrosine kinase inhibitors. Pro-inflammatory mediators were recently shown to play an important role in tumor-mediated angiogenesis and blocking their function can impair tumor progression. Interleukin-1 (IL-1 is an “alarm”, upstream, pro-inflammatory cytokine that is primarily generated by myeloid cells. IL-1 initiates and propagates inflammation, mainly by inducing a local cytokine network and enhancing inflammatory cell infiltration to affected sites and by augmenting adhesion molecule expression on endothelial cells and leukocytes. In this review, we summarize the involvement of IL-1 in tumor-mediated angiogenesis and discuss the future feasibility of IL-1 neutralization approaches in anti-cancer therapy.

ElenaVoronov

2014-03-01

174

Susceptibility to tumors induced by polyoma virus is conferred by an endogenous mouse mammary tumor virus superantigen  

OpenAIRE

A dominant gene carried in certain inbred mouse strains confers susceptibility to tumors induced by polyoma virus. This gene, designated Pyvs, was defined in crosses between the highly susceptible C3H/BiDa strain and the highly resistant but H-2k-identical C57BR/cdJ strain. The resistance of C57BR/cdJ mice is overcome by irradiation, indicating an immunological basis. In F1 x C57BR/cdJ backcross mice, tumor susceptibility cosegregates with Mtv-7, a mouse mammary tumor provirus carried by the ...

1995-01-01

175

ATRAZINE INCREASES DIMETHYLBENZ[A]ANTHRACENE-INDUCED MAMMARY TUMOR INCIDENCE IN LONG EVANS OFFSPRING EXPOSED IN UTERO  

Science.gov (United States)

ATRAZINE INCREASES DIMETHYLBENZ[A]ANTHRACENE-INDUCED MAMMARY TUMOR INCIDENCE IN LONG EVANS OFFSPRING EXPOSED IN UTERO. SE Fenton and CC Davis Reproductive Toxicology Division, NHEERL, ORD, USEPA, Durham, NC, USA Recently, we found that ATR exposure during ma...

176

Monoclonal antibodies against antigens displayed on a progressively growing mammary tumor.  

OpenAIRE

We have produced lymphocyte hybridomas between mouse myeloma cells and either spleen cells of C3H/f/C57BL/6 mice bearing the Mm5mt/c1 tumor-producing murine mammary tumor virus (MMTV) or spleen cells from Fisher rats inoculated with the same tumor. Two classes of hybridoma-secreted monoclonal antibodies were obtained. In the first class are IVC11, IIIA1, and VE7, each of which precipitated a 52,000-dalton protein from 125I-labeled purified preparations of MMTV and [3H]glucosamine-labeled Mm5m...

Tax, A.; Manson, L. A.

1981-01-01

177

Obesity, expression of adipocytokines, and macrophage infiltration in canine mammary tumors.  

Science.gov (United States)

Obesity influences the development, progression and prognosis of human breast cancer and canine mammary cancer (MC) but the precise underlying mechanism is not well-documented in the fields of either human or veterinary oncology. In the present study, the expression of major adipocytokines, including leptin, adiponectin, and leptin receptor (ObR) in benign (n?=?28) and malignant (n?=?70) canine mammary tumors was investigated by immunohistochemistry and on the basis of the subject's body condition score (BCS). To evaluate the relationship between obesity and chronic inflammation of the mammary gland, macrophages infiltrating within and around tumoral areas were counted. The mean age of MC development was lower in overweight or obese dogs (9.0?±?1.8 years) than in lean dogs or optimal bodyweight (10.2?±?2.9 years), and the evidence of lymphatic invasion of carcinoma cells was found more frequently in overweight or obese group than in lean or optimal groups. Decreased adiponectin expression and increased macrophage numbers in overweight or obese subjects were significantly correlated with factors related to a poor prognosis, such as high histological grade and lymphatic invasion. Leptin expression was correlated with progesterone receptor status, and ObR expression was correlated with estrogen receptor status of MCs, regardless of BCS. Macrophage infiltration within and around the tumor may play an important role in tumor progression and metastasis in obese female dogs and may represent a prognostic factor for canine MCs. PMID:25641553

Lim, H Y; Im, K S; Kim, N H; Kim, H W; Shin, J I; Sur, J H

2015-03-01

178

Nestin in gastrointestinal and other cancers: Effects on cells and tumor angiogenesis  

Directory of Open Access Journals (Sweden)

Full Text Available Nestin is a class VI intermediate filament protein that was originally described as a neuronal stem cell marker during central nervous system (CNS development, and is currently widely used in that capacity. Nestin is also expressed in non-neuronal immature or progenitor cells in normal tissues. Under pathological conditions, nestin is expressed in repair processes in the CNS, muscle, liver, and infarcted myocardium. Furthermore, increased nestin expression has been reported in various tumor cells, including CNS tumors, gastrointestinal stromal tumors, pancreatic cancer, prostate cancer, breast cancer, malignant melanoma, dermatofibrosarcoma protuberances, and thyroid tumors. Nestin is reported to correlate with aggressive growth, metastasis, and poor prognosis in some tumors; however, the roles of nestin in cancer cells have not been well characterized. Furthermore, nestin is more specifically expressed in proliferating small-sized tumor vessels in glioblastoma and gastric, colorectal, and prostate cancers than are other tumor vessel markers. These findings indicate that nestin may be a marker for newly synthesized tumor vessels and a therapeutic target for tumor angiogenesis. It has received a lot of attention recently as a cancer stem cell marker in various cancer cells including brain tumors, malignant rhabdoid tumors, and uterine, cervical, prostate, bladder, head and neck, ovarian, testicular, and pancreatic cancers. The purpose of this review is to clarify the roles of nestin in cancer cells and in tumor angiogenesis, and to examine the association between nestin and cancer stem cells. Nestin has the potential to serve as a molecular target for cancers with nestin-positive cancer cells and nestin-positive tumor vasculature.

Toshiyuki Ishiwata, Yoko Matsuda, Zenya Naito

2011-01-01

179

Two genetically transmitted BALB/c mouse mammary tumor virus genomes located on chromosomes 12 and 16.  

OpenAIRE

We have examined EcoRI-restricted cellular DNA from BALB/c mouse-hamster somatic cell hybrids by blot hybridization for the presence of mouse mammary tumor virus-related sequences. Results of this analysis show that mouse mammary tumor virus-related proviral copies are located on chromosomes 16 (16-kilobase-pair fragment) and 12 (10.5- and 7.7-kilobase-pair fragments).

Callahan, R.; Gallahan, D.; Kozak, C.

1984-01-01

180

Luteolin Inhibits Human Prostate Tumor Growth by Suppressing Vascular Endothelial Growth Factor Receptor 2-Mediated Angiogenesis  

Science.gov (United States)

Angiogenesis, the formation of new blood vessels from pre-existing vascular beds, is essential for tumor growth, invasion, and metastasis. Luteolin is a common dietary flavonoid found in fruits and vegetables. We studied the antiangiogenic activity of luteolin using in vitro, ex vivo, and in vivo models. In vitro studies using rat aortic ring assay showed that luteolin at non-toxic concentrations significantly inhibited microvessel sprouting and proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Luteolin also inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM) and matrigel plug assay. Gelatin zymographic analysis demonstrated the inhibitory effect of luteolin on the activation of matrix metalloproteinases MMP-2 and MMP-9. Western blot analysis showed that luteolin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT, ERK, mTOR, P70S6K, MMP-2, and MMP-9 in HUVECs. Proinflammatory cytokines such as IL-1?, IL-6, IL-8, and TNF-? level were significantly reduced by the treatment of luteolin in PC-3 cells. Luteolin (10 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that luteolin inhibited tumorigenesis by targeting angiogenesis. CD31 and CD34 immunohistochemical staining further revealed that the microvessel density could be remarkably suppressed by luteolin. Moreover, luteolin reduced cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, ERK, mTOR, P70S6K, MMP-2, and MMP-9 expressions. Taken together, our findings demonstrate that luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis. PMID:23300633

Pratheeshkumar, Poyil; Son, Young-Ok; Budhraja, Amit; Wang, Xin; Ding, Songze; Wang, Lei; Hitron, Andrew; Lee, Jeong-Chae; Kim, Donghern; Divya, Sasidharan Padmaja; Chen, Gang; Zhang, Zhuo; Luo, Jia; Shi, Xianglin

2012-01-01

181

Tumores de glándula mamaria en caninos Tumors of mammary gland in canine  

Directory of Open Access Journals (Sweden)

Full Text Available De los animales de compañía, los caninos son los que sufren con mayor frecuencia tumores de glándula mamaria y dentro de ellos las hembras son las que contribuyen con el mayor número de casos. Cuando estos tumores se presentan en machos por lo general tienen características histológicas malignas. Para el diagnóstico histopatológico la clasificación que ha tenido mayor aceptación es la propuesta por Hampe and Misdorp. A través de muchos años de investigación en este campo se han descrito varios factores considerados como predisponentes, entre los cuales están: raza, sexo, edad, dentro de estos la que presenta mayor disparidad de conceptos es la raza ya que, según algunos autores, se puede ver influenciada por factores externos como la localización geográfica y el gusto de los propietarios por ciertas razas como animales de compañía. Otro hecho importante es la descripción de agentes causales: el invalance hormonal (estrógenos, progesterona, mutaciones genéticas, (gen supresor del tumor, protooncogenes y consumo de dietas ricas en grasas. Finalmente, es importante hacer énfasis en el hecho que del diagnóstico adecuado y pautas de tratamiento llevados a cabo por el médico veterinario clínico, depende el pronóstico y las expectativas de vida del paciente canino.Among domestic animals, canines are those that most frequently suffertumors of mammary gland and among them females are those that present the biggest number of cases. When these tumors are present in males, they have malign hystologic characteristics. For the hysto-pathologic diagnosis the best accepted classification is Hampe and Misford ' s proposal. Through many years of research in this field several predisposition factors, as race, sex andage have been described. Among these, race accounts for the highest disparity of concepts since, as some authors argue, this can be influenced by some external factors as geographic location and the owners ' likes for certain races as company animals. Another important fact is the description of causal agents such as hormonal imbalance (estrogens, progesterone, genetic mutations (suppressive gene of the tumor and proto- oncogenesis, consumption of fat-rich diets. Finally, it is important to emphasize the fact that the prognosis and life expectations of the canine patient depend on the basis of a good diagnosis and clues for treatment carried out by the Clinic Veterinarian.

Osmar Fajardo

2005-10-01

182

Endostar attenuates melanoma tumor growth via its interruption of b-FGF mediated angiogenesis.  

Science.gov (United States)

To develop optimal therapeutics is one of the hotspots in both clinical and basic melanoma studies. Previous studies indicate that fibroblast growth factors (b-FGF/FGF-2), an angiogenesis inducer beyond VEGF, might be a potential drug target in melanoma. As a novel anti-angiogenesis peptide drug, Endostar has shown promising therapeutic efficacy in non-small cell lung cancer. However, the effect of Endostar on b-FGF-induced angiogenesis in melanoma is unraveled. To this end, both in vivo and in vitro experiments were conducted and it was found that treatment of Endostar could inhibit tumor growth, which was accompanied by decreased micro-vessel density and serum b-FGF levels in a mouse melanoma model. In addition, treatment with Endostar in blood vessel endothelial cells could reduce their proliferation, cell migration and tube formation capacity in a dosage-dependent manner. Moreover, treatment of Endostar could also attenuate b-FGF-activated phosphorylation of p38 and ERK1/2 in HUVECs. These findings indicate that Endostar might exert its anti-tumor effect via suppressing b-FGF-induced angiogenesis and b-FGF-activated MAPK signaling pathway, suggesting that Endostar might be a potential choice for clinical melanoma treatment. PMID:25597785

Xiao, Lijia; Yang, ShuCai; Hao, Jianhua; Yuan, Xue; Luo, Wei; Jiang, Liping; Hu, Yang; Fu, Zhongping; Zhang, Yun; Zou, Chang

2015-04-01

183

Magnetic resonance imaging of breast cancer. Correlation between contrast enhancement and tumor angiogenesis  

International Nuclear Information System (INIS)

To evaluate the association between enhancement characteristics of breast cancers obtained by three-dimensional dynamic MRI and histopathologic findings, especially tumor angiogenesis. Forty-four women with invasive breast cancer under went preoperative MR imaging. Three-dimensional fast low angle shot (3D-FLASH) images of the whole breast (section thickness, 2 mm; gap, 0 mm; number of sections, 50; acquisition time, 87 sec) were obtained at 90-second intervals for three images (the first image before the injection of Gd-DTPA). Microvessel densities were evaluated in specimens immunohistochemically stained with anti-CD34 antibody. Pearson correlation tests were used to determine the strength of the relationships between enhancement parameters and microvessel densities. Univariate and multivariate analyses were performed to explore the associations with histopathologic factors, including histological grade. The enhancement parameters were correlated with microvessel densities (p<0.0001). The peripheral microvessel densities were significantly higher than central microvessel densities (p<0.0001). A significant association with histological grade was observed for the steepest slopes of the dynamic curve and microvessel densities (p<0.05). A correlation between three-dimensional dynamic MRI parameters and microvessel densities, and associations with histological grade were seen. This may allow MRI to be used in the prediction of tumor angiogenesis and tumor grade. (authorumor angiogenesis and tumor grade. (author)

184

Paradox between angiogenesis and oxygen effect in the treatment of tumor  

International Nuclear Information System (INIS)

The paradox in the title is described on recent findings concerning the effects of anti-angiogenetic drugs on possible radiation resistance and sensitivity of tumor tissue. Suppression of angiogenesis leads to inhibition of tumor growth, based on which anti-tumor drugs like anti- vascular endotherial growth factor (VEGF) antibody bevacizumab to suppress the genesis have been developed and clinically used, but they conceivably increase the population of hypoxic tumor cells. Those drugs are essentially used in combination with other chemotherapeutic agents and/or radiation. Hypoxic tumor cells present in the tissue are generally radioresistant. There are reported findings, however, that the drugs sometimes elevate the efficacy of radiotherapy, which hypothesizes that the drugs induces a proangiogenetic state, where increased level of growth factors in the tissue is reduced to normalize the vasculature and thereby reoxygenation occurs, the oxygen effect. Because copper is a cofactor of growth factors like VEGF and basic fibroblast growth factor (bFGF) and essential for angiogenesis, authors have studied the effect of a Cu-chelator, trientine, on transplanted mouse tumors which has been shown to induce apoptosis of the target cells. Combination of the chelator with X-ray irradiation is found effective in tumor growth inhibition and in survival increase. For more effective combination therapy, the interaction occurring in combinations of regimen should be elucidated. (R.T.ons of regimen should be elucidated. (R.T.)

185

Targeted microbubbles for imaging tumor angiogenesis: assessment of whole-body biodistribution with dynamic micro-PET in mice  

DEFF Research Database (Denmark)

To evaluate in vivo whole-body biodistribution of microbubbles (MBs) targeted to tumor angiogenesis-related vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) by using dynamic micro-positron emission tomography (PET) in living mice.

Willmann, Jürgen K; Cheng, Zhen

2008-01-01

186

An experimental research into endostatin microbubble combined with focused ultrasound for anti-tumor angiogenesis in colon cancer  

OpenAIRE

Objective: to evaluate the therapeutic effect of targeted endostatin-loaded microbubbles, combined with improved, focused, directional ultrasound radiation for inhibition of subcutaneous translocation in situ colon tumor angiogenesis in colon cancer.

Zhang, Xiufeng; Yang, Guangen; Zhang, Ying; Huang, Pintong; Qiu, Jianming; Sun, Yu; Shen, Zhong; Liao, Xiujun; Xia, Hongsheng; Shao, Shuxian; Wang, Dong

2014-01-01

187

Mammary Tumors Initiated by Constitutive Cdk2 Activation Contain an Invasive Basal-like Component  

Directory of Open Access Journals (Sweden)

Full Text Available The basal-like subtype of breast cancer is associated with invasiveness, high rates of postsurgical recurrence, and poor prognosis. Aside from inactivation of the BRCA1 tumor-suppressor gene, little is known concerning the mechanisms that cause basal breast cancer or the mechanisms responsible for its invasiveness. Here, we show that the heterogeneous mouse mammary tumor virus-cyclin D1-Cdk2 (MMTV-D1K2 transgenic mouse mammary tumors contain regions of spindle-shaped cells expressing both luminal and myoepithelial markers. Cell lines cultured from these tumors exhibit the same luminal/myoepithelial mixed-lineage phenotype that is associated with human basal-like breast cancer and express a number of myoepithelial markers including cytokeratin 14, P-cadherin, ? smooth muscle actin, and nestin. The MMTV-D1K2 tumor-derived cell lines form highly invasive tumors when injected into mouse mammary glands. Invasion is associated with E-cadherin localization to the cytoplasm or loss of E-cadherin expression. Cytoplasmic E-cadherin correlates with lack of colony formation in vitro and ?-catenin and p120ctn localization to the cytoplasm. The data suggest that the invasiveness of these cell lines results from a combination of factors including mislocalization of E-cadherin, ?-catenin, and p120ctn to the cytoplasm. Nestin expression and E-cadherin mislocalization were also observed in human basal-like breast cancer cell lines, suggesting that these results are relevant to human tumors. Together, these results suggest that abnormal Cdk2 activation may contribute to the formation of basal-like breast cancers.

Patrick E. Corsino

2008-11-01

188

Glucocorticoid regulation of mouse mammary tumor virus: identification of a short essential DNA region.  

OpenAIRE

Transcription of mouse mammary tumor virus (MMTV) DNA is stimulated by steroid hormones. To determine the DNA sequences involved in this regulation, we constructed a plasmid containing the MMTV long terminal repeat (LTR) in front of the coding region of the herpes simplex thymidine kinase gene, from which the promoter had been removed. Portions of the LTR were removed by the nuclease Ba/31, and the deleted molecules were recloned and tested for transcriptional activity in transfections of Ltk...

Buetti, E.; Diggelmann, H.

1983-01-01

189

A mouse mammary tumor virus promoter element near the transcription initiation site.  

OpenAIRE

Transcription from the promoter of mouse mammary tumor virus is subject to both positive and negative control by cellular factors, and proviral promoter elements that mediate a basal level of transcription must in some way respond to these cellular regulatory signals. Several such elements, including a TATA box, a region containing three octamer-related sequences, and a binding site for nuclear factor 1, have been previously defined. Additional promoter mutations have allowed a fourth basal p...

Pierce, J.; Fee, B. E.; Toohey, M. G.; Peterson, D. O.

1993-01-01

190

Phenotypic knockout of VEGF-R2 and Tie-2 with an intradiabody reduces tumor growth and angiogenesis in vivo  

OpenAIRE

The endothelial cell receptor-tyrosine kinases, VEGF receptor 2 (VEGF-R2) and Tie-2, and their ligands, vascular endothelial growth factor (VEGF) and angiopoietins 1 and 2, respectively, play key roles in tumor angiogenesis. Several studies suggest that the VEGF receptor pathway and the Tie-2 pathway are independent and essential mediators of angiogenesis, leading to the hypothesis that simultaneous interference with both pathways should result in additive effects on tumor growth. In this stu...

Jendreyko, Nina; Popkov, Mikhail; Rader, Christoph; Barbas, Carlos F.

2005-01-01

191

Luteolin Inhibits Human Prostate Tumor Growth by Suppressing Vascular Endothelial Growth Factor Receptor 2-Mediated Angiogenesis  

OpenAIRE

Angiogenesis, the formation of new blood vessels from pre-existing vascular beds, is essential for tumor growth, invasion, and metastasis. Luteolin is a common dietary flavonoid found in fruits and vegetables. We studied the antiangiogenic activity of luteolin using in vitro, ex vivo, and in vivo models. In vitro studies using rat aortic ring assay showed that luteolin at non-toxic concentrations significantly inhibited microvessel sprouting and proliferation, migration, invasion and tube for...

Pratheeshkumar, Poyil; Son, Young-ok; Budhraja, Amit; Wang, Xin; Ding, Songze; Wang, Lei; Hitron, Andrew; Lee, Jeong-chae; Kim, Donghern; Divya, Sasidharan Padmaja; Chen, Gang; Zhang, Zhuo; Luo, Jia; Shi, Xianglin

2012-01-01

192

Rapid Analysis of Vessel Elements (RAVE): A Tool for Studying Physiologic, Pathologic and Tumor Angiogenesis  

OpenAIRE

Quantification of microvascular network structure is important in a myriad of emerging research fields including microvessel remodeling in response to ischemia and drug therapy, tumor angiogenesis, and retinopathy. To mitigate analyst-specific variation in measurements and to ensure that measurements represent actual changes in vessel network structure and morphology, a reliable and automatic tool for quantifying microvascular network architecture is needed. Moreover, an analysis tool capable...

Seaman, Marc E.; Peirce, Shayn M.; Kelly, Kimberly

2011-01-01

193

Tetrandrine Suppresses Cancer Angiogenesis and Metastasis in 4T1 Tumor Bearing Mice  

OpenAIRE

Metastasis remains the most deadly aspect of cancer and still evades direct treatment. Thus, there is a great need to develop new treatment regimens to suppress tumor cells that have escaped surgical removal or that may have already disseminated. We have found that tetrandrine (TET) exhibits anticolon cancer activity. Here, we investigate the inhibition effect of TET to breast cancer metastasis, angiogenesis and its molecular basis underlying TET's anticancer activity. We compare TET with che...

Jian-Li Gao; Xing Ji; Tong-Chuan He; Qi Zhang; Kai He; Yan Zhao; Su-Hong Chen; Gui-Yuan Lv

2013-01-01

194

?-Elemene-Attenuated Tumor Angiogenesis by Targeting Notch-1 in Gastric Cancer Stem-Like Cells  

OpenAIRE

Emerging evidence suggests that cancer stem cells are involved in tumor angiogenesis. The Notch signaling pathway is one of the most important regulators of these processes. ?-Elemene, a naturally occurring compound extracted from Curcumae Radix, has been used as an antitumor drug for various cancers in China. However, its underlying mechanism in the treatment of gastric cancer remains largely unknown. Here, we report that CD44+ gastric cancer stem-like cells (GCSCs) showed enhanced prolifer...

Yan, Bing; Zhou, Yuqi; Feng, Shouhan; Lv, Can; Xiu, Lijuan; Zhang, Yingcheng; Shi, Jun; Li, Yongjin; Wei, Pinkang; Qin, Zhifeng

2013-01-01

195

Myeloid Cell Receptor LRP1/CD91 Regulates Monocyte Recruitment and Angiogenesis in Tumors  

OpenAIRE

Recruitment of monocytes into sites of inflammation is essential in the immune response. In cancer, recruited monocytes promote invasion, metastasis, and possibly angiogenesis. LDL receptor-related protein (LRP1) is an endocytic and cell-signaling receptor that regulates cell migration. In this study, we isografted PanO2 pancreatic carcinoma cells into mice in which LRP1 is deleted in myeloid lineage cells. Recruitment of monocytes into orthotopic and subcutaneous tumors was significantly inc...

Staudt, Nicole D.; Jo, Minji; Hu, Jingjing; Bristow, Jeanne M.; Pizzo, Donald P.; Gaultier, Alban; Vandenberg, Scott R.; Gonias, Steven L.

2013-01-01

196

Paradoxical antiproliferative effect by a murine mammary tumor-derived epithelial cell line  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background Despite significant advancement in breast cancer therapy, there is a great need for a better understanding of the mechanisms involved in breast carcinogenesis and progression, as well as of the role of epigenetic contributions from stromal cells in mammary tumorigenesis. In this study, we isolated and characterized murine mammary tumor-derived epithelial and myofibroblast cell lines, and investigated the in vitro and in vivo effect of cellular soluble factors produced by the epithelial cell line on tumor cells. Methods Morphology, immunophenotype, cytogenetics, invasiveness, and tumorigenicity of epithelial (LM-234ep and myofibroblast (LM-234mf cell lines isolated from two murine mammary adenocarcinomas with common ancestor were studied. The in vitro effects of LM-234ep conditioned medium on proliferation, cell cycle distribution, and expression of cell cycle proteins, were investigated in LM-234mf cells, mouse melanoma cells (B16-F10, and human cervical adenocarcinoma cells (HeLa. The in vivo anti-tumor activity of LM-234ep conditioned media was evaluated in subcutaneous tumors formed in nude mice by B16-F10 and HeLa cells. Results LM-234ep cells were found to be cytokeratin positive and hipertriploid, whereas LM-234mf cells were ?-smooth muscle actin positive and hypohexaploid. Chromosome aberrations were found in both cases. Only LM-234mf revealed to be invasive in vitro and to secrete active MMP-2, though neither of the cell types were able to produce progressing tumors. LM-234ep-derived factors were able to inhibit the in vitro growth of LM-234mf, B16-F10, and HeLa cells, inducing cell cycle arrest in G0/G1 phase. The administration of LM-234ep conditioned medium inhibited the growth of B16-F10 and HeLa tumors in nude mice. Conclusion Our data suggest the existence of epithelial cell variants with tumor suppressive properties within mammary tumors. To our knowledge, this is the first report showing antiproliferative and antineoplastic activities induced by tumor-derived epithelial cells.

Scharovsky O Graciela

2007-10-01

197

TIMP-1 Overexpression in Lung Carcinoma Enhances Tumor Kinetics and Angiogenesis in Brain Metastasis.  

Science.gov (United States)

Tissue inhibitors of matrix metalloproteinase (TIMP) orchestrate many biologic activities, including inhibition of matrix metalloproteinase activity, activation of pro-matrix metalloproteinases, and regulation of cell proliferation, angiogenesis, and apoptosis induction. Tissue inhibitors of matrix metalloproteinase can play a protective role during tumor invasion and metastasis, but elevated TIMP messenger RNA levels have also been associated with aggressive cancers and poor clinical outcome. We examined the potential roles of TIMP-1 in H2009 lung adenocarcinoma cells and in cells transfected with a human TIMP-1-overexpressing vector (HB-6 and HB-1). Tumors resulting from the implantation of parental cell lines and transfected HB-1 cells into the brains of nude mice had a typical carcinoma profile, but human TIMP-1-overexpressing tumors showed enhanced tumor kinetics and focally more infiltrative features; vessel density assessed with anti-CD31 immunohistochemistry was also greater within HB-1 tumor implants. Similar effects on HB-6 and HB-1 cells versus parental cell lines and empty vector clones were observed in endothelial cell assays. Anchorage-independent growth and invasion through Matrigel were also increased in TIMP-1-overexpressing cells. Together, these results indicate tumor-promoting functions of TIMP-1 through alterations in angiogenesis, increased tumorigenicity, and invasive behavior. Although matrix metalloproteinase inhibition has been the traditionally identified function of TIMP-1, matrix metalloproteinase-independent interactions may contribute to the growth of metastatic carcinomas in the brain. PMID:25756591

Rojiani, Mumtaz V; Ghoshal-Gupta, Sampa; Kutiyanawalla, Ammar; Mathur, Sunil; Rojiani, Amyn M

2015-04-01

198

Development of Spontaneous Mammary Tumors in BALB/c p53 Heterozygous Mice : A Model for Li-Fraumeni Syndrome  

OpenAIRE

Breast cancer is the most frequent tumor type among women in the United States and in individuals with Li-Fraumeni syndrome. The p53 tumor suppressor gene is altered in a large proportion of both spontaneous breast malignancies and Li-Fraumeni breast cancers. This suggests that loss of p53 can accelerate breast tumorigenesis, yet p53-deficient mice rarely develop mammary tumors. To evaluate the effect of p53 loss on mammary tumor formation, the p53null allele was back-crossed onto the BALB/c ...

Kuperwasser, Charlotte; Hurlbut, Gregory D.; Kittrell, Frances S.; Dickinson, Ellen S.; Laucirica, Rudy; Medina, Daniel; Naber, Stephen P.; Jerry, D. Joseph

2000-01-01

199

Dual-action combination therapy enhances angiogenesis while reducing tumor growth and spread.  

Science.gov (United States)

Increasing chemotherapy delivery to tumors, while enhancing drug uptake and reducing side effects, is a primary goal of cancer research. In mouse and human cancer models in vivo, we show that coadministration of low-dose Cilengitide and Verapamil increases tumor angiogenesis, leakiness, blood flow, and Gemcitabine delivery. This approach reduces tumor growth, metastasis, and minimizes side effects while extending survival. At a molecular level, this strategy alters Gemcitabine transporter and metabolizing enzyme expression levels, enhancing the potency of Gemcitabine within tumor cells in vivo and in vitro. Thus, the dual action of low-dose Cilengitide, in vessels and tumor cells, improves chemotherapy efficacy. Overall, our data demonstrate that vascular promotion therapy is a means to improve cancer treatment. PMID:25584895

Wong, Ping-Pui; Demircioglu, Fevzi; Ghazaly, Essam; Alrawashdeh, Wasfi; Stratford, Michael R L; Scudamore, Cheryl L; Cereser, Biancastella; Crnogorac-Jurcevic, Tatjana; McDonald, Stuart; Elia, George; Hagemann, Thorsten; Kocher, Hemant M; Hodivala-Dilke, Kairbaan M

2015-01-12

200

Chemokine receptor CXCR7 regulates the invasion, angiogenesis and tumor growth of human hepatocellular carcinoma cells  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background In spite of recent advances in diagnostic and therapeutic measures, the prognosis of hepatocellular carcinoma (HCC patients remains poor. Therefore, it is crucial to understand what factors are involved in promoting development of HCC. Evidence is accumulating that members of the chemokine receptor family are viewed as promising therapeutic targets in the fight against cancer. More recent studies have revealed that chemokine receptor CXCR7 plays an important role in cancer development. However, little is known about the effect of CXCR7 on the process of HCC cell invasion and angiogenesis. The aim of this study is to investigate the expression of CXCR7 in hepatocellular carcinoma tissues and cell lines and to evaluate the role of CXCR7 in tumor growth, angiogenesis and invasion of HCC cells. Methods We constructed CXCR7 expressing shRNA, and CXCR7shRNA was subsequently stably transfected into human HCC cells. We evaluated the effect of CXCR7 inhibition on cell invasion, adhesion, VEGF secretion, tube formation and tumor growth. Immunohistochemistry was done to assess the expression of CXCR7 in human hepatocellular carcinoma tissues and CD31 in tumor of mice. We also evaluated the effect of VEGF stimulation on expression of CXCR7. Results CXCR7 was overexpressed in hepatocellular carcinoma tissues. We showed that high invasive potential HCC cell lines express high levels of CXCR7. In vitro, CXCL12 was found to induce invasion, adhesion, tube formation, and VEGF secretion in SMMC-7721 cells. These biological effects were inhibited by silencing of CXCR7 in SMMC-7721 cells. In addition, we also found that VEGF stimulation can up-regulate CXCR7 expression in SMMC-7721 cells and HUVECs. More importantly, enhanced expression of CXCR7 by VEGF was founctional. In vivo, tumor growth and angiogenesis were suppressed by knockdown of CXCR7 in SMMC-7721 cells. However, silencing of CXCR7 did not affect metastasis of tumor in vivo. Conclusions Increased CXCR7 expression was found in hepatocellular carcinoma tissues. Knockdown of CXCR7 expression by transfected with CXCR7shRNA significantly inhibits SMMC-7721 cells invasion, adhesion and angiogenesis. Finally, down-regulation of CXCR7 expression lead to a reduction of tumor growth in a xenograft model of HCC. This study provides new insights into the significance of CXCR7 in invasion and angiogenesis of HCC.

Li Fan

2010-04-01

201

Integrin-Associated CD151 Drives ErbB2-Evoked Mammary Tumor Onset and Metastasis  

Directory of Open Access Journals (Sweden)

Full Text Available ErbB2+ human breast cancer is a major clinical problem. Prior results have suggested that tetraspanin CD151 might contribute to ErbB2-driven breast cancer growth, survival, and metastasis. In other cancer types, CD151 sometimes supports tumor growth and metastasis. However, a definitive test of CD151 effects on de novo breast cancer initiation, growth, and metastasis has not previously been done. We used CD151 gene-deleted mice expressing the MMTV-ErbB2 transgene to show that CD151 strongly supports ErbB2+ mammary tumor initiation and metastasis. Delayed tumor onset (by 70–100 days in the absence of CD151 was accompanied by reduced survival of mammary epithelial cells and impaired activation of FAK- and MAPK-dependent pathways. Both primary tumors and metastatic nodules showed smooth, regular borders, consistent with a less invasive phenotype. Furthermore, consistent with impaired oncogenesis and decreased metastasis, CD151-targeted MCF-10A/ErbB2 cells showed substantial decreases in three-dimensional colony formation, EGF-stimulated tumor cell motility, invasion, and transendothelial migration. These CD151-dependent functions were largely mediated through ?6?4 integrin. Moreover, CD151 ablation substantially prevented PKC- and EGFR/ERK-dependent ?6?4 integrin phosphorylation, consistent with retention of epithelial cell polarity and intermediate filament cytoskeletal connections, which helps to explain diminished metastasis. Finally, clinical data analyses revealed a strong correlation between CD151 and ErbB2 expression and metastasis-free survival of breast cancer patients. In conclusion, we provide strong evidence that CD151 collaborates with LB integrins (particularly ?6?4 and ErbB2 (and EGFR receptors to regulate multiple signaling pathways, thereby driving mammary tumor onset, survival, and metastasis. Consequently, CD151 is a useful therapeutic target in malignant ErbB2+ breast cancer.

Xinyu Deng

2012-08-01

202

Connexin 43 Suppresses Tumor Angiogenesis by Down-Regulation of Vascular Endothelial Growth Factor via Hypoxic-Induced Factor-1?  

Directory of Open Access Journals (Sweden)

Full Text Available Previous work showed that connexin 43 (Cx43 reduced the expression of hypoxic-induced factor-1? (HIF-1? in astrocytes. HIF-1? is a master transcription factor for angiogenesis in tumor. Angiogenesis is essential for tumor progression. Here, we investigated the role of Cx43 in vascular endothelial growth factor (VEGF production and angiogenesis in murine tumor. In the study, mouse B16F10 and 4T1 cells were overexpressed or knockdown with Cx43. The expression profiles as well as activity of the treated cells were examined. Furthermore, reduced Cx43 expression in B16F10 and 4T1 cells causes increased expression of VEGF and enhanced the proliferation of endothelial cells. On the contrary, the expression of VEGF and the proliferation of endothelial were increased in the conditioned medium of Cx43-knockdown tumor cells. We subcutaneously transplanted Cx43-overexpressing B16F10 cells into mice to evaluate the roles of Cx43 in the tumor angiogenesis. Both tumor size and the number of vessels growing in the tumor were markedly decreased compare with control group. Our findings suggest that Cx43 inhibited tumor growth by reducing angiogenesis.

Wei-Kuang Wang

2014-12-01

203

Optimizing the time of doxil injection to increase the drug retention in transplanted murine mammary tumors  

Directory of Open Access Journals (Sweden)

Full Text Available Shaojin You, Lian Zuo, Wei LiExperimental Cancer Therapeutic Laboratory and Histopathology Core, Atlanta Research and Educational Foundation (151F, Atlanta VA Medical Center, Decatur, GA, USAAbstract: Sex hormonal milieus during the female fertility cycle modulate the tumor vascular permeability of breast cancer. It has been proposed that the liposomal formulated doxorubicin (ie, Doxil, given at the menstrual/estrous stage with the predicted highest tumor vascular permeability, allows significantly increased drug retention in the breast tumor. In the current study, syngeneic murine 4T1 mammary tumors were established on the backs of female BALB/c mice and Doxil was administered at particular mouse estrous cycle stages. The results indicated that Doxil administration during certain times in the mouse estrous cycle was crucial for drug retention in 4T1 tumor tissues. Significantly higher drug concentrations were detected in the tumor tissues when Doxil was administered during the diestrus stage, as compared to when the drug injection was given at all other estrous stages. Our study also showed that the tumor-bearing mice exhibited nearly normal rhythmicity of the estrous cycle post drug injection, indicating the feasibility of continual injection of Doxil at the same estrous cycle stage. By using 4T1 cells cultured in vitro, we showed that progesterone (P4 significantly inhibited cell proliferation and the production of six tumor-derived cytokines, eg, sTNF-RI, CXCL-16, GM-CSF, MIP-1?, MIP-1?, and Flt3-L. Some of these factors have been shown to be vascular modulators in diverse tissues. In this report, we demonstrated that the concentration of P4 in the plasma and/or estrous cycle stage of 4T1 tumor-bearing mice can be used to select the best time for administrating the liposomal anticancer drugs.Keywords: progesterone, menstrual cycle, mouse mammary tumor, Doxil, breast cancer therapy

Shaojin You

2010-03-01

204

c-erbB-2 expression and nuclear pleomorphism in canine mammary tumors  

OpenAIRE

The objective of the present investigation was to study the expression of c-erbB-2 and MIB-1 and try to associate them with morphological features of the cell such as nuclear pleomorphism, mitotic count and histological grade in a series of 70 canine mammary gland tumors, 22 of them benign and 48 malignant. Tumors were collected at the Veterinary Hospital of UFMG (Brazil) and the Veterinary Faculty of Porto University (Portugal). c-erbB-2 expression was determined according to the guidelines ...

Dutra, A. P.; Granja, N. V. M.; Schmitt, F. C.; Cassali, G. D.

2004-01-01

205

The Protective Effect Of SPIRULINA PLATENSIS Against MAMMARY Tumors Induction By Dimethylbenz(A)Anthracene In Sprague- Dawley Female Rats  

International Nuclear Information System (INIS)

Breast cancer is the most common cancer and the second most frequent cause of cancer death in women. Despite extensive studies, the precise mechanisms of breast carcinogenesis remain unclear. One of the reasons for this is due, at least in part, to a lack of a suitable animal model, which can closely mimic the breast carcinogenesis in normal situations without using chemical carcinogens. Dimethylbenz(a)anthracene (DMBA) was used to developed mammary gland carcinogenesis in an animal model and succeeded in inducing mammary cancer in a relatively short time (?6 months) in Sprague-Dawely female rats. The possible therapeutic and protective effects of Spirulina platensis in Sprague-Dawely female rats were investigated. The results showed significant increased androgen testosterone level and significant decreased estrogen level in mammary gland carcinogenesis. Histopathological examination revealed hyperplasia and dysplasia and fully developed carcinoma of various forms including cribriform, papillary and camedo types which were observed after 6 months. They ranged from well differentiated to poorly differentiated forms with predominantly infiltrating ductal carcinoma. In addition to the high incidence of carcinoma, there was also a peculiar unexplained allocation of mammary gland tumors in virgin female rats between the site of implantation and the location of tumors through the whole body, and the highest incidence of carcinogenesis was found to be in thoracic mammary sis was found to be in thoracic mammary gland. Both estrogen and testosterone have a role in mammary cancers. The study showed that both estrogen and testosterone were important in mammary cancer diagnosis. It is suggested that sex hormones have a role in late stages in breast carcinogenesis. Estradiol, which is the main form of estrogen, affects the different stage of mammary gland carcinogenesis. Furthermore, the results indicated that Spirulina platensis may have therapeutic and protective effects (30%) on mammary cancers of Sprague-Dawely female rats chemically induced by DMBA.

206

Role of thrombin in the proliferative response of T-47D mammary tumor cells  

International Nuclear Information System (INIS)

The growth of the human metastatic cell line (T-47D) in a chemically defined medium (DM) is shown to be dependent on the presence of three traditional growth factors: epidermal growth factor, insulin, and transferrin. The addition of thrombin further stimulates its growth. The mitogenic action on a human mammary tumor cell lines from epithelial origin is a novel action of thrombin. Cells in the DM show striking morphological changes which are dramatically enhanced by the addition of thrombin. These observations are part of a pleiotropic response to the growth factors: the protein content of the cells increases in the defined medium; the 2DG gels of the 35S- and 35P-labeled proteins show important changes in spots, several of which are probably of cytoskeletal origin. It is also shown that cells in a semisolid growth factor-supplemented medium have growth advantages over their counterparts grown with serum. All the phenotypic changes mentioned above reveal the important role of growth factors in the growth and behavior of this mammary cell line. The results obtained with thrombin indicate a new site of action of this enzyme which may be important in the metastatic spread of human mammary tumor cells

207

Lentivirus-Mediated Oncogene Introduction into Mammary Cells In Vivo Induces Tumors  

Directory of Open Access Journals (Sweden)

Full Text Available We recently reported the introduction of oncogene-expressing avian retroviruses into somatic mammary cells in mice susceptible to infection by transgenic expression of tva, encoding the receptor for subgroup A avian leukosis-sarcoma virus (ALSV. Because ALSV-based vectors poorly infect nondividing cells, they are inadequate for studying carcinogenesis initiated from nonproliferative cells (e.g., stem cells. Lentivirus pseudotyped with the envelope protein of ALSV infects nondividing TVA-producing cells in culture but has not previously been tested for introducing genes in vivo. Here, we demonstrate that these vectors infected mammary cells in vivo when injected into the mammary ductal lumen of mice expressing tva under the control of the keratin 19 promoter. Furthermore, intraductal injection of this lentiviral vector carrying the polyoma middle T antigen gene induced atypical ductal hyperplasia and ductal carcinoma in situ-like premalignant lesions in 30 days and palpable invasive tumors at a median latency of 3.3 months. Induced tumors were a mixed epithelial/myoepithelial histologic diagnosis, occasionally displayed squamous metaplasia, and were estrogen receptor-negative. This work demonstrates the first use of a lentiviral vector to introduce oncogenes for modeling cancer in mice, and this vector system may be especially suitable for introducing genetic alterations into quiescent cells in vivo.

Stefan K. Siwko

2008-07-01

208

Vascular Normalization Induced by Sinomenine Hydrochloride Results in Suppressed Mammary Tumor Growth and Metastasis  

Science.gov (United States)

Solid tumor vasculature is characterized by structural and functional abnormality and results in a hostile tumor microenvironment that mediates several deleterious aspects of tumor behavior. Sinomenine is an alkaloid extracted from the Chinese medicinal plant, Sinomenium acutum, which has been utilized to treat rheumatism in China for over 2000 years. Though sinomenine has been demonstrated to mediate a wide range of pharmacological actions, few studies have focused on its effect on tumor vasculature. We showed here that intraperitoneally administration of 100?mg/kg sinomenine hydrochloride (SH, the hydrochloride chemical form of sinomenine) in two orthotopic mouse breast cancer models for 14 days, delayed mammary tumor growth and decreased metastasis by inducing vascular maturity and enhancing tumor perfusion, while improving chemotherapy and tumor immunity. The effects of SH on tumor vessels were caused in part by its capability to restore the balance between pro-angiogenic factor (bFGF) and anti-angiogenic factor (PF4). However 200?mg/kg SH didn't exhibit the similar inhibitory effect on tumor progression due to the immunosuppressive microenvironment caused by excessive vessel pruning, G-CSF upregulation, and GM-CSF downregulation. Altogether, our findings suggest that SH induced vasculature normalization contributes to its anti-tumor and anti-metastasis effect on breast cancer at certain dosage. PMID:25749075

Zhang, Huimin; Ren, Yu; Tang, Xiaojiang; Wang, Ke; Liu, Yang; Zhang, Li; Li, Xiao; Liu, Peijun; Zhao, Changqi; He, Jianjun

2015-01-01

209

Vascular normalization induced by sinomenine hydrochloride results in suppressed mammary tumor growth and metastasis.  

Science.gov (United States)

Solid tumor vasculature is characterized by structural and functional abnormality and results in a hostile tumor microenvironment that mediates several deleterious aspects of tumor behavior. Sinomenine is an alkaloid extracted from the Chinese medicinal plant, Sinomenium acutum, which has been utilized to treat rheumatism in China for over 2000 years. Though sinomenine has been demonstrated to mediate a wide range of pharmacological actions, few studies have focused on its effect on tumor vasculature. We showed here that intraperitoneally administration of 100?mg/kg sinomenine hydrochloride (SH, the hydrochloride chemical form of sinomenine) in two orthotopic mouse breast cancer models for 14 days, delayed mammary tumor growth and decreased metastasis by inducing vascular maturity and enhancing tumor perfusion, while improving chemotherapy and tumor immunity. The effects of SH on tumor vessels were caused in part by its capability to restore the balance between pro-angiogenic factor (bFGF) and anti-angiogenic factor (PF4). However 200?mg/kg SH didn't exhibit the similar inhibitory effect on tumor progression due to the immunosuppressive microenvironment caused by excessive vessel pruning, G-CSF upregulation, and GM-CSF downregulation. Altogether, our findings suggest that SH induced vasculature normalization contributes to its anti-tumor and anti-metastasis effect on breast cancer at certain dosage. PMID:25749075

Zhang, Huimin; Ren, Yu; Tang, Xiaojiang; Wang, Ke; Liu, Yang; Zhang, Li; Li, Xiao; Liu, Peijun; Zhao, Changqi; He, Jianjun

2015-01-01

210

Keratins as markers that distinguish normal and tumor-derived mammary epithelial cells  

International Nuclear Information System (INIS)

Keratin 5 (K5) mRNA and protein are shown to be expressed in normal mammary epithelial cells in culture and are absent from tumor-derived dell lines. To extend these findings, the full complements of keratins in normal, immortalized, and tumor cells were compared. It is shown here that normal cells produce keratins K5, K6, K7, K14, and K17, whereas tumor cells produce mainly keratins K8, K18, and K19. In immortalized cells, which are preneoplastic or partially transformed, the levels of K5 mRNA and protein are lower than in normal cells, whereas the amount of K18 is increased. Thus, K5 is an important marker in the tumorigenic process, distinguishing normal from tumor cells, and decrease K5 expression correlates with tumorigenic progression

211

Effects of ionizing irradiation on the estradiol and progesterone receptors in rat mammary tumors  

International Nuclear Information System (INIS)

The determination of estradiol and progesterone receptor concentrations in mammary tumors is useful in predicting the hormone responsiveness. As this assay is carried out on tumor tissue which may have been subjected to radiotherapy, the possibility of an ionizing irradiation affecting the steroid receptor levels in neoplastic tissue should be taken into account. The steroid receptor concentrations are examined in dimethylbenz(a)anthracene-induced tumors os Sprague-Dawley rats. The estradiol and the progesterone receptor titers become reduced significantly after treatment with 20 Gray while an application with 7 Gray does not affect the titer values. After treatment of the tumor with 20 Gray, the steroid receptor concentrations decrease progressively, reaching a maximal reduction 20 to 30 days after exposure. As radiation treatment affects the receptor concentrations, this should be kept in mind when interpreting the steroid receptor concentrations

212

The targeted delivery of IL17 to the mouse tumor neo-vasculature enhances angiogenesis but does not reduce tumor growth rate.  

Science.gov (United States)

There has been a long controversy as to whether interleukin-17 (IL17) has an impact on tumor growth. In order to assess whether IL17 may affect tumor growth, it would be convenient to achieve high levels of this pro-inflammatory cytokine at the tumor neo-vasculature, since IL17 is known to promote angiogenesis. Here, we have generated and tested in vivo a fusion protein, consisting of the F8 antibody (specific to the alternatively spliced EDA domain of fibronectin, a marker of angiogenesis) and of murine IL17 (mIL17). The resulting immunocytokine (termed F8-mIL17) was shown to selectively localize at the tumor neo-vasculature and to vigorously promote tumor angiogenesis, without however reducing or enhancing tumor growth rate both in immunocompetent and in immunodeficient mice. PMID:22052195

Pasche, Nadine; Frey, Katharina; Neri, Dario

2012-03-01

213

Revisiting a role for a mammary tumor retrovirus in human breast cancer.  

Science.gov (United States)

There remains great controversy as to whether mouse mammary tumor virus (MMTV), the etiological agent of mammary cancer in mice, or a closely related human retrovirus, plays a role in the development of breast cancer in humans. On one hand, retroviruses such as human T-cell lymphotropic virus and human immunodeficiency virus (HIV) are known causative agents of cancer (in the case of HIV, albeit, indirectly), but attempts to associate other retroviruses with human cancers have been difficult. A recent, high profile, example has been the postulated involvement of another mouse virus, xenotropic murine leukemia virus-related virus, in human prostate cancer, which is now thought to be due to contamination. Here, we review some of the more recent evidence for and against the involvement of MMTV in human breast cancer and suggest future studies that may allow a definitive answer to this conundrum. PMID:23580334

Salmons, Brian; Gunzburg, Walter H

2013-10-01

214

Ephrin B expression in epithelial ovarian neoplasms correlates with tumor differentiation and angiogenesis.  

Science.gov (United States)

Differential gene expression studies are identifying new sets of genes with a role in the classification, differential diagnosis, and prognosis of some human tumors. Ephrin B1, a factor involved in angiogenesis, has been shown to be up-regulated in ovarian carcinomas, making it a potential target for cancer treatment. This study investigates ephrin B expression in ovarian tumors to validate results from gene expression studies and evaluates its significance with a clinical-pathological correlation. Specimens from 112 benign, borderline, and malignant epithelial ovarian tumors were examined. Tissue microarrays were constructed, and ephrin B expression was studied by immunohistochemistry. To correlate ephrin B expression with angiogenesis, CD31 immunostaining was performed to assess microvessel density. Ephrin B was detected in 50% of ovarian tumors: clear cell carcinomas (93%), serous carcinomas (74%), mucinous carcinomas (29%), and endometrioid carcinomas (27%). High-grade carcinomas showed greatest ephrin B expression, whereas benign tumors and low-grade carcinomas were rarely positive. A correlation was found between ephrin B expression and microvessel density, supporting the angiogenic role of this factor in ovarian carcinomas. Ephrin B expression was associated with higher rates of disease recurrence and a decrease in overall survival. A distinctive pattern of ephrin B expression was observed in ovarian tumors: high-grade tumors and clear cell and serous carcinomas show higher expression, correlating with the aggressiveness. On the other hand, ephrin B expression correlated with microvessel density of the tumors. Because Eph receptors and ephrins are targets for new therapeutic inhibitors, this pattern of ephrin B expression should be considered in future clinical studies. PMID:16784989

Castellvi, Josep; Garcia, Angel; de la Torre, Javier; Hernandez, Javier; Gil, Antonio; Xercavins, Jordi; Ramón y Cajal, Santiago

2006-07-01

215

Establishment of linear accelerator-based image guided radiotherapy for orthotopic 4T1 mouse mammary tumor model  

OpenAIRE

This study was conducted to assess the feasibility of image guided radiotherapy (IGRT) for orthotopic 4T1 mouse mammary tumor using linear accelerator (LINAC). Eighteen Balb/C mice were inoculated with 4T1 cells on left mammary fat pad and nine of them were irradiated using LINAC. Tumors, planning target volumes (PTV), bowels adjacent to tumors, bones and lungs were delineated on planning CT images. IGRT plans were generated to irradiate prescription dose to at least 90% of the PTV and then c...

Lee, Seung-heon; Kim, Ji-young; Lee, Kyu-chan; Nam, Jeong-seok; Choi, Jinho; Lee, Seok-ho; Sung, Ki-hoon; Ahn, So-hyun

2014-01-01

216

Correlation Between PSMA and VEGF Expression as Markers for LNCaP Tumor Angiogenesis  

Science.gov (United States)

Our aim is the identification and correlation of changes in tumor-associated protein expression which results from therapy. LNCaP tumors, excised from nude mice treated either by orchiectomy or with the chemotherapeutic agent paclitaxel, were evaluated for the expression of proteins and receptors associated with growth, differentiation, and angiogenesis using immunohistologic procedures. Compared to untreated control tumors, both treatments reduced the expression of vascular endothelial growth factor (VEGF), prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), androgen receptor (AR), and epidermal growth factor receptor (EGFR). The effect of paclitaxel treatment on AR expression was the most significant (P = .005). Of particular interest was identifying a significant correlation (P < .000801) between PSMA and VEGF expression regardless of treatment modality. These altered expressions suggest that PSMA may also be a marker for angiogenesis and could represent a target for deliverable agents recognizing either prostatic tumors or endothelial development. Cell surface PSMA would then present a unique target for treatment of patients early in their development of prostatic metastases. PMID:16192687

2005-01-01

217

Correlation Between PSMA and VEGF Expression as Markers for LNCaP Tumor Angiogenesis  

Directory of Open Access Journals (Sweden)

Full Text Available Our aim is the identification and correlation of changes in tumor-associated protein expression which results from therapy. LNCaP tumors, excised from nude mice treated either by orchiectomy or with the chemotherapeutic agent paclitaxel, were evaluated for the expression of proteins and receptors associated with growth, differentiation, and angiogenesis using immunohistologic procedures. Compared to untreated control tumors, both treatments reduced the expression of vascular endothelial growth factor (VEGF, prostate-specific membrane antigen (PSMA, prostate-specific antigen (PSA, androgen receptor (AR, and epidermal growth factor receptor (EGFR. The effect of paclitaxel treatment on AR expression was the most significant ( P = .005 . Of particular interest was identifying a significant correlation ( P < .000801 between PSMA and VEGF expression regardless of treatment modality. These altered expressions suggest that PSMA may also be a marker for angiogenesis and could represent a target for deliverable agents recognizing either prostatic tumors or endothelial development. Cell surface PSMA would then present a unique target for treatment of patients early in their development of prostatic metastases.

Tsui Paulus

2005-01-01

218

Interleukin-12 Inhibits Tumor Growth in a Novel Angiogenesis Canine Hemangiosarcoma Xenograft Model  

Directory of Open Access Journals (Sweden)

Full Text Available We established a canine hemangiosarcoma cell line derived from malignant endothelial cells comprising a spontaneous tumor in a dog to provide a renewable source of endothelial cells for studies of angiogenesis in malignancy. Pieces of the hemangiosarcoma biopsy were engrafted subcutaneously in a bg/nu/XID mouse allowing the tumor cells to expand in vivo. A cell line, SB-HSA, was derived from the xenograft. SB-HSA cells expressed vascular endothelial growth factor (VEGF receptors 1 and 2, CD31, CD146, and ?v?3 integrin, and produced several growth factors and cytokines, including VEGF, basic fibroblast growth factor, and interleukin (IL-8 that are stimulatory to endothelial cell growth. These results indicated that the cells recapitulated features of mitotically activated endothelia. In vivo, SB-HSA cells stimulated robust angiogenic responses in mice and formed tumor masses composed of aberrant vascular channels in immunocompromised mice providing novel opportunities for investigating the effectiveness of antiangiogenic agents. Using this model, we determined that IL-12, a cytokine with both immunostimulatory and antiangiogenic effects, suppressed angiogenesis induced by, and tumor growth of, SB-HSA cells. The endothelial cell model we have described offers unique opportunities to pursue further investigations with IL-12, as well as other antiangiogenic approaches in cancer therapy.

Nasim Akhtar

2004-03-01

219

The selective Cox-2 inhibitor Celecoxib suppresses angiogenesis and growth of secondary bone tumors: An intravital microscopy study in mice  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background The inhibition of angiogenesis is a promising strategy for the treatment of malignant primary and secondary tumors in addition to established therapies such as surgery, chemotherapy, and radiation. There is strong experimental evidence in primary tumors that Cyclooxygenase-2 (Cox-2 inhibition is a potent mechanism to reduce angiogenesis. For bone metastases which occur in up to 85% of the most frequent malignant primary tumors, the effects of Cox-2 inhibition on angiogenesis and tumor growth remain still unclear. Therefore, the aim of this study was to investigate the effects of Celecoxib, a selective Cox-2 inhibitor, on angiogenesis, microcirculation and growth of secondary bone tumors. Methods In 10 male severe combined immunodeficient (SCID mice, pieces of A549 lung carcinomas were implanted into a newly developed cranial window preparation where the calvaria serves as the site for orthotopic implantation of the tumors. From day 8 after tumor implantation, five animals (Celecoxib were treated daily with Celecoxib (30 mg/kg body weight, s.c., and five animals (Control with the equivalent amount of the CMC-based vehicle. Angiogenesis, microcirculation, and growth of A549 tumors were analyzed by means of intravital microscopy. Apoptosis was quantified using the TUNEL assay. Results Treatment with Celecoxib reduced both microvessel density and tumor growth. TUNEL reaction showed an increase in apoptotic cell death of tumor cells after treatment with Celecoxib as compared to Controls. Conclusion Celecoxib is a potent inhibitor of tumor growth of secondary bone tumors in vivo which can be explained by its anti-angiogenic and pro-apoptotic effects. The results indicate that a combination of established therapy regimes with Cox-2 inhibition represents a possible application for the treatment of bone metastases.

Abdollahi Amir

2006-01-01

220

Effect of annatto-tocotrienols supplementation on the development of mammary tumors in HER-2/neu transgenic mice.  

Science.gov (United States)

Tocotrienols (T3), the lesser known isomers of vitamin E, have been reported to possess anticancer activity both in in vitro and in vivo experimental models of rodents transplanted with parental tumors or treated with carcinogens. We investigated the effects of dietary supplementation with annatto-T3 (90% ?-T3 and 10% ?-T3) on the spontaneous development of mammary tumors in HER-2/neu transgenic mice. Underlying mechanisms of the antitumor effect were evaluated by studying apoptosis, senescent-like growth arrest, immune modulation, oxidative effect and the expression of HER-2/neu in tumoral mammary glands of transgenic mice and in vitro in human and mice tumor cell lines. Annatto-T3 supplementation delayed the development of mammary tumors, reducing the number and size of mammary tumor masses and those of lung metastases. In annatto-T3-supplemented mice, both apoptosis and senescent-like growth arrest of tumor cells were increased in mammary glands while no immune modulation was observed. In vitro, a dose-dependent inhibition of cell growth, increased apoptosis and senescent-like growth arrest and a time-dependent accumulation of reactive oxygen species were observed in tumor cells treated with annatto-T3 or purified ?-T3. Annatto-T3 reduced both HER-2/neu mRNA and p185(HER-2/neu) protein in tumors and in tumor cell lines. The results show that the antitumor effect of annatto-T3 supplementation in HER-2/neu transgenic mice is mainly related to the direct induction of oxidative stress, senescent-like growth arrest and apoptosis of tumor cells rather than to an immune modulation. PMID:23430951

Pierpaoli, Elisa; Viola, Valentina; Barucca, Alessandra; Orlando, Fiorenza; Galli, Francesco; Provinciali, Mauro

2013-06-01

221

Interleukin-12 and interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis.  

OpenAIRE

The antitumor effect and mechanisms activated by murine IL-12 and IL-18, cytokines that induce IFN-gamma production, were studied using engineered SCK murine mammary carcinoma cells. In syngeneic A/J mice, SCK cells expressing mIL-12 or mIL-18 were less tumorigenic and formed tumors more slowly than control cells. Neither SCK.12 nor SCK.18 cells protected significantly against tumorigenesis by distant SCK cells. However, inoculation of the two cell types together synergistically protected 70%...

Coughlin, C. M.; Salhany, K. E.; Wysocka, M.; Aruga, E.; Kurzawa, H.; Chang, A. E.; Hunter, C. A.; Fox, J. C.; Trinchieri, G.; Lee, W. M.

1998-01-01

222

Hypercholesterolemia induces angiogenesis and accelerates growth of breast tumors in vivo.  

Science.gov (United States)

Obesity and metabolic syndrome are linked to an increased prevalence of breast cancer among postmenopausal women. A common feature of obesity, metabolic syndrome, and a Western diet rich in saturated fat is a high level of circulating cholesterol. Epidemiological reports investigating the relationship between high circulating cholesterol levels, cholesterol-lowering drugs, and breast cancer are conflicting. Here, we modeled this complex condition in a well-controlled, preclinical animal model using innovative isocaloric diets. Female severe combined immunodeficient mice were fed a low-fat/no-cholesterol diet and then randomized to four isocaloric diet groups: low-fat/no-cholesterol diet, with or without ezetimibe (cholesterol-lowering drug), and high-fat/high-cholesterol diet, with or without ezetimibe. Mice were implanted orthotopically with MDA-MB-231 cells. Breast tumors from animals fed the high-fat/high-cholesterol diet exhibited the fastest progression. Significant differences in serum cholesterol level between groups were achieved and maintained throughout the study; however, no differences were observed in intratumoral cholesterol levels. To determine the mechanism of cholesterol-induced tumor progression, we analyzed tumor proliferation, apoptosis, and angiogenesis and found a significantly greater percentage of proliferating cells from mice fed the high-fat/high-cholesterol diet. Tumors from hypercholesterolemic animals displayed significantly less apoptosis compared with the other groups. Tumors from high-fat/high-cholesterol mice had significantly higher microvessel density compared with tumors from the other groups. These results demonstrate that hypercholesterolemia induces angiogenesis and accelerates breast tumor growth in vivo. PMID:24952430

Pelton, Kristine; Coticchia, Christine M; Curatolo, Adam S; Schaffner, Carl P; Zurakowski, David; Solomon, Keith R; Moses, Marsha A

2014-07-01

223

Overexpression of 5-lipoxygenase and its relation with cell proliferation and angiogenesis in 7,12-dimethylbenz(?)anthracene-induced rat mammary carcinogenesis.  

Science.gov (United States)

The present study was performed to investigate the critical role of 5-lipoxygenase (5-LOX) in 7,12-dimethylbenz(?)anthracene (DMBA)-induced rat mammary inflammation associated carcinogenesis. Female Sprague-Dawley rats at 50 days of age were treated with 7,12-dimethylbenz(?)anthracene (DMBA; 0.5 mg/100 g body weight) by a single tail vein injection, followed by administration of zileuton (2000 mg/kg diet) from week 7 until the termination of the study at 31 wk. 5-LOX protein expression, 5-hydroxyeicosatetraenoic acid (5-HETE), and leukotriene B4 (LTB4 ) production in rat mammary tissue were analyzed at 6, 12, and 24 wk post-DMBA injection. Rate of cell proliferation was analyzed by bromodioxyuridine labeling index (BrdU-LI). Microvessel density, level of VEGF, and MMP-2 were also measured. DMBA induces inflammation in rat mammary gland as early as 6 wk. 5-LOX is upregulated in DMBA treated rats right from 6 wk when compared with their normal counterparts. An overexpression of 5-LOX is accompanied with increase in 5-HETE, LTB4 production and high BrdU-LI with an increase of two key angiogenic factors for tumorigenesis; MMP-2 and VEGF. It was found that 5-LOX specific inhibitor brought about substantial protection against DMBA-induced mammary carcinogenesis. Histological findings showed substantial repair of hyperplastic lesions. There was a significant reduction in the rate of cell proliferation and expression of angiogenic factors, MMP-2 and VEGF. 5-LOX plays an important role in DMBA-induced inflammation associated carcinogenesis via activation of MMP-2 and VEGF. 5-LOX expression can be considered as a critical event in controlling the process of mammary tumor development. PMID:22213124

Chatterjee, Mary; Das, Subhadeep; Roy, Kaushik; Chatterjee, Malay

2013-05-01

224

Mammary tumor induction in ACI rats exposed to low levels of 17beta-estradiol.  

Science.gov (United States)

Animal models play a major role in understanding the etiology, molecular mechanisms, strategizing intervention and treatment of human diseases. ACI, an inbred line derived from August and Copenhagen strains, is unique for its susceptibility to estrogen-induced mammary tumors. Histologically and in many molecular aspects, the tumors formed in these rats are similar to human breast cancers. Previous studies have shown high mortality and significant weight loss in this model associated with pituitary gland abnormality. We hypothesized that this could be due to overwhelming the biological system with estrogen. Three groups of female ACI rats (7-8 weeks) received either 3-cm sham silastic implants, or the conventional 3-cm silastic implants containing 27 mg of 17beta-estradiol, or 1.2-cm silastic implants containing 9 mg 17beta-estradiol. The sham and 3-cm implant rats were euthanized at 180 days while the 1.2-cm implant rats were euthanized at 240 days. The 1.2-cm implants resulted in significantly reduced serum estrogen levels and pituitary gland size. Animals with 1.2-cm implants had 100% tumor incidence, while not all rats developed tumors with 3-cm implants. Both the tumor burden (from 1,011+/-402 to 2,324+/-454 mm(3); p=0.01) and tumor multiplicity (from 5.78+/-1.4 to 7.6+/-1.04) increased by lowering the estrogen dose, and the inter-animal variability in the tumor indices decreased. Finally, the weight of the pituitary gland was also significantly (p=0.0004) reduced (from 178+/-23.5 mg to 80+/-8.9 mg) and the mortality rate decreased from 42% to 0% (p=0.01). Our data indicate that the improvised model will provide valuable insights into the molecular alterations in the estrogen-induced mammary tumorigenesis and will be ideal for inhibition studies. PMID:17549411

Ravoori, Srivani; Vadhanam, Manicka V; Sahoo, Sunati; Srinivasan, Cidambi; Gupta, Ramesh C

2007-07-01

225

Canine classical seminoma: a specific malignant type with human classifications is highly correlated with tumor angiogenesis  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background Human seminoma is classified as classical seminoma (SE and spermatocytic seminoma (SS. Human SE is known to be more malignant and metastasizing more frequently than SS. Tumor angiogenesis is highly related with tumor progression and metastasis, with microvessel density (MVD being an important parameter of metastatic potential. Canine seminoma is not yet well-established as SE or SS type including correlation with angiogenesis. We classified canine SE and SS, and then compared them to tumor associated vessels. Methods Twenty-three cases of canine seminomas (2 intratubular, 9 diffuse, and 12 intratubular/diffuse seminomas showing both intratubular and diffuse patterns were classified as SE or SS by immunohistochemistry (IHC using monoclonal antibody against PLAP and by PAS stain. The histopathological data were then compared to see if there was a correlation with SE or SS. Angiogenesis of seminomas were evaluated by immunohistochemical assay using polyclonal antibody against Von Willebrand factor (vWF and by calculating the means of MVD, vessels area and perimeters using computerized image analysis. Statistical Package for Social Sciences (SPSS program was used for various statistical analyses. Results The numbers of PLAP+/PAS+ canine SEs were 8/23 (34.8% and PLAP-/PAS- SSs were 15/23 (61.2%. All SE cases (8/8, 100% were intratubular/diffuse types. SS types included 2 intratubular (2/15, 13.3%, 9 diffuse (9/15, 60%, and 4 intratubular/diffuse (4/15, 26.7% types. MVD and vascular parameters in SEs were significantly higher than in SSs, showing the highest value in the intratubular/diffuse type. Seminomas observed with neoplastic cells invasion of vessels presented higher perimeter and area values than seminomas without conformed neoplastic cells invasion. Conclusion In this study, we demonstrated a positive relationship between canine SE and tumor angiogenesis. Furthermore, we also showed that a tumor cells invasion of vessels were a correlated vascular parameter. Although metastasis of canine seminomas has rarely been reported, our results support that canine SE could have high metastatic potential similar to the human counterpart. Further studies are required to clarify the relationship between canine SE and clinical data with metastatic factors.

Kim Jong-Hyuk

2010-05-01

226

An experimental study on angiogenesis in rabbit VX2 brain tumor using perfusion CT  

International Nuclear Information System (INIS)

Objective: To validate the perfusion CT method for the reflection of angiogenesis in VX2 rabbit brain tumors, and to correlate CT findings with MVD and VEGF. Methods: VX2 rabbit brain tumor model was established by injection of viable tumor cells (107/ml) through a 5 mm-hole to the right of the sagittal suture and 5 mm posterior to the coronal suture bored by dental drill. MRI was performed every 2 days after seven days of implantation to evaluate the growth of the tumor. 20 New Zealand white rabbits with tumor size over 3 mm in diameter were randomly divided into 2 groups according to the tumor growth time with those less than 3 weeks as group 1 and those more than 3 weeks as group 2, and perfusion CT were performed accordingly. CT measurements of BV, BF and PS from tumor, peritumor and contralateral normal tissue regions were obtained. After that the animals were sacrificed and 2% Evans blue (2 ml/kg) was given intravenously in 16 of these animals 1 hour prior to sacrifice to detect breakdown of the blood brain barrier. VEGF and MVD were evaluated in immunohistochemical examination of the specimens. Results: Tumor had significantly higher BV [(13.25±4.58) ml·100 g-1], BF[(166.14±69.62) ml·100 g-1·min-1], and PS(8.01 ml·min-1·100 g-1) than peritumor[(2.38±0.80)ml·100 g-1, (62.49±25.83)ml· 100 g-1·min-1 and 0.03 ml·min-1·100 g-1-1·100 g-1] and normal tissue region [(2.24±0.75)ml·100 g-1, (55.72±21.24)ml·100 g-1·min-1, and 0.04 ml·min-1·100 g-l] (P=0.000). Tumor BV [(16.41±4.12)ml·100 g-1], BF[(208.77±63.00)ml·100 g-1·min-1], and MVD (61.20± 12.93)/high power field in group 2 were significantly higher than those [(10.09±2.27) ml·100 g-l, (123.51±47.18)ml·100 g-1·min-l, and (41.40±7.34)/high power field] in group 1 (Ps=0.861, P=0.000). Conclusion: Perfusion CT can distinguish tumor from peritumor and normal tissue clearly, reflect tumor angiogenesis accurately, and provide useful information for the evaluation of brain tumor. (authors)

227

BAC CGH-array identified specific small-scale genomic imbalances in diploid DMBA-induced rat mammary tumors  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background Development of breast cancer is a multistage process influenced by hormonal and environmental factors as well as by genetic background. The search for genes underlying this malignancy has recently been highly productive, but the etiology behind this complex disease is still not understood. In studies using animal cancer models, heterogeneity of the genetic background and environmental factors is reduced and thus analysis and identification of genetic aberrations in tumors may become easier. To identify chromosomal regions potentially involved in the initiation and progression of mammary cancer, in the present work we subjected a subset of experimental mammary tumors to cytogenetic and molecular genetic analysis. Methods Mammary tumors were induced with DMBA (7,12-dimethylbenz[a]anthrazene in female rats from the susceptible SPRD-Cu3 strain and from crosses and backcrosses between this strain and the resistant WKY strain. We first produced a general overview of chromosomal aberrations in the tumors using conventional kartyotyping (G-banding and Comparative Genome Hybridization (CGH analyses. Particular chromosomal changes were then analyzed in more details using an in-house developed BAC (bacterial artificial chromosome CGH-array platform. Results Tumors appeared to be diploid by conventional karyotyping, however several sub-microscopic chromosome gains or losses in the tumor material were identified by BAC CGH-array analysis. An oncogenetic tree analysis based on the BAC CGH-array data suggested gain of rat chromosome (RNO band 12q11, loss of RNO5q32 or RNO6q21 as the earliest events in the development of these mammary tumors. Conclusions Some of the identified changes appear to be more specific for DMBA-induced mammary tumors and some are similar to those previously reported in ACI rat model for estradiol-induced mammary tumors. The later group of changes is more interesting, since they may represent anomalies that involve genes with a critical role in mammary tumor development. Genetic changes identified in this work are at very small scales and thus may provide a more feasible basis for the identification of the target gene(s. Identification of the genes underlying these chromosome changes can provide new insights to the mechanisms of mammary carcinogenesis.

Samuelson Emma

2012-08-01

228

Inhibitory effect of the peptide epitalon on the development of spontaneous mammary tumors in HER-2/neu transgenic mice.  

Science.gov (United States)

Female FVB/N HER-2/neu transgenic mice from the age of 2 months were subcutaneously injected with saline, the peptide Epitalon(R) (Ala-Glu-Asp-Gly) or with the peptide Vilon(R) (Lys-Glu) in a single dose of 1 microg/mouse for 5 consecutive days every month. Epitalon treatment reduced the cumulative number and the maximum size of tumors (p < 0.05). Furthermore, the number of mice bearing 1 mammary tumor was increased, whereas the number of mice bearing 2 or more mammary tumors was reduced in Epitalon-treated in comparison to saline-treated animals (p < 0.05). The size but not the number of lung metastases was reduced in Epitalon-treated compared to saline-treated mice (p < 0.05). The treatment with Vilon produced significant negative effects when compared to the control group, with an increased incidence of mammary cancer development (p < 0.05), a shorter mean latent period of tumors (p < 0.05) and an increased cumulative number of tumors (p < 0.05). A 3.7-fold reduction in the expression of HER-2/neu mRNA was found in mammary tumors from HER-2/neu transgenic mice treated with Epitalon compared to control animals. The expression of mRNA for HER-2/neu was also partially reduced in Vilon-treated mice, but it remained significantly higher in Vilon- than in Epitalon-treated animals (1.9-fold increase). The data demonstrate the inhibitory effect of Epitalon in the development of spontaneous mammary tumors in HER-2/neu mice, suggesting that a downregulation of HER-2/neu gene expression in mammary adenocarcinoma may be responsible, at least in part, for the antitumor effect of the peptide. PMID:12209581

Anisimov, Vladimir N; Khavinson, Vladimir K H; Provinciali, Mauro; Alimova, Irina N; Baturin, Dmitri A; Popovich, Irina G; Zabezhinski, Mark A; Imyanitov, Eugeni N; Mancini, Romina; Franceschi, Claudio

2002-09-01

229

BRCA2-Deficient Sarcomatoid Mammary Tumors Exhibit Multidrug Resistance.  

Science.gov (United States)

Pan- or multidrug resistance is a central problem in clinical oncology. Here, we use a genetically engineered mouse model of BRCA2-associated hereditary breast cancer to study drug resistance to several types of chemotherapy and PARP inhibition. We found that multidrug resistance was strongly associated with an EMT-like sarcomatoid phenotype and high expression of the Abcb1b gene, which encodes the drug efflux transporter P-glycoprotein. Inhibition of P-glycoprotein could partly resensitize sarcomatoid tumors to the PARP inhibitor olaparib, docetaxel, and doxorubicin. We propose that multidrug resistance is a multifactorial process and that mouse models are useful to unravel this. Cancer Res; 75(4); 732-41. ©2014 AACR. PMID:25511378

Jaspers, Janneke E; Sol, Wendy; Kersbergen, Ariena; Schlicker, Andreas; Guyader, Charlotte; Xu, Guotai; Wessels, Lodewyk; Borst, Piet; Jonkers, Jos; Rottenberg, Sven

2015-02-15

230

Radiation-induced responses in heterogeneous murine mammary tumor cells  

International Nuclear Information System (INIS)

The radiation responses of two heterogeneous murine tumor lines in vitro was studied at the time of X-irradiation. The proliferating (P-cells) 66 and 67 cells displayed equal radiosensitives, however, the quiescent (Q) cells were considerably more radiosensitive than the P-cells, with the 66 Q being more radioresponsive than the 67 Q. A detailed analysis of the metabolic status vs cell-cycle age (i.e., G1 vs S-phase) indicates that the cell-cycle age was the predominat influencing factor for radiation-induced responses. The data also showed that in the plateau phase Q-cell cultures pH and cell density were not the influencing factors

231

Direct measurement of reoxygenation in malignant mammary tumors after a single large dose of irradiation  

International Nuclear Information System (INIS)

Measurements of the tissue O2 partial pressure distribution in C3H mouse mammary adenocarcinomas were performed just before and 72 - 74 hrs. after X- irradiation using O2 microelectrodes of the gold in glass type. The results obtained before irradiation were similar to those usually obtained previously in fast growing murine tumors during advanced growth stages. After exposure to a single dose of 60 Gy, the distribution curve significantly changed. This change was particularly evident in the very low pO2 range which is of crucial importance for the efficacy of radiotherapy. Due to this improvement of the tumor tissue oxygenation the number of radioresistant cells can be drastically reduced in the post- irradiation period at the time of maximum reoxygenation. Judiciously chosen fractionated treatment regimens, thus, should maintain tumor cells in optimum radiosensitivity states

232

Rat differences in mammary tumor induction with estrogen and neutron radiation  

International Nuclear Information System (INIS)

Young adult female rats of either the Sprague--Dawley stock or the ACI strain were each given an implant of a compressed pellet of 5 mg diethylstilbestrol (DES) and 15 mg cholesterol 2 days before irradiation with 0.4, 1.3, or 4.0 rads of 0.43-MeV neutrons. These rats were studied, along with appropriate irradiated and nonirradiated controls, until death or for a maximum of 48 weeks. Response differences between the strain and stock included the following: DES produced both pituitary tumors and mammary adenocarcinomas (MAC) only. Neutron radiation increased mammary fibroadenoma (MFA) formation in Sprague--Dawley rats only. No interactions between DES and radiation on MAC formation in Sprague--Dawley rats. However, when DES and neutron radiation were combined, DES appeared to inhibit the MFA response to radiation in Sprague--Dawley rats. In contrast, DES appeared to act synergistically with neutron radiation on MAC formation in ACI rats. These results clearly demonstrate rat differences in mammary gland carcinogenesis in response to estrogen, to radiation, or to a combination of both agents

233

Significance and relationship between infiltrating inflammatory cell and tumor angiogenesis in hepatocellular carcinoma tissues  

Science.gov (United States)

AIM: To investigate the relationship between infiltrating inflammatory cell and tumor angiogenesis in hepatocellular carcinoma (HCC) tissues and their clinicopathological features. METHODS: The paraffin-embedded specimens from 70 cases with HCC were stained using EliVision immunohistochemistry with mAbs against CD68, tryptase, and CD34. The counts of tumor-associated macrophage (TAM), mast cell (MC) and tumor microvessel (MV) were performed in the tissue sections. RESULTS: The mean counts of TAM, MC, and MV in HCC tissues were significantly higher than those in pericarcinomatous liver tissues (TAM: 69.31?±?11.58 vs 40.23?±?10.36; MC: 16.74?±?5.67 vs 7.59?±?4.18; MV: 70.11?±?12.45 vs 38.52?±?11.16, P<0.01). The MV count in the patients with metastasis was markedly higher than that with non-metastasis (P?tumor angiogenesis. The MV count might be associated with tumor invasion and metastasis. Moreover, the MC count might be associated with tumor differentiation and prognosis of HCC. PMID:16425427

Peng, Shao-Hua; Deng, Hong; Yang, Jian-Feng; Xie, Ping-Ping; Li, Cheng; Li, Hao; Feng, De-Yun

2005-01-01

234

Pazopanib, a Receptor Tyrosine Kinase Inhibitor, Suppresses Tumor Growth through Angiogenesis in Dedifferentiated Liposarcoma Xenograft Models  

Directory of Open Access Journals (Sweden)

Full Text Available INTRODUCTION: The rarity of dedifferentiated liposarcoma (DDLPS and the lack of experimental DDLPS models limit the development of novel therapeutic strategies. Pazopanib (PAZ is a tyrosine kinase inhibitor that is approved for the treatment of non-adipocytic advanced soft tissue sarcoma. The activity of this agent has not yet been properly explored in preclinical liposarcoma models nor in a randomized phase ? clinical trial in this entity. The aim of the present study was to investigate whether PAZ had antitumor activity in DDLPS models in vivo. MATERIAL AND METHODS: We established two patient-derived DDLPS xenograft models (UZLX-STS3 and UZLX-STS5 through implantation of tumor material from sarcoma patients in athymic nude NMRI mice. An animal model of the SW872 liposarcoma cell line was also used. To investigate the efficacy of PAZ in vivo, mice bearing tumors were treated for 2 weeks with sterile water, doxorubicin (1.2 mg/kg, intraperitoneally, twice per week, PAZ [40 mg/kg, orally (p.o., twice per day], or PAZ plus doxorubicin (same schedules as for single treatments. RESULTS: Patient-derived xenografts retained the histologic and molecular features of DDLPS. PAZ significantly delayed tumor growth by decreasing proliferation and inhibited angiogenesis in all models tested. Combining the angiogenesis inhibitor with an anthracycline did not show superior efficacy. CONCLUSION: These results suggest that PAZ has potential antitumor activity in DDLPS primarily through antiangiogenic effects and therefore should be explored in clinical trials.

Haifu Li

2014-12-01

235

CEACAM6 promotes tumor angiogenesis and vasculogenic mimicry in gastric cancer via FAK signaling.  

Science.gov (United States)

CEACAM6 is a member of glycosylphosphatidylinositol-linked immunoglobulin superfamily that is implicated in a variety of human cancers. In our previous study, we reported that CEACAM6 was overexpressed in gastric cancer tissues and promoted cancer metastasis. The purpose of this study is to determine the role of CEACAM6 in tumor angiogenesis and mimicry formation. We found that overexpressed CEACAM6 promoted tubule formation dependent on HUVEC cells and vasculogenic mimicry formation of gastric cancer cells; opposing results were achieved in CEACAM6-silenced groups. Moreover, we found that mosaic vessels formed by HUVEC cells and gastric cancer cells were observed in vitro by 3D-culture assay. Overexpressed CEACAM6 in gastric cancer cells promoted tumor growth, VEGF expression and vasculogenic mimicry structures formation in vivo. In accordance with these observations, we found that phosphorylation of FAK and phosphorylation of paxillin were up-regulated in CEACAM6-overexpressing gastric cancer cells, and FAK inhibitor Y15 could reduce tubule and vasculogenic mimicry formation. These findings suggest that CEACAM6 promotes tumor angiogenesis and vasculogenic mimicry formation via FAK signaling in gastric cancer and CEACAM6 may be a new target for cancer anti-vascular treatment. PMID:25703140

Zang, Mingde; Zhang, Yunqiang; Zhang, Baogui; Hu, Lei; Li, Jianfang; Fan, Zhiyuan; Wang, Hexiao; Su, Liping; Zhu, Zhenggang; Li, Chen; Yan, Chao; Gu, Qinlong; Liu, Bingya; Yan, Min

2015-05-01

236

Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization.  

Science.gov (United States)

While tumor blood vessels share many characteristics with normal vasculature, they also exhibit morphological and functional aberrancies. For example, the neural adhesion molecule L1, which mediates neurite outgrowth, fasciculation, and pathfinding, is expressed on tumor vasculature. Here, using an orthotopic mouse model of pancreatic carcinoma, we evaluated L1 functionality in cancer vessels. Tumor-bearing mice specifically lacking L1 in endothelial cells or treated with anti-L1 antibodies exhibited decreased angiogenesis and improved vascular stabilization, leading to reduced tumor growth and metastasis. In line with these dramatic effects of L1 on tumor vasculature, the ectopic expression of L1 in cultured endothelial cells (ECs) promoted phenotypical and functional alterations, including proliferation, migration, tubulogenesis, enhanced vascular permeability, and endothelial-to-mesenchymal transition. L1 induced global changes in the EC transcriptome, altering several regulatory networks that underlie endothelial pathophysiology, including JAK/STAT-mediated pathways. In particular, L1 induced IL-6-mediated STAT3 phosphorylation, and inhibition of the IL-6/JAK/STAT signaling axis prevented L1-induced EC proliferation and migration. Evaluation of patient samples revealed that, compared with that in noncancerous tissue, L1 expression is specifically enhanced in blood vessels of human pancreatic carcinomas and in vessels of other tumor types. Together, these data indicate that endothelial L1 orchestrates multiple cancer vessel functions and represents a potential target for tumor vascular-specific therapies. PMID:25157817

Magrini, Elena; Villa, Alessandra; Angiolini, Francesca; Doni, Andrea; Mazzarol, Giovanni; Rudini, Noemi; Maddaluno, Luigi; Komuta, Mina; Topal, Baki; Prenen, Hans; Schachner, Melitta; Confalonieri, Stefano; Dejana, Elisabetta; Bianchi, Fabrizio; Mazzone, Massimiliano; Cavallaro, Ugo

2014-10-01

237

Asymmetric transcription of mouse mammary tumor virus genes in vivo and in vitro.  

OpenAIRE

Mouse mammary tumor virus (MMTV) DNA fragments were cloned into M13 bacteriophage, and the single-stranded recombinant phage DNAs were used as strand-specific nucleic acid hybridization probes to measure synthesis of plus (genomic) and minus strands of MMTV RNA in cultured cell lines and in cell-free preparations of nuclei. Pulse-labeling studies showed that synthesis of MMTV RNA in three different cell lines was highly asymmetric. In nuclear preparations from a cloned line of MMTV-infected r...

Prewitt, R. S.; Washington, L. D.; Stallcup, M. R.

1984-01-01

238

Pharmaceuticals That Cause Mammary Gland Tumors in Animals: Findings in Women  

OpenAIRE

Risk of breast cancer in women was assessed for eight pharmaceuticals that produce mammary tumors in experimental animals, using nested case-control analyses in two cohorts with prescription records in a comprehensive medical care program. The two cohorts were: 1) earlier cohort: 78,118 female members who received prescriptions in 1969-1973, of whom 2,467 developed breast cancer, and 2) later cohort: 3,289,408 female members who received prescriptions in 1994-2006 of whom 24,528 developed bre...

Friedman, Gary D.; Jiang, Sheng-fang; Udaltsova, Natalia; Chan, James; Quesenberry, Charles P.; Habel, Laurel A.

2008-01-01

239

Multivariate statistical analysis of Raman spectra to distinguish normal, tumor, lymph nodes and mastitis in mouse mammary tissues  

Science.gov (United States)

Raman spectra ( > 680) of normal mammary gland, malignant mammary gland tumors, and lymph node tissues from mice injected with 4T1 tumor cells have been recorded using 785 nm excitation laser. The state of the tissues was confirmed by standard pathological tests. The multivariate statistical analysis methods (principle component analysis and discriminant functional analysis) have been used to categorize the Raman spectra. The statistical algorithms based on the Raman spectral peak heights, clearly separated tissues into six distinct classes, including mastitis, which is clearly separated from normal and tumor. This study suggests that the Raman spectroscopy can possibly perform a real-time analysis of the human mammary tissues for the detection of cancer.

Dai, H.; Thakur, J. S.; Serhatkulu, G. K.; Pandya, A. K.; Auner, G. W.; Naik, R.; Freeman, D. C.; Naik, V. M.; Cao, A.; Klein, M. D.; Rabah, R.

2006-03-01

240

?-Mangostin extracted from the pericarp of the mangosteen (Garcinia mangostana Linn reduces tumor growth and lymph node metastasis in an immunocompetent xenograft model of metastatic mammary cancer carrying a p53 mutation  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background The mangosteen fruit has a long history of medicinal use in Chinese and Ayurvedic medicine. Recently, the compound ?-mangostin, which is isolated from the pericarp of the fruit, was shown to induce cell death in various types of cancer cells in in vitro studies. This led us to investigate the antitumor growth and antimetastatic activities of ?-mangostin in an immunocompetent xenograft model of mouse metastatic mammary cancer having a p53 mutation that induces a metastatic spectrum similar to that seen in human breast cancers. Methods Mammary tumors, induced by inoculation of BALB/c mice syngeneic with metastatic BJMC3879luc2 cells, were subsequently treated with ?-mangostin at 0, 10 and 20 mg/kg/day using mini-osmotic pumps and histopathologically examined. To investigate the mechanisms of antitumor ability by ?-mangostin, in vitro studies were also conducted. Results Not only were in vivo survival rates significantly higher in the 20 mg/kg/day ?-mangostin group versus controls, but both tumor volume and the multiplicity of lymph node metastases were significantly suppressed. Apoptotic levels were significantly increased in the mammary tumors of mice receiving 20 mg/kg/day and were associated with increased expression of active caspase-3 and -9. Other significant effects noted at this dose level were decreased microvessel density and lower numbers of dilated lymphatic vessels containing intraluminal tumor cells in mammary carcinoma tissues. In vitro, ?-mangostin induced mitochondria-mediated apoptosis and G1-phase arrest and S-phase suppression in the cell cycle. Since activation by Akt phosphorylation plays a central role in a variety of oncogenic processes, including cell proliferation, anti-apoptotic cell death, angiogenesis and metastasis, we also investigated alterations in Akt phosphorylation induced by ?-mangostin treatment both in vitro and in vivo. Quantitative analysis and immunohistochemistry showed that ?-mangostin significantly decreased the levels of phospho-Akt-threonine 308 (Thr308, but not serine 473 (Ser473, in both mammary carcinoma cell cultures and mammary carcinoma tissues in vivo. Conclusions Since lymph node involvement is the most important prognostic factor in breast cancer patients, the antimetastatic activity of ?-mangostin as detected in mammary cancers carrying a p53 mutation in the present study may have specific clinical applications. In addition, ?-mangostin may have chemopreventive benefits and/or prove useful as an adjuvant therapy, or as a complementary alternative medicine in the treatment of breast cancer.

Okuno Yasushi

2011-06-01

241

Relationship of binding specificity and structural property of the technetium-99m complexes for tumor hypoxia and tumor angiogenesis imaging  

International Nuclear Information System (INIS)

The growth of tumor requires nutrition and oxygen. Tumor cells will become hypoxic when the supply of oxygen is insufficient. Hypoxic tumor cells will not only resist radiation therapy and chemotherapy, but also induce angiogenesis for oxygen supply and for metastasis. Therefore, detection of tumor hypoxia and tumor angiogenesis with high sensitive radio labeled imaging agents is important. Hypoxic tumor cells may display some molecules as tumor markers for the specific binding with radiopharmaceuticals. Radiopharmaceuticals, unlike the non-radioactive drugs, are trace compounds in a given dosage. Due to the extreme low concentration, the non-specific accumulation of the radiotracers by blood cells and proteins, tissues, and organs can be even more serious compared to the non-radioactive drugs. The non-specific accumulation of the radiotracers can make the ratios of tumor/tissue (in terms of i.d.%/g) falling to the range of 2?7 [1-2]. Non-specific binding of radiopharmaceuticals is common, but detailed studies on it are poor documented. This presentation reports the study of the relationship of non-specific accumulation and the structural property of two type of 99mTC labeled compounds: (a) 99mTc-(amineoxime) containing either 2-nitroimidazole (2-NI, as hypoxia tumor cells specific agents), or 4-nitro- imidazole (4-NI, as control), or aniline (as reference) groups; (b) 99mTc-(arginine-glycine- aspartic acid, RGD, as tumor e-glycine- aspartic acid, RGD, as tumor angiogenesis specific agents) and 99mTc-(arginine-glycine- glutarmic acid, RGE, as control). The 99mTc-(amine-oxime) complexes, in addition to the 2-NI, 4-NI, and aniline groups, contain methyl-, ethyl-, propyl-, iso-butyl-, t-butyl-, phenyl-, and Benzyl- groups as well to make the radiotracers differing in structure and in lipophilicity , while the lipophilicity of a radiotracer plays an important role in non-specific cellular accumulation and protein binding, The results demonstrated that (1) the complex containing 2-NI showed specific accumulation to hypoxic cells, while those containing 4-NI and aniline did not; (2) among the 7 99mTc complexes containing 2-NI group, complex of greater lipophilicity showed higher level of non-specific cellular accumulation; (3) among the 99mTc complexes containing 2-NI, 4-NI, and aniline, the complexes with aniline group displayed greatest lipophilicity, greatest non-specific cellular uptake, and greatest serum protein binding. The 99mTc labeled RGD and RGE are similar in lipophilicity, but only the RGD has affinity to ?v?3 integrin proteins over expressing on tumor cells and exhibited 6 to 28 fold greater cellular accumulation than the RGE. However, the two labeled peptides, despite of the specific radioactivity, revealed identical accumulation in xenographed tumor, indicating non-specific uptake of the RGD in the tumor and non-specific binding to ?v?3 integrin proteins. These results implied that the non-specific accumulation and binding in vivo prevents a radiotracer reaching and binding to the target molecules of cancer cells. Therefore, besides binding specificity, non-specific effects of a compound is also an important aspect for consideration in designing effective radiopharmaceuticals for tumor imaging and therapy.

242

Visualization of a human mammary tumor in nude mice with In-111 labeled monoclonal antibody  

International Nuclear Information System (INIS)

A monoclonal antibody designated 103D2, specific for a tumor associated 126 kilodalton phosphoglycoprotein antigen from human mammary carcinoma (HMC) was used to determine the feasibility of tumor detection and visualization in nude mice. 103D2 was precoupled to DTPA and labeled with In-111 by the transchelation method. The labeled 103D2 (200?Ci/20?g) was injected intravenously via the tail veins into nude mice hosting a HMC BT-20(n=8). The mice were imaged at 1 hr, and every 24 hr thereafter for up to 6 days with a pinhole collimator. Four animals were killed at 48 hr and 4 at 7 days, and biodistribution determined by gamma counting of various organs. To define the specificity of distribution of the antibody, 8 additional tumor bearing animals were studied: 4 with a different In-111 labeled IgG (MOPC-21-myeloma IgG/sub 1/) and 4 with injection of ionic In-111. Localization of the In-111 labeled 103D2 was 14.72 +- 2.25% injected dose per gram of the tumor (D/g) at 48 hr, whereas In-111 labeled MOPC-21 was 5.78 +- 1.08 D/g and ionic In-111 was 3.8 +- 0.81% D/g. Tumor localization at 7 days after iv administration of In-111 labeled 103D2 was observed to be 21.97 +- 4.44% D/g. Tumors were visualized with In-111 labeled 103D2 as early as 1-2 hr after iv injection but by 24 hr, unequivocal delineation of the tumors was observed in all animals, with the best tumor delineation at 2 to 4 days. Tumor visualization with In-111 labeled 103D2 was also possible even when the tumors were inplanted in the upper abdominal region over the liver and spleen. The authors conclude that monoclonal antibody specific to a HMC associated 126 kd phosphoglycoprotein antigen can be used to visualize human mammary tumors hosted in nude mice by gamma scintigraphy

243

Aspectos clínico e cirúrgicos do tumor mamário canino: clinical and surgical evolution Canine mammary neoplasia  

Directory of Open Access Journals (Sweden)

Full Text Available As neoplasias mamárias em cadelas representam importante parcela das neoplasias em cães, merecendo atenção dos pesquisadores quanto ao diagnóstico, tratamento e prognóstico. No presente trabalho, 23 cadelas de várias raças ou cruzamentos, com idades entre 8 e 11 anos portadoras de neoplasia mamária foram estudadas. Doze eram multíparas, 6 primíparas e 5 nulíparas. Todas eram da região de Jaboticabal, SP, atendidas no Hospital Veterinário da FCAVJ-UNESP. Os animais foram avaliados clínica e radiolagicamente e submetidos à punção aspirativa da massa anormal de tecido, com agulha fina. Dessa mesma massa foi também retirado, cirurgicamente, um fragmento para exame histopatológico. A maior incidência foi de carcinoma (52,17%, seguidos por tumores mistos (17,39%. Os tratamentos cirúrgicos empregados nos 23 animais foram: mastectomia regional ou mastectomia em bloco, com remoção de linfonodos. Quinze cadelas foram tratadas com doxorubicina, na dose de 20mg/m² e ciclofosfamida, na dose de 100mg/m², aos 7, 9 e 11 dias após o ato cirúrgico. Todos os animais tiveram evolução favorável e, 12 meses após a cirurgia, 18 deles foram reavaliados, não constatando nenhuma recidiva ou surgimento de metástase.Mammary gland tumors in female dogs are among the most important neoplasia in dogs, deserving special attention regarding its diagnosis, treatment and prognosis. In this study, 23 biches of different breeds, from 8 to 11 years of age, with mammary tumors were evaluated. Of the se, 12 were multiparous, 6 primiparous and 5 were nuliparous. All dogs came from the region of Jaboticabal, SP and were referred to the Veterinary Teaching Hospital of the FCAVJ-UNESP. The animals were evaluated clinically and radiographically and the mammary mass submitted to an aspirative needle. A fragment of the tumor was also removed surgically for histopathological examination. Most tumors were classified as carcinomas (52.17°/o, followed in number by mixed tumors (17.39%. Treatment included mamectomy, partial mastectomy or "en bloc" mastectomy with removal of the lymphnodes. Most dogs also received Doxorubicin (20mg/m² and Cyclokphosphamide (100mg/m² at, 7, 9 and 11 days post-operative. All dogs recovered uneventfully and at one year post-operative. Twelve dogs were reevaluated an considered to be free of recurrence of metastasis.

Carlos Roberto Daleck

1998-03-01

244

Serum human chorionic gonadotropin is associated with angiogenesis in germ cell testicular tumors  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background Germ cell testicular tumors have survival rate that diminishes with high tumor marker levels, such as human chorionic gonadotropin (hCG. hCG may regulate vascular neoformation through vascular endothelial growth factor (VEGF. Our purpose was to determine the relationship between hCG serum levels, angiogenesis, and VEGF expression in germ cell testicular tumors. Methods We conducted a retrospective study of 101 patients. Serum levels of hCG, alpha-fetoprotein (AFP, and lactate dehydrogenase were measured prior to surgery. Vascular density (VD and VEGF tissue expression were determined by immunohistochemistry and underwent double-blind analysis. Results Histologically, 46% were seminomas and 54%, non-seminomas. Median follow-up was 43 ± 27 months. Relapse was present in 7.5% and mortality in 11.5%. Factors associated with high VD included non-seminoma type (p = 0.016, AFP ? 14.7 ng/mL (p = 0.0001, and hCG ? 25 mIU/mL (p = 0.0001. In multivariate analysis, the only significant VD-associated factor was hCG level (p = 0.04. When hCG levels were stratified, concentrations ? 25 mIU/mL were related with increased neovascularization (p Conclusion This is the first study that relates increased serum hCG levels with vascularization in testicular germ cell tumors. Hence, its expression might play a role in tumor angiogenesis, independent of VEGF expression, and may explain its association with poor prognosis. hCG might represent a molecular target for therapy.

Avilés-Salas Alejandro

2009-08-01

245

Disruption of the Lcn2 gene in mice suppresses primary mammary tumor formation but does not decrease lung metastasis  

OpenAIRE

Based largely on studies in xenograft models, lipocalin-2 (Lcn2) has been implicated in the progression of multiple types of human tumors, including breast cancer. Here we examine the role of Lcn2 in mammary tumorigenesis and lung metastasis using an in vivo molecular genetics approach. We crossed a well-characterized transgenic mouse model of breast cancer, the MMTV-PyMT (mouse mammary tumor virus-polyoma middle T antigen) mouse, with two independent gene-targeted Lcn2?/? mouse strains o...

Berger, Thorsten; Cheung, Carol C.; Elia, Andrew J.; Mak, Tak W.

2010-01-01

246

PTK6/BRK is expressed in the normal mammary gland and activated at the plasma membrane in breast tumors  

OpenAIRE

Protein Tyrosine kinase 6 (PTK6/BRK) is overexpressed in the majority of human breast tumors and breast tumor cell lines. It is also expressed in normal epithelial linings of the gastrointestinal tract, skin, and prostate. To date, expression of PTK6 has not been extensively examined in the normal human mammary gland. We detected PTK6 mRNA and protein expression in the immortalized normal MCF-10A human mammary gland epithelial cell line, and examined PTK6 expression and activation in a normal...

Peng, Maoyu; Emmadi, Rajyasree; Wang, Zebin; Wiley, Elizabeth L.; Gann, Peter H.; Khan, Seema A.; Banerji, Nilanjana; Mcdonald, William; Asztalos, Szilard; Pham, Thao N. D.; Tonetti, Debra A.; Tyner, Angela L.

2014-01-01

247

Lectin-like oxidized LDL receptor-1 is an enhancer of tumor angiogenesis in human prostate cancer cells.  

Science.gov (United States)

Altered expression and function of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) has been associated with several diseases such as endothelial dysfunction, atherosclerosis and obesity. In these pathologies, oxLDL/LOX-1 activates signaling pathways that promote cell proliferation, cell motility and angiogenesis. Recent studies have indicated that olr1 mRNA is over-expressed in stage III and IV of human prostatic adenocarcinomas. However, the function of LOX-1 in prostate cancer angiogenesis remains to be determined. Our aim was to analyze the contribution of oxLDL and LOX-1 to tumor angiogenesis using C4-2 prostate cancer cells. We analyzed the expression of pro-angiogenic molecules and angiogenesis on prostate cancer tumor xenografts, using prostate cancer cell models with overexpression or knockdown of LOX-1 receptor. Our results demonstrate that the activation of LOX-1 using oxLDL increases cell proliferation, and the expression of the pro-angiogenic molecules VEGF, MMP-2, and MMP-9 in a dose-dependent manner. Noticeably, these effects were prevented in the C4-2 prostate cancer model when LOX-1 expression was knocked down. The angiogenic effect of LOX-1 activated with oxLDL was further demonstrated using the aortic ring assay and the xenograft model of tumor growth on chorioallantoic membrane of chicken embryos. Consequently, we propose that LOX-1 activation by oxLDL is an important event that enhances tumor angiogenesis in human prostate cancer cells. PMID:25170920

González-Chavarría, Iván; Cerro, Rita P; Parra, Natalie P; Sandoval, Felipe A; Zuñiga, Felipe A; Omazábal, Valeska A; Lamperti, Liliana I; Jiménez, Silvana P; Fernandez, Edelmira A; Gutiérrez, Nicolas A; Rodriguez, Federico S; Onate, Sergio A; Sánchez, Oliberto; Vera, Juan C; Toledo, Jorge R

2014-01-01

248

Loss of STAT1 from Mouse Mammary Epithelium Results in an Increased Neu-Induced Tumor Burden  

Directory of Open Access Journals (Sweden)

Full Text Available Type I and type II classes of interferons (IFNs signal through the JAK/STAT1 pathway and are known to be important in adaptive and innate immune responses and in protection against tumors. Although STAT1 is widely considered a tumor suppressor, it remains unclear, however, if this function occurs in tumor cells (cell autonomous or if STAT1 acts primarily through immune cells. Here, the question of whether STAT1 has a cell autonomous role in mammary tumor formation was addressed in a mouse model of ERBB2/neu-induced breast cancer in the absence and presence of STAT1. For this purpose, mice that carry floxed Stat1 alleles, which permit cell-specific removal of STAT1, were generated. To induce tumors only in mammary cells lacking STAT1, Stat1 floxed mice were crossed with transgenic mice that express cre recombinase and the neu oncogene under the mouse mammary tumor virus LTR (Stat1fl/fl NIC. Stat1 was effectively deleted in mammary epithelium of virgin Stat1fl/fl NIC females. Time-to-tumor onset was significantly shorter in Stat1fl/fl NIC females than in WT NIC (Wilcoxon rank sum test, P = .02. The median time-to-tumor onset in the Stat1fl/fl NIC mice was 49.4 weeks, whereas it was 62.4 weeks in the WT NIC mice. These results suggest that STAT1 in mammary epithelial cells may play a role in suppressing tumorigenesis. The Stat1 floxed allele described in this study is also a unique resource to determine the cellular targets of IFNs and STAT1 action, which should aid our understanding and appreciation of these pathways.

Peter J. Klover

2010-11-01

249

Effects of Acanthus ebracteatus Vahl on tumor angiogenesis and on tumor growth in nude mice implanted with cervical cancer  

Directory of Open Access Journals (Sweden)

Full Text Available Taksanee Mahasiripanth,1 Sanya Hokputsa,2 Somchai Niruthisard,3 Parvapan Bhattarakosol,4 Suthiluk Patumraj51Inter-Department of Physiology, Chulalongkorn University, Bangkok, Thailand; 2Research and Development Institute, Government Pharmaceutical Organization, Bangkok, Thailand; 3Obstetrics and Gynecology Department, 4Department of Microbiology, 5Center of Excellence for Microcirculation, Faculty of Medicine, Chulalongkorn University, Bangkok, ThailandPurpose: The aim of this study was to examine the effects of the crude extract of Acanthus ebracteatus Vahl (AE on tumor growth and angiogenesis by utilizing a tumor model in which nude mice were implanted with cervical cancer cells containing human papillomavirus 16 DNA (HPV-16 DNA.Materials and methods: The growth-inhibitory effect of AE was investigated in four different cell types: CaSki (HPV-16 positive, HeLa (HPV-18 positive, hepatocellular carcinoma cells (HepG2, and human dermal fibroblast cells (HDFs. The cell viabilities and IC50 values of AE were determined in cells incubated with AE for different lengths of time. To conduct studies in vivo, female BALB/c nude mice (aged 6–7 weeks, weighing 20–25 g were used. A cervical cancer-derived cell line (CaSki with integrated HPV-16 DNA was injected subcutaneously (1 × 107 cells/200 µL in the middle dorsum of each animal (HPV group. One week after injection, mice were fed orally with AE crude extract at either 300 or 3000 mg/kg body weight/day for 14 or 28 days (HPV-AE groups. Tumor microvasculature and capillary vascularity were determined using laser scanning confocal microscopy. Tumor tissue was collected from each mouse to evaluate tumor histology and vascular endothelial growth factor (VEGF immunostaining.Results: The time-response curves of AE and the dose-dependent effect of AE on growth inhibition were determined. After a 48-hour incubation period, the IC50 of AE in CaSki was discovered to be significantly different from that of HDFs (P < 0.05. A microvascular network was observed around the tumor area in the HPV group on days 21 and 35. Tumor capillary vascularity in the HPV group was significantly increased compared with the control group (P < 0.001. High-dose treatment of AE extract (HPV-3000AE group significantly attenuated the increase in VEGF expression and tumor angiogenesis in mice that received either the 14- or 28-day treatment period (P < 0.001.Conclusion: Our novel findings demonstrated that AE crude extract could inhibit cervical cancer growth, VEGF expression, and angiogenesis in a CaSki-cell transplant model in mice.Keywords: Acanthus ebracteatus Vahl, tumor angiogenesis, VEGF, CaSki cell-implanted nude mice, capillary vascularity, laser scanning confocal microscopy

Mahasiripanth T

2012-08-01

250

Direct external imaging of nascent cancer, tumor progression, angiogenesis, and metastasis on internal organs in the fluorescent orthotopic model  

OpenAIRE

Mouse tumor models have undergone profound improvements in the fidelity of emulating human disease. Replacing ectopic s.c. implantation with organ-specific orthotopic implantation reproduces human tumor growth and metastasis. Strong fluorescent labeling with green fluorescent protein along with inexpensive video detectors, positioned externally to the mouse, allows the monitoring of details of tumor growth, angiogenesis, and metastatic spread. However, the sensitivity of external imaging is l...

Yang, Meng; Baranov, Eugene; Wang, Jin-wei; Jiang, Ping; Wang, Xiaoen; Sun, Fang-xian; Bouvet, Michael; Moossa, A. R.; Penman, Sheldon; Hoffman, Robert M.

2002-01-01

251

Mechanisms regulating tumor angiogenesis by 12-lipoxygenase in prostate cancer cells.  

Science.gov (United States)

12-Lipoxygenase utilizes arachidonic acid to synthesize 12(S)-hydroperoxyeicosatetraenoic acid, which is converted to the end product 12(S)-hydroxyeicosatetraenoic acid, an eicosanoid that promotes tumorigenesis and metastasis. Increased expression of 12-lipoxygenase has been documented in a number of carcinomas. When overexpressed in human prostate or breast cancer, 12-lipoxygenase promotes tumor angiogenesis and growth in vivo. The present study was undertaken to delineate the mechanisms by which 12-lipoxygenase enhances angiogenesis. Herein we report that nordihydroguaiaretic acid, a pan inhibitor of lipoxygenases and baicalein, a selective inhibitor of 12-lipoxygenase, reduced VEGF expression in human prostate cancer PC-3 cells. Overexpression of 12-lipoxygenase in PC-3 cells resulted in a 3-fold increase in VEGF protein level when compared with vector control cells. An increase in PI 3-kinase activity was found in 12-LOX-transfected PC-3 cells and inhibition of PI 3-kinase by LY294002 significantly reduced VEGF expression. Northern blot and real time PCR analyses revealed an elevated VEGF transcript level in PC-3 cells transfected with a 12-lipoxygenase expression construct. Using a VEGF promoter luciferase construct (-1176/+54), we found a 10-fold increase in VEGF promoter activity in 12-lipoxygenase-transfected PC-3 cells. The region located between -88 and -66 of the VEGF promoter was identified as 12-lipoxygenase responsive using VEGF promoter-based luciferase assays. Further analysis with mutant constructs indicated Sp1 as a transcription factor required for 12-lipoxygenase stimulation of VEGF. Neutralization of VEGF by a function-blocking antibody significantly decreased the ability of 12-lipoxygenase-transfected PC-3 cells to stimulate endothelial cell migration, suggesting VEGF as an important effector for 12-lipoxygenase-mediated stimulation of tumor angiogenesis. PMID:16638750

Nie, Daotai; Krishnamoorthy, Sriram; Jin, Rongxian; Tang, Keqin; Chen, YuChyu; Qiao, Yan; Zacharek, Alex; Guo, Yande; Milanini, Julie; Pages, Gilles; Honn, Kenneth V

2006-07-01

252

Evaluation of angiogenesis of VX2 soft tissue tumor by arterial spin labeling perfusion imaging  

International Nuclear Information System (INIS)

Objective: To evaluate the relationship between the blood flow values generated from MR arterial spin labeling (ASL) perfusion imaging and pathologic indicators of angiogenesis including microvascular density (MVD) counts and vascular endothelial growth factor (VEGF) expression levels of VX2 carcinoma in rabbit soft tissue. Methods: VX2 tumor was inoculated in the muscular tissue of right posterior limbs of 18 healthy New Zealand white rabbits, on which arterial spin labeling perfusion imaging was performed by using flow sensitive alternating inversion recovery pulse sequence 3 to 4 weeks later. Arterial spin labeling images were transferred to an independent computer for post-processing and blood flow (BF) maps were generated from them. BF values were measured in 2-4 regions of interest (ROIs) for each tumor. The rabbits were sacrificed after MR imaging. The gross specimens of tumors were obtained and tumor tissues were taken from the non-necrotic regions corresponding to ROIs on BF maps. Immunohistochemical staining of the specimens was performed by using CD31 monoclonal antibody to calculate MVD counts, using VEGF antibody to calculate VEGF expression levels. Correlation between BF values and MVD counts as well as between BF values and VEGF expression levels was evaluated using Spearman, correlative analysis. Results: On BF maps, viable tumor tissues showed high BF values compared with muscle, but there were areas without blood perfusion in some tumors. Under microscope, the microvessels positively stained by CD31 appeared as light brown areas, and the cells positively staied by VEGF showed reddish brown areas within their cytoplasm. Totally 39 pieces of VX2 tumor tissue were analyzed. There was a significant positive correlation between the BF values (M =6.4 ml · 100 g-1 · min-1) and MVD counts (M=6.8) (r=0.906, P<0.01), and no significant correlation between BF values and VEGF expression levels (M=8%) (r= 0.116, P=0.483). Conclusion: BF value can be used in evaluating angiogenesis of soft tissue tumor through its reflection of MVD counts, and thus may be helpful in evaluating the prognosis of soft tissue tumor and making plan for their treatment. (authors)

253

Prognostic significance of tumor angio-genesis in advanced breast carcinoma: And Indian experience  

International Nuclear Information System (INIS)

Angio-genesis is essential for tumor growth and metastasis. In the present study we investigated the prognostic significance of microvessels (MV) density using immunohisto-localization of factor VIII antigen i 51 breast cancer patients. We counted microvessels per 200 x field in the most active areas of neovasculilarization by staining factor VIII related antigen and correlated with stage, LN involvement and histologic grade. Patient who subsequently developed metastases had significantly high MV counts than patients without metastatic disease (p25 MV per 200 x field had tumor recurrence faster as compared with patients having <25 MV (p<0.02). Thus, the MV count correlates with the prediction for metastasis and poor survival. Such an indicator would be useful in selection of a subgroup of patients with breast cancer who are at high risk for having occult metastasis at presentation and subsequently would benefit from aggressive therapy. (author)

254

Anticancer activity of phenolic antioxidants against breast cancer cells and a spontaneous mammary tumor  

Directory of Open Access Journals (Sweden)

Full Text Available Phenolics such as ferulic, caffeic, gallic acids and curcumin were tested for their potential anti proliferative and cytotoxic properties in human breast cancer cell line (MCF-7 as well as on a spontaneous mammary adenocarcinoma tumor. As a single agent, caffeic acid showed substantial growth inhibitory activity. In combination with cisplatin it was also found to be effective. For the current study we used a chick embryo model to assess antiangiogenic activity. Curcumin and its beta cyclodextrin complex were observed to interfere with capillary formation. The selected phenolics were structurally related which allowed us to gather additional information regarding the structure - activity relationship underlying the biological activity of these bioactive compounds. It was verified that the hydroxylated acid derivatives yielded better results than the merely hydroxylated ones in these tumor systems.

Indap M

2006-01-01

255

Oncogene pathway activation in mammary tumors dictates FDG-PET uptake.  

Science.gov (United States)

Increased glucose utilization is a hallmark of human cancer that is used to image tumors clinically. In this widely used application, glucose uptake by tumors is monitored by positron emission tomography of the labeled glucose analogue 2[(18)F]fluoro-2-deoxy-D-glucose (FDG). Despite its widespread clinical use, the cellular and molecular mechanisms that determine FDG uptake--and that underlie the heterogeneity observed across cancers-remain poorly understood. In this study, we compared FDG uptake in mammary tumors driven by the Akt1, c-MYC, HER2/neu, Wnt1, or H-Ras oncogenes in genetically engineered mice, correlating it to tumor growth, cell proliferation, and expression levels of gene involved in key steps of glycolytic metabolism. We found that FDG uptake by tumors was dictated principally by the driver oncogene and was not independently associated with tumor growth or cellular proliferation. Oncogene downregulation resulted in a rapid decrease in FDG uptake, preceding effects on tumor regression, irrespective of the baseline level of uptake. FDG uptake correlated positively with expression of hexokinase-2 (HK2) and hypoxia-inducible factor-1? (HIF1?) and associated negatively with PFK-2b expression and p-AMPK. The correlation between HK2 and FDG uptake was independent of all variables tested, including the initiating oncogene, suggesting that HK2 is an independent predictor of FDG uptake. In contrast, expression of Glut1 was correlated with FDG uptake only in tumors driven by Akt or HER2/neu. Together, these results demonstrate that the oncogenic pathway activated within a tumor is a primary determinant of its FDG uptake, mediated by key glycolytic enzymes, and provide a framework to interpret effects on this key parameter in clinical imaging. PMID:25239452

Alvarez, James V; Belka, George K; Pan, Tien-Chi; Chen, Chien-Chung; Blankemeyer, Eric; Alavi, Abass; Karp, Joel S; Chodosh, Lewis A

2014-12-15

256

Dendra2 photoswitching through the Mammary Imaging Window.  

Science.gov (United States)

In the last decade, intravital microscopy of breast tumors in mice and rats at single-cell resolution has resulted in important insights into mechanisms of metastatic behavior such as migration, invasion and intravasation of tumor cells, angiogenesis, and immune cells response. We have recently reported a technique to image orthotopic mammary carcinomas over multiple intravital imaging sessions in living mice. For this, we have developed a Mammary Imaging Window (MIW) and optimized imaging parameters for Dendra2 photoswitching and imaging in vivo. Here, we describe the protocol for the manufacturing of MIW, insertion of the MIW on top of a tumor and imaging of the Dendra2- labeled tumor cells using a custom built imaging box. This protocol can be used to image the metastatic behavior of tumor cells in distinct microenvironments in tumors and allows for long term imaging of blood vessels, tumor cells and host cells. PMID:19578330

Gligorijevic, Bojana; Kedrin, Dmitriy; Segall, Jeffrey E; Condeelis, John; van Rheenen, Jacco

2009-01-01

257

Positron emission tomography imaging of CD105 expression during tumor angiogenesis  

International Nuclear Information System (INIS)

Overexpression of CD105 (endoglin) correlates with poor prognosis in many solid tumor types. Tumor microvessel density (MVD) assessed by CD105 staining is the current gold standard for evaluating tumor angiogenesis in the clinic. The goal of this study was to develop a positron emission tomography (PET) tracer for imaging CD105 expression. TRC105, a chimeric anti-CD105 monoclonal antibody, was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and labeled with 64Cu. FACS analysis and microscopy studies were performed to compare the CD105 binding affinity of TRC105 and DOTA-TRC105. PET imaging, biodistribution, blocking, and ex vivo histology studies were performed on 4T1 murine breast tumor-bearing mice to evaluate the ability of 64Cu-DOTA-TRC105 to target tumor angiogenesis. Another chimeric antibody, cetuximab, was used as an isotype-matched control. FACS analysis of human umbilical vein endothelial cells (HUVECs) revealed no difference in CD105 binding affinity between TRC105 and DOTA-TRC105, which was further validated by fluorescence microscopy. 64Cu labeling was achieved with high yield and specific activity. Serial PET imaging revealed that the 4T1 tumor uptake of the tracer was 8.0 ± 0.5, 10.4 ± 2.8, and 9.7 ± 1.8%ID/g at 4, 24, and 48 h post-injection, respectively (n = 3), higher than most organs at late time points which provided excellent tumor contrast. Biodistribution data as measured by gammiodistribution data as measured by gamma counting were consistent with the PET findings. Blocking experiments, control studies with 64Cu-DOTA-cetuximab, as well as ex vivo histology all confirmed the in vivo target specificity of 64Cu-DOTA-TRC105. This is the first successful PET imaging study of CD105 expression. Fast, prominent, persistent, and CD105-specific uptake of the tracer in the 4T1 tumor was observed. Further studies are warranted and currently underway. (orig.)

258

Positron emission tomography imaging of CD105 expression during tumor angiogenesis  

Energy Technology Data Exchange (ETDEWEB)

Overexpression of CD105 (endoglin) correlates with poor prognosis in many solid tumor types. Tumor microvessel density (MVD) assessed by CD105 staining is the current gold standard for evaluating tumor angiogenesis in the clinic. The goal of this study was to develop a positron emission tomography (PET) tracer for imaging CD105 expression. TRC105, a chimeric anti-CD105 monoclonal antibody, was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and labeled with {sup 64}Cu. FACS analysis and microscopy studies were performed to compare the CD105 binding affinity of TRC105 and DOTA-TRC105. PET imaging, biodistribution, blocking, and ex vivo histology studies were performed on 4T1 murine breast tumor-bearing mice to evaluate the ability of {sup 64}Cu-DOTA-TRC105 to target tumor angiogenesis. Another chimeric antibody, cetuximab, was used as an isotype-matched control. FACS analysis of human umbilical vein endothelial cells (HUVECs) revealed no difference in CD105 binding affinity between TRC105 and DOTA-TRC105, which was further validated by fluorescence microscopy. {sup 64}Cu labeling was achieved with high yield and specific activity. Serial PET imaging revealed that the 4T1 tumor uptake of the tracer was 8.0 {+-} 0.5, 10.4 {+-} 2.8, and 9.7 {+-} 1.8%ID/g at 4, 24, and 48 h post-injection, respectively (n = 3), higher than most organs at late time points which provided excellent tumor contrast. Biodistribution data as measured by gamma counting were consistent with the PET findings. Blocking experiments, control studies with {sup 64}Cu-DOTA-cetuximab, as well as ex vivo histology all confirmed the in vivo target specificity of {sup 64}Cu-DOTA-TRC105. This is the first successful PET imaging study of CD105 expression. Fast, prominent, persistent, and CD105-specific uptake of the tracer in the 4T1 tumor was observed. Further studies are warranted and currently underway. (orig.)

Hong, Hao [University of Wisconsin - Madison, Department of Radiology, Madison, WI (United States); Yang, Yunan [University of Wisconsin - Madison, Department of Radiology, Madison, WI (United States); Third Military Medical University, Department of Ultrasound, Xinqiao Hospital, Chongqing (China); Zhang, Yin; Engle, Jonathan W.; Barnhart, Todd E.; Nickles, Robert J. [University of Wisconsin - Madison, Department of Medical Physics, Madison, WI (United States); Leigh, Bryan R. [TRACON Pharmaceuticals, Inc., San Diego, CA (United States); Cai, Weibo [University of Wisconsin - Madison, Department of Radiology, Madison, WI (United States); University of Wisconsin - Madison, Department of Medical Physics, Madison, WI (United States); University of Wisconsin Carbone Cancer Center, Madison, WI (United States); University of Wisconsin - Madison, Departments of Radiology and Medical Physics, School of Medicine and Public Health, Madison, WI (United States)

2011-07-15

259

SOX11 promotes tumor angiogenesis through transcriptional regulation of PDGFA in mantle cell lymphoma.  

Science.gov (United States)

SOX11 is overexpressed in several solid tumors and in the vast majority of aggressive mantle cell lymphomas (MCLs). We have recently proven that SOX11 silencing reduces tumor growth in a MCL xenograft model, consistent with the indolent clinical course of the human SOX11-negative mantle cell lymphoma (MCL). However, the direct oncogenic mechanisms and downstream effector pathways implicated in SOX11-driven transformation remain poorly understood. Here, we observed that SOX11-positive xenograft and human primary MCL tumors overexpressed angiogenic gene signatures and had a higher microvascular density compared with their SOX11-negative counterparts. Conditioned media of SOX11-positive MCL cell lines induced in vitro endothelial cell proliferation, migration, tube formation, and activation of downstream angiogenic pathways. We identified PDGFA as a SOX11 direct target gene upregulated in MCL cells whose inhibition impaired SOX11-enhanced in vitro angiogenic effects on endothelial cells. In addition, platelet-derived growth factor A (PDGFA) was overexpressed in SOX11-positive but not in SOX11-negative MCL. In vivo, imatinib impaired tumor angiogenesis and lymphoma growth in SOX11-positive MCL xenograft tumors. Overall, our results demonstrate a prominent role for SOX11 as a driver of proangiogenic signals in MCL, and highlight the SOX11-PDGFA axis as a potential therapeutic target for the treatment of this aggressive disease. PMID:25092176

Palomero, Jara; Vegliante, Maria Carmela; Rodríguez, Marta Leonor; Eguileor, Alvaro; Castellano, Giancarlo; Planas-Rigol, Ester; Jares, Pedro; Ribera-Cortada, Inmaculada; Cid, Maria C; Campo, Elias; Amador, Virginia

2014-10-01

260

Kalkitoxin inhibits angiogenesis, disrupts cellular hypoxic signaling, and blocks mitochondrial electron transport in tumor cells.  

Science.gov (United States)

The biologically active lipopeptide kalkitoxin was previously isolated from the marine cyanobacterium Moorea producens (Lyngbya majuscula). Kalkitoxin exhibited N-methyl-d-aspartate (NMDA)-mediated neurotoxicity and acted as an inhibitory ligand for voltage-sensitive sodium channels in cultured rat cerebellar granule neurons. Subsequent studies revealed that kalkitoxin generated a delayed form of colon tumor cell cytotoxicity in 7-day clonogenic cell survival assays. Cell line- and exposure time-dependent cytostatic/cytotoxic effects were previously observed with mitochondria-targeted inhibitors of hypoxia-inducible factor-1 (HIF-1). The transcription factor HIF-1 functions as a key regulator of oxygen homeostasis. Therefore, we investigated the ability of kalkitoxin to inhibit hypoxic signaling in human tumor cell lines. Kalkitoxin potently and selectively inhibited hypoxia-induced activation of HIF-1 in T47D breast tumor cells (IC50 5.6 nM). Mechanistic studies revealed that kalkitoxin inhibits HIF-1 activation by suppressing mitochondrial oxygen consumption at electron transport chain (ETC) complex I (NADH-ubiquinone oxidoreductase). Further studies indicate that kalkitoxin targets tumor angiogenesis by blocking the induction of angiogenic factors (i.e., VEGF) in tumor cells. PMID:25803180

Morgan, J Brian; Liu, Yang; Coothankandaswamy, Veena; Mahdi, Fakhri; Jekabsons, Mika B; Gerwick, William H; Valeriote, Frederick A; Zhou, Yu-Dong; Nagle, Dale G

2015-01-01

261

Tetrandrine Suppresses Cancer Angiogenesis and Metastasis in 4T1 Tumor Bearing Mice.  

Science.gov (United States)

Metastasis remains the most deadly aspect of cancer and still evades direct treatment. Thus, there is a great need to develop new treatment regimens to suppress tumor cells that have escaped surgical removal or that may have already disseminated. We have found that tetrandrine (TET) exhibits anticolon cancer activity. Here, we investigate the inhibition effect of TET to breast cancer metastasis, angiogenesis and its molecular basis underlying TET's anticancer activity. We compare TET with chemotherapy drug doxorubicin in 4T1 tumor bearing BALB/c mice model and find that TET exhibits an anticancer metastatic and antiangiogenic activities better than those of doxorubicin. The lung metastatic sites were decreased by TET, which is confirmed by bioluminescence imaging in vivo. On the other hand, laser doppler perfusion imaging (LDI) was used for measuring the blood flow of tumor in 4T1-tumor bearing mice. As a result, the local blood perfusion of tumor was markedly decreased by TET after 3 weeks. Mechanistically, TET treatment leads to a decrease in p-ERK level and an increase in NF- ? B levels in HUVECs. TET also regulated metastatic and angiogenic related proteins, including vascular endothelial growth factor, hypoxia-inducible factor-1 ? , integrin ? 5, endothelial cell specific molecule-1, and intercellular adhesion molecule-1 in vivo. PMID:23762115

Gao, Jian-Li; Ji, Xing; He, Tong-Chuan; Zhang, Qi; He, Kai; Zhao, Yan; Chen, Su-Hong; Lv, Gui-Yuan

2013-01-01

262

Antisense targeting of perlecan blocks tumor growth and angiogenesis in vivo.  

Science.gov (United States)

Perlecan, a ubiquitous heparan sulfate proteoglycan, possesses angiogenic and growth-promoting attributes primarily by acting as a coreceptor for basic fibroblast growth factor (FGF-2). In this report we blocked perlecan expression by using either constitutive CMV-driven or doxycycline- inducible antisense constructs. Growth of colon carcinoma cells was markedly attenuated upon obliteration of perlecan gene expression and these effects correlated with reduced responsiveness to and affinity for mitogenic keratinocyte growth factor (FGF-7). Exogenous perlecan effectively reconstituted the activity of FGF-7 in the perlecan-deficient cells. Moreover, soluble FGF-7 specifically bound immobilized perlecan in a heparan sulfate-independent manner. In both tumor xenografts induced by human colon carcinoma cells and tumor allografts induced by highly invasive mouse melanoma cells, perlecan suppression caused substantial inhibition of tumor growth and neovascularization. Thus, perlecan is a potent inducer of tumor growth and angiogenesis in vivo and therapeutic interventions targeting this key modulator of tumor progression may improve cancer treatment. PMID:9788974

Sharma, B; Handler, M; Eichstetter, I; Whitelock, J M; Nugent, M A; Iozzo, R V

1998-10-15

263

Hyperoxia increases the uptake of 5-fluorouracil in mammary tumors independently of changes in interstitial fluid pressure and tumor stroma  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background Hypoxia is associated with increased resistance to chemo- and radiation-therapy. Hyperoxic treatment (hyperbaric oxygen has previously been shown to potentiate the effect of some forms of chemotherapy, and this has been ascribed to enhanced cytotoxicity or neovascularisation. The aim of this study was to elucidate whether hyperoxia also enhances any actual uptake of 5FU (5-fluorouracil into the tumor tissue and if this can be explained by changes in the interstitium and extracellular matrix. Methods One group of tumor bearing rats was exposed to repeated hyperbaric oxygen (HBO treatment (2 bar, pO2 = 2 bar, 4 exposures à 90 min, whereas one group was exposed to one single identical HBO treatment. Animals housed under normal atmosphere (1 bar, pO2 = 0.2 bar served as controls. Three doses of 5FU were tested for dose response. Uptake of [3H]-5FU in the tumor was assessed, with special reference to factors that might have contributed, such as interstitial fluid pressure (Pif, collagen content, oxygen stress (measured as malondialdehyd levels, lymphatics and transcapillary transport in the tumors. Results The uptake of the cytostatic agent increases immediately after a single HBO treatment (more than 50%, but not 24 hours after the last repeated HBO treatment. Thus, the uptake is most likely related to the transient increase in oxygenation in the tumor tissue. Factors like tumor Pif and collagen content, which decreased significantly in the tumor interstitium after repeated HBO treatment, was without effect on the drug uptake. Conclusion We showed that hyperoxia increases the uptake of [3H]-5FU in DMBA-induced mammary tumors per se, independently of changes in Pif, oxygen stress, collagen fibril density, or transendothelial transport alone. The mechanism by which such an uptake occur is still not elucidated, but it is clearly stimulated by elevated pO2.

Salvesen Gerd S

2009-12-01

264

Paracrine Interactions between Adipocytes and Tumor Cells Recruit and Modify Macrophages to the Mammary Tumor Microenvironment: The Role of Obesity and Inflammation in Breast Adipose Tissue.  

Science.gov (United States)

The relationship between obesity and breast cancer (BC) has focused on serum factors. However, the mammary gland contains adipose tissue (AT) which may enable the crosstalk between adipocytes and tumor cells contributing to tumor macrophage recruitment. We hypothesize that the breast AT (bAT) is inflamed in obese females and plays a major role in breast cancer development. The effects of this interplay on macrophage chemotaxis were examined in vitro, using co-cultures of mouse macrophages, mammary tumor cells and adipocytes. Macrophages were exposed to the adipocyte and tumor paracrine factors leptin, CCL2 and lauric acid (alone or in combinations). In cell supernatants Luminex identified additional molecules with chemotactic and other pro-tumor functions. Focus on the adipokine leptin, which has been shown to have a central role in breast cancer pathogenesis, indicated it modulates macrophage phenotypes and functions. In vivo experiments demonstrate that mammary tumors from obese mice are larger and that bAT from obese tumor-bearers contains higher numbers of macrophages/CLS and hypertrophic adipocytes than bAT from lean tumor-bearers, thus confirming it is more inflamed. Also, bAT distal from the tumor is more inflamed in obese than in lean mice. Our results reveal that bAT plays a role in breast cancer development in obesity. PMID:25599228

Santander, Ana M; Lopez-Ocejo, Omar; Casas, Olivia; Agostini, Thais; Sanchez, Lidia; Lamas-Basulto, Eduardo; Carrio, Roberto; Cleary, Margot P; Gonzalez-Perez, Ruben R; Torroella-Kouri, Marta

2015-01-01

265

Paracrine Interactions between Adipocytes and Tumor Cells Recruit and Modify Macrophages to the Mammary Tumor Microenvironment: The Role of Obesity and Inflammation in Breast Adipose Tissue  

Directory of Open Access Journals (Sweden)

Full Text Available The relationship between obesity and breast cancer (BC has focused on serum factors. However, the mammary gland contains adipose tissue (AT which may enable the crosstalk between adipocytes and tumor cells contributing to tumor macrophage recruitment. We hypothesize that the breast AT (bAT is inflamed in obese females and plays a major role in breast cancer development. The effects of this interplay on macrophage chemotaxis were examined in vitro, using co-cultures of mouse macrophages, mammary tumor cells and adipocytes. Macrophages were exposed to the adipocyte and tumor paracrine factors leptin, CCL2 and lauric acid (alone or in combinations. In cell supernatants Luminex identified additional molecules with chemotactic and other pro-tumor functions. Focus on the adipokine leptin, which has been shown to have a central role in breast cancer pathogenesis, indicated it modulates macrophage phenotypes and functions. In vivo experiments demonstrate that mammary tumors from obese mice are larger and that bAT from obese tumor-bearers contains higher numbers of macrophages/CLS and hypertrophic adipocytes than bAT from lean tumor-bearers, thus confirming it is more inflamed. Also, bAT distal from the tumor is more inflamed in obese than in lean mice. Our results reveal that bAT plays a role in breast cancer development in obesity.

Ana M. Santander

2015-01-01

266

Twist1 induces CCL2 and recruits macrophages to promote angiogenesis  

OpenAIRE

The transcription factor Twist1 induces Epithelial-Mesenchymal Transition and extracellular matrix degradation to promote tumor metastasis. Although Twist1 also plays a role in embryonic vascular development and tumor angiogenesis, the molecular mechanisms that underlie these processes are not as well understood. Here, we report a novel function for Twist1 in modifying the tumor microenvironment to promote progression. We found that expression of Twist1 in human mammary epithelial cells poten...

Low-marchelli, Janine M.; Ardi, Veronica C.; Vizcarra, Edward A.; Rooijen, Nico; Quigley, James P.; Yang, Jing

2013-01-01

267

PTK6/BRK is expressed in the normal mammary gland and activated at the plasma membrane in breast tumors.  

Science.gov (United States)

Protein Tyrosine kinase 6 (PTK6/BRK) is overexpressed in the majority of human breast tumors and breast tumor cell lines. It is also expressed in normal epithelial linings of the gastrointestinal tract, skin, and prostate. To date, expression of PTK6 has not been extensively examined in the normal human mammary gland. We detected PTK6 mRNA and protein expression in the immortalized normal MCF-10A human mammary gland epithelial cell line, and examined PTK6 expression and activation in a normal human breast tissue microarray, as well as in human breast tumors. Phosphorylation of tyrosine residue 342 in the PTK6 activation loop corresponds with its activation. Similar to findings in the prostate, we detect nuclear and cytoplasmic PTK6 in normal mammary gland epithelial cells, but no phosphorylation of tyrosine residue 342. However, in human breast tumors, striking PTK6 expression and phosphorylation of tyrosine 342 is observed at the plasma membrane. PTK6 is expressed in the normal human mammary gland, but does not appear to be active and may have kinase-independent functions that are distinct from its cancer promoting activities at the membrane. Understanding consequences of PTK6 activation at the plasma membrane may have implications for developing novel targeted therapies against this kinase. PMID:25153721

Peng, Maoyu; Emmadi, Rajyasree; Wang, Zebin; Wiley, Elizabeth L; Gann, Peter H; Khan, Seema A; Banerji, Nilanjana; McDonald, William; Asztalos, Szilard; Pham, Thao N D; Tonetti, Debra A; Tyner, Angela L

2014-08-15

268

1H-NMR METABONOMICS ANALYSIS OF SERA DIFFERENTIATES BETWEEN MAMMARY TUMOR-BEARING MICE AND HEALTHY CONTROLS  

Science.gov (United States)

Global analysis of 1H-NMR spectra of serum is an appealing approach for the rapid detection of cancer. To evaluate the usefulness of this method in distinguishing between mammary tumor-bearing mice and healthy controls, we conducted 1H-NMR metabonomic analyses on serum samples ob...

269

A histopathological study of spontaneous Wistar rat mammary tumor. The relation of the histopathological findings and X-ray CT image  

Energy Technology Data Exchange (ETDEWEB)

The spontaneous malignant mammary tumor of Wistar female rat is relatively rare. The study of the tumor has not been performed from the histopathological and radiological points of view, especially in comparison with histopathological and X-ray CT findings. We examined the spontaneous mammary tumor of a 28 weeks Wistar female rat and studied it to make clear the relationship between histopathological findings and X-ray CT images. The results obtained were as follows; 1. Histopathologically, the necrosis and calcification were observed in the mammary tumor. These findings corresponded to the low density and several high density foci in the precontrast X-ray CT image of the mammary tumor. 2. Histopathologically, the nodular tubular pattern with separation of vascular fibrous tissue was observed in the tumor. The finding was corresponded to the position marked enhancement in the postcontrast CT image. (author).

Jinkoji, Tomio; Kiba, Hideo; Kaneda, Takashi; Suzuki, Hiromi; Yamamoto, Hirotsugu [Nihon Univ., Matsudo, Chiba (Japan). School of Dentistry at Matsudo

1995-09-01

270

Protein tyrosine phosphatase receptor type O expression in the tumor niche correlates with reduced tumor growth, angiogenesis, circulating tumor cells and metastasis of breast cancer.  

Science.gov (United States)

Protein tyrosine phosphatase receptor type O (PTPRO) has been recognized as a tumor suppressor in various types of cancer cells. However, little attention has been given to the role of PTPRO expression in the tumor microenvironment. We aimed to reveal the role of PTPRO in the breast cancer niche. Py8119 mouse breast cancer cells were implanted orthotopically into female wild-type or ptpro-/- C57Bl/6 mice. We observed that the loss of PTPRO in the tumor niche was correlated with larger tumor volume, more metastases, increased number of circulating tumor cells (CTCs), less apoptosis and reduced necrosis rates in the orthotopic mouse model of breast cancer. The tumor microenvironment in the ptpro-/- mice also showed increased microvessel density. Moreover, an intracardiac injection mouse model was used to determine the role of PTPRO in the pre-metastatic niche. Notably, more metastases were observed in the mice of the ptpro-/- group. Taken together, PTPRO expression in the tumor niche prevents tumor growth and the formation of metastases of breast cancer, in part by attenuating tumor-associated angiogenesis and inducing the apoptosis and necrosis of tumor cells. PMID:25646811

Liu, Zhao; Hou, Jiajie; Ren, Lidong; He, Jing; Sun, Beicheng; Sun, Lu-Zhe; Wang, Shui

2015-04-01

271

Inhibition of tumor angiogenesis by TTF1 from extract of herbal medicine  

Directory of Open Access Journals (Sweden)

Full Text Available AIM: To study the inhibition of tumor angiogenesis by 5,2,4´-trihydroxy-6,7,5´-trimethoxyflavone (TTF1 isolated from an extract of herbal medicine Sorbaria sorbifolia. METHODS: Angiogenic activity was assayed using the chick embryo chorioallantoic membrane (CAM method. Microvessel density (MVD was determined by staining tissue sections immunohistochemically for CD34 using the Weidner capillary counting method. The mRNA and protein levels of vascular endothelial growth factor (VEGF, vascular endothelialgrowth factor receptor 2 (VEGFR2, Flk-1/KDR, basic fibroblast growth factor (bFGF, cyclo-oxygenase (COX-2 and hypoxia-inducible factor (HIF-1? were detected by quantitative real-time polymerase chain reaction and Western blotting analysis. RESULTS: The TTF1 inhibition rates for CAM were 30.8%, 38.2% and 47.5% with treatment concentrations of 25, 50 and 100 ?g/embryo × 5 d, respectively. The inhibitory rates for tumor size were 43.8%, 49.4% and 59.6% at TTF1 treatment concentrations of 5, 10, and 20 ?mol/kg, respectively. The average MVD was 14.2, 11.2 and 8.5 at treatment concentrations of 5 ?mol/kg, 10 ?mol/kg and 20 ?mol/kg TTF1, respectively. The mRNA and protein levels of VEGF, KDR, bFGF, COX-2 and HIF-1? in mice treated with TTF1 were significantly decreased. CONCLUSION: TTF1 can inhibit tumor angiogenesis, and the mechanism may be associated with the down-regulation of VEGF, KDR, bFGF, HIF-1? and COX-2.

Chao Liu

2011-01-01

272

Murine mammary tumor virus pol-related sequences in human DNA: characterization and sequence comparison with the complete murine mammary tumor virus pol gene  

International Nuclear Information System (INIS)

Sequences in the human genome with homology to the murine mammary tumor virus (MMTV) pol gene were isolated from a human phage library. Ten clones with extensive pol homology were shown to define five separate loci. These loci share common sequences immediately adjacent to the pol-like segments and, in addition, contain a related repeat element which bounds this region. This organization is suggestive of a proviral structure. The authors estimate that the human genome contains 30 to 40 copies of these pol-related sequences. The pol region of one of the cloned segments (HM16) and the complete MMTV pol gene were sequenced and compared. The nucleotide homology between these pol sequences is 52% and is concentrated in the terminal regions. The MMTV pol gene contains a single long open reading frame encoding 899 amino acids and is demarcated from the partially overlapping putative gag gene by termination codons and a shift in translational reading frame. The pol sequence of HM16 is multiply terminated but does contain open reading frames which encode 370, 105, and 112 amino acids residues in separate reading frames. The authors deduced a composite pol protein sequence for HM16 by aligning it to the MMTV pol gene and then compared these sequences with other retroviral pol protein sequences. Conserved sequences occur in both the amino and carboxyl regions which lie within the polymerase and endonuclease domains of pol, respectively

273

Murine mammary tumor virus pol-related sequences in human DNA: characterization and sequence comparison with the complete murine mammary tumor virus pol gene  

Energy Technology Data Exchange (ETDEWEB)

Sequences in the human genome with homology to the murine mammary tumor virus (MMTV) pol gene were isolated from a human phage library. Ten clones with extensive pol homology were shown to define five separate loci. These loci share common sequences immediately adjacent to the pol-like segments and, in addition, contain a related repeat element which bounds this region. This organization is suggestive of a proviral structure. The authors estimate that the human genome contains 30 to 40 copies of these pol-related sequences. The pol region of one of the cloned segments (HM16) and the complete MMTV pol gene were sequenced and compared. The nucleotide homology between these pol sequences is 52% and is concentrated in the terminal regions. The MMTV pol gene contains a single long open reading frame encoding 899 amino acids and is demarcated from the partially overlapping putative gag gene by termination codons and a shift in translational reading frame. The pol sequence of HM16 is multiply terminated but does contain open reading frames which encode 370, 105, and 112 amino acids residues in separate reading frames. The authors deduced a composite pol protein sequence for HM16 by aligning it to the MMTV pol gene and then compared these sequences with other retroviral pol protein sequences. Conserved sequences occur in both the amino and carboxyl regions which lie within the polymerase and endonuclease domains of pol, respectively.

Deen, K.C.; Sweet, R.W.

1986-02-01

274

Autoantibodies against Muscarinic Receptors in Breast Cancer: Their Role in Tumor Angiogenesis  

Science.gov (United States)

The presence of autoantibodies in cancer has become relevant in recent years. We demonstrated that autoantibodies purified from the sera of breast cancer patients activate muscarinic acetylcholine receptors in tumor cells. Immunoglobulin G (IgG) from breast cancer patients in T1N0Mx stage (tumor size?2 cm, without lymph node metastasis) mimics the action of the muscarinic agonist carbachol stimulating MCF-7 cell proliferation, migration and invasion. Angiogenesis is a central step in tumor progression because it promotes tumor invasion and metastatic spread. Vascular endothelial growth factor-A (VEGF-A) is the main angiogenic mediator, and its levels have been correlated with poor prognosis in cancer. The aim of the present work was to investigate the effect of T1N0Mx-IgG on the expression of VEGF-A, and the in vivo neovascular response triggered by MCF-7 cells, via muscarinic receptor activation. We demonstrated that T1N0Mx-IgG (10?8 M) and carbachol (10?9 M) increased the constitutive expression of VEGF-A in tumor cells, effect that was reverted by the muscarinic antagonist atropine. We also observed that T1N0Mx-IgG and carbachol enhanced the neovascular response produced by MCF-7 cells in the skin of NUDE mice. The action of IgG or carbachol was reduced in the presence of atropine. In conclusion, T1N0Mx-IgG and carbachol may promote VEGF-A production and neovascularization induced by breast tumor cells via muscarinic receptors activation. These effects may be accelerating breast tumor progression. PMID:23460876

Lombardi, María Gabriela; Negroni, María Pía; Pelegrina, Laura Tatiana; Castro, María Ester; Fiszman, Gabriel L.; Azar, María Eugenia; Morgado, Carlos Cresta; Sales, María Elena

2013-01-01

275

Dissecting the dynamics of dysregulation of cellular processes in mouse mammary gland tumor  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background Elucidating the sequence of molecular events underlying breast cancer formation is of enormous value for understanding this disease and for design of an effective treatment. Gene expression measurements have enabled the study of transcriptome-wide changes involved in tumorigenesis. This usually occurs through identification of differentially expressed genes or pathways. Results We propose a novel approach that is able to delineate new cancer-related cellular processes and the nature of their involvement in tumorigenesis. First, we define modules as densely interconnected and functionally enriched areas of a Protein Interaction Network. Second, 'differential expression' and 'differential co-expression' analyses are applied to the genes in these network modules, allowing for identification of processes that are up- or down-regulated, as well as processes disrupted (low co-expression or invoked (high co-expression in different tumor stages. Finally, we propose a strategy to identify regulatory miRNAs potentially responsible for the observed changes in module activities. We demonstrate the potential of this analysis on expression data from a mouse model of mammary gland tumor, monitored over three stages of tumorigenesis. Network modules enriched in adhesion and metabolic processes were found to be inactivated in tumor cells through the combination of dysregulation and down-regulation, whereas the activation of the integrin complex and immune system response modules is achieved through increased co-regulation and up-regulation. Additionally, we confirmed a known miRNA involved in mammary gland tumorigenesis, and present several new candidates for this function. Conclusions Understanding complex diseases requires studying them by integrative approaches that combine data sources and different analysis methods. The integration of methods and data sources proposed here yields a sensitive tool, able to pinpoint new processes with a role in cancer, dissect modulation of their activity and detect the varying assignments of genes to functional modules over the course of a disease.

de la Fuente Alberto

2009-12-01

276

64Cu-Labeled tetraiodothyroacetic acid-conjugated liposomes for PET imaging of tumor angiogenesis  

International Nuclear Information System (INIS)

Introduction: We synthesized and evaluated 64Cu-labeled tetraiodothyroacetic acid (tetrac)-conjugated liposomes for PET imaging of tumor angiogenesis, because tetrac inhibits angiogenesis via integrin ?V?3. Methods: Tetrac-PEG-DSPE and DOTA-PEG-DSPE were synthesized and formulated with other lipids into liposomes. The resulting tetrac/DOTA-liposomes were labeled with 64Cu at 40 °C for 1 h and purified using a PD-10 column. 64Cu-DOTA-liposomes were also prepared for comparison. Human aortic endothelial cell (HAEC) binding studies were performed by incubating the liposomes with the cells at 37 °C. MicroPET imaging followed by tissue distribution study was carried out using U87MG tumor-bearing mice injected with tetrac/64Cu-DOTA-liposomes or 64Cu-DOTA-liposomes. Results: HAEC binding studies exhibited that tetrac/64Cu-DOTA-liposomes were avidly taken up by the cells from 1.02 %ID at 1 h to 11.89 %ID at 24 h, while 64Cu-DOTA-liposomes had low uptake from 0.47 %ID at 1 h to 1.57 %ID at 24 h. MicroPET imaging of mice injected with tetrac/64Cu-DOTA-liposomes showed high radioactivity accumulation in the liver and spleen. ROI analysis of the tumor images revealed 1.93 ± 0.12 %ID/g at 1 h and 2.70 ± 0.36 %ID/g at 22 h. In contrast, tumor ROI analysis of 64Cu-DOTA-liposomes revealed 0.54 ± 0.08 %ID/g at 1 h and 0.52 ± 0.09 %ID/g at 22 h. Tissue distribution studies confirmed that the tumor uptakes of tetrac/64Cu-DOTA-liposomes and 64Cu-DOTA-liposomes were 1.75 ± 0.03 %ID/g and 0.36 ± 0.01 %ID/g at 22 h, respectively. Conclusion: These results demonstrate that tetrac/64Cu-DOTA-liposomes have significantly enhanced tumor uptake compared to 64Cu-DOTA-liposomes due to tetrac conjugation. Further studies are warranted to reduce the liver and spleen uptake of tetrac/64Cu-DOTA-liposomes

277

The basic and additional immunohistochemical criteria in differential diagnostics of tumors and tumor-like processes of mammary gland  

Directory of Open Access Journals (Sweden)

Full Text Available Morphological diagnostics of mammary gland neoplasm is complex due to polymorphism of tumors and tumor-like processes. The purpose of our research was to reveal the basic and additional immunohistochemical markers for differential diagnostics of some diseases. We have established that the basic markers for differential diagnostics of adenosis and invasive carcinomas were MSA, ?-SMA, S100, collagen IV, ?63, ??-67 and ?53, additional - 34??12, ??7, ??8, ??5/6, E-cadgerin. The loss of expression of myoepithelial markers, positive reaction with ??-67, ?53, Her2/neu also matters. Mutually contrary patterns of 34??12 and E-cadgerin expression allow to differentiate ductal or lobular primacy of process. ??7, ??8, 34??12 play a key role in differential diagnostics of carcinosarcomas and sarcomas. myoepithelial markers and basal membrane also give the additional information. At differential diagnostics of carcinoma and malignant tumors of other nature ??7, ??8, E-cadgerin, Her2/neu, ER/PgR, myoepithelial markers were the most important, being typical only for epithelial tumors. At Paget disease the reliable diagnostic criteria are absence of S100 and expression of certain classes ?? (more often luminal epithelium ??7, ??8, E-cadgerin, ???. Clone AE1/AE3 and revealing ??7 is valuable for diagnostics of micro-metastasises.

Shponka I.S.

2009-01-01

278

Uptake of radiolabeled alpha-fetoprotein by mouse mammary carcinomas and its usefulness in tumor scintigraphy  

International Nuclear Information System (INIS)

The ability to internalize alpha-fetoprotein (AFP) and serum albumin, which is characteristic of embryonic and fetal elements undergoing differentiation, may reappear in some cultured neoplastic cells (i.e., the MCF-7 human breast cancer cell line). The in vivo uptake of AFP by spontaneous carcinomas of the CH3/Bi mouse was investigated. Nineteen mice were given i.v. injections of approximately 10 muCi of mouse 125I-AFP (0.6 to 4 micrograms of AFP according to the specific ratio of the preparation used). Four to 7 days later, the animals were sacrificed. The radioactivity concentration in the tumor was the highest among all solid tissues examined. Tumor:liver radioactivity ratios were clearly positive [3.6 +/- 0.3 (S.E.)] in 27 of 31 specimens studied. Microscopy examination of autoradiograms from various tissue sections confirmed the selective accumulation of radioactive AFP in the tumors. In order to assess the specificity of AFP uptake by mammary tumors, 4 mice were given simultaneous injections of 125I-AFP and 131I-ovalbumin, respectively. Compared to AFP, the retention of ovalbumin was very low in all tissues studied, including the tumor. The possibility of tumor localization of radiolabeled AFP by external photoscanning was also explored. Two mice were given injections of 131I-AFP, one mouse received 131I-serum albumin, and one was given 131I-ovalbumin. Images were obtained 6 days after with a staages were obtained 6 days after with a standard gamma-camera linked to a computer with data display. About 50% of the total radioactivity retained was concentrated in the tumor areas of mice given injections of iodinated AFP, while it was only 15% in the mouse that received 131I-serum albumin

279

Inhibition of Tumor Angiogenesis and Tumor Growth by the DSL Domain of Human Delta-Like 1 Targeted to Vascular Endothelial Cells  

Directory of Open Access Journals (Sweden)

Full Text Available The growth of solid tumors depends on neovascularization. Several therapies targeting tumor angiogenesis have been developed. However, poor response in some tumors and emerging resistance necessitate further investigations of newdrug targets. Notch signal pathway plays a pivotal role in vascular development and tumor angiogenesis. Either blockade or forced activation of this pathway can inhibit angiogenesis. As blocking Notch pathway results in the formation of vascular neoplasm, activation of Notch pathway to prevent tumor angiogenesis might be an alternative choice. However, an in vivo deliverable reagent with highly efficient Notch-activating capacity has not been developed. Here, we generated a polypeptide, hD1R, which consists of the Delta-Serrate-Lag-2 fragment of the human Notch ligand Delta-like 1 and an arginine-glycine-aspartate (RGD motif targeting endothelial cells (ECs. We showed that hD1R could bind to ECs specifically through its RGD motif and effectively triggered Notch signaling in ECs. We demonstrated both in vitro and in vivo that hD1R inhibited angiogenic sprouting and EC proliferation. In tumor-bearing mice, the injection of hD1R effectively repressed tumor growth, most likely through increasing tumor hypoxia and tissue necrosis. The amount and width of vessels reduced remarkably in tumors of mice treated with hD1R. Moreover, vessels in tumors of mice treated with hD1R recruited more NG2+ perivascular cells and were better perfused. Combined application of hD1R and chemotherapy with cisplatin and teniposide revealed that these two treatments had additive antitumor effects. Our study provided a new strategy for antiangiogenic tumor therapy.

Xing-Cheng Zhao

2013-07-01

280

c-erbB-2 expression and nuclear pleomorphism in canine mammary tumors  

Scientific Electronic Library Online (English)

Full Text Available SciELO Brazil | Language: English Abstract in english The objective of the present investigation was to study the expression of c-erbB-2 and MIB-1 and try to associate them with morphological features of the cell such as nuclear pleomorphism, mitotic count and histological grade in a series of 70 canine mammary gland tumors, 22 of them benign and 48 ma [...] lignant. Tumors were collected at the Veterinary Hospital of UFMG (Brazil) and the Veterinary Faculty of Porto University (Portugal). c-erbB-2 expression was determined according to the guidelines provided by the manufacturer of the HercepTest system and nuclear pleomorphism, mitotic count and histological grade according the Elston and Ellis grading system. The HercepTest is the FDA-approved in vitro diagnostic test marketed by Dako. It is a semi-quantitative immunohistochemical assay used to determine overexpression of HER2 protein (human epidermal growth factor receptor) in breast cancer tissue. MIB-1 expression was also evaluated in 28 malignant tumors. Seventeen (35.4%) of the malignant tumors were positive for c-erbB-2 expression, which was positively associated with nuclear pleomorphism (P

A.P., Dutra; N.V.M., Granja; F.C., Schmitt; G.D., Cassali.

1673-16-01

281

Misregulation of Stromelysin-1 in Mouse Mammary Tumor Cells Accompanies Acquisition of Stromelysin-1 dependent Invasive Properties  

Energy Technology Data Exchange (ETDEWEB)

Stromelysin-1 is a member of the metalloproteinase family of extracellular matrix-degrading enzymes that regulates tissue remodeling. We previously established a transgenic mouse model in which rat stromelysin-1 targeted to the mammary gland augmented expression of endogenous stromelysin-1, disrupted functional differentiation, and induced mammary tumors. A cell line generated from an adenocarcinoma in one of these animals and a previously described mammary tumor cell line generated in culture readily invaded both a reconstituted basement membrane and type I collagen gels, whereas a nonmalignant, functionally normal epithelial cell line did not. Invasion of Matrigel by tumor cells was largely abolished by metalloproteinase inhibitors, but not by inhibitors of other proteinase families. Inhibition experiments with antisense oligodeoxynucleotides revealed that Matrigel invasion of both cell lines was critically dependent on stromelysin-1 expression. Invasion of collagen, on the other hand, was reduced by only 40-50%. Stromelysin-1 was expressed in both malignant and nonmalignant cells grown on plastic substrata. Its expression was completely inhibited in nonmalignant cells, but up-regulated in tumor cells, in response to Matrigel. Thus misregulation of stromelysin-1 expression appears to be an important aspect of mammary tumor cell progression to an invasive phenotype. The matrix metalloproteinases (MMPs) are a family of extracellular matrix (ECM)-degrading enzymes that have been implicated in a variety of normal developmental and pathological processes, including tumorigenesis. The MMP family comprises at least 15 members with different, albeit overlapping, substrate specificities. During activation of latent MMPs, their propeptides are cleaved and they are converted to a lower molecular weight form by other enzymes, including serine proteinases, and by autocatalytic cleavage. Among the MMPs, stromelysin-1 (SL1) possesses the broadest substrate specificity. Despite increasing knowledge about its enzymatic properties and the regulation of its expression, little is known about its function. We have generated transgenic animals that express an autoactivating mutant of rat SL1 targeted to the epithelial compartment of the mammary gland. Phenotypically, SL1 transgenic mice display increased branching morphogenesis and lactogenic differentiation at prepubertal stages and premature involution during late pregnancy. Branching morphogenesis requires the invasion of epithelial cells into the adipose tissue, a process reminiscent of invasion of stromal compartments by tumor cells. Strikingly, a large number of SL1 transgenic animals also develop mammary tumors of various histotypes, including invasive adenocarcinomas. Because tumor development is a late response of SL1 transgenic mice to overexpression of the transgene, it remains unclear whether SL1 plays a direct role in tumor growth and/or invasion or whether the observed tumors are a consequence of other molecular alterations in the microenvironment of the mammary gland before the onset of tumor growth. Studies performed with synthetic inhibitors of MMP activity and tissue inhibitors of metalloproteinases (TIMPs) have shown that suppression of MMP activity also suppresses tumor growth and metastasis. In many cases, the level of SL1 expression in tumors of the mammary gland and other tissues is positively correlated with the degree of malignancy. However, the only direct evidence for the nature of the MMPs involved was provided by the demonstration that function-blocking antibodies against gelatinase A and antisense inhibition of matrilysin expression decreased the invasiveness of tumor cells in a reconstituted basement membrane assay. These studies encouraged us to investigate whether SL1 plays a direct role in invasion of ECM. We used two carcinoma cell lines, TCL1 and SCg6 that formed rapidly growing, invasive tumors in vivo and migrated through Matrigel and collagen gels in culture. Antisense oligodeoxynucleotides (ODNs) against SL1 inhibited Matrigel invasion by TCL1 and SCg

Lochter, A.; Srebrow, A.; Sympson, C.J.; Terracio, N.; Werb, Z.; Bissell, M.J.

1997-02-21

282

A model of spontaneous mouse mammary tumor for human estrogen receptor- and progesterone receptor-negative breast cancer  

Science.gov (United States)

Breast cancer (BC) is the most frequently malignancy in women. Therefore, establishment of an animal model for the development of preventative measures and effective treatment for tumors is required. A novel heterogeneous spontaneous mammary tumor animal model of Kunming mice was generated. The purpose of this study was to characterize the spontaneous mammary tumor model. Histopathologically, invasive nodular masses of pleomorphic tubular neoplastic epithelial cells invaded fibro-vascular stroma, adjacent dermis and muscle tissue. Metastatic spread through blood vessel into liver and lungs was observed by hematoxylin eosin staining. No estrogen receptor (ER) or progesterone receptor (PR) immunoreactivity was detected in their associated malignant tumors, human epidermal growth factor receptor-2 (HER-2) protein weak expression was found by immunohistochemistry. High expression of vascular endothelial growth factor (VEGF), moderate or high expression of c-Myc and cyclin D1 were observed in tumor sections at different stages (2, 4, 6 and 8 weeks after cancer being found) when compared with that of the normal mammary glands. The result showed that the model is of an invasive ductal carcinoma. Remarkably in the mouse model, ER and PR-negative and HER2 weak positivity are observed. The high or moderate expressions of breast cancer markers (VEGF, c-Myc and cyclin D1) in mammary cancer tissue change at different stages. To our knowledge, this is the first report of a spontaneous mammary model displaying colony-strain, outbred mice. This model will be an attractive tool to understand the biology of anti-hormonal breast cancer in women. PMID:25230850

ZHENG, LIXIANG; ZHOU, BUGAO; MENG, XIANMING; ZHU, WEIFENG; ZUO, AIREN; WANG, XIAOMIN; JIANG, RUNDE; YU, SHIPING

2014-01-01

283

BRCA1 suppresses epithelial-to-mesenchymal transition and stem cell dedifferentiation during mammary and tumor development.  

Science.gov (United States)

BRCA1 mutation carriers are predisposed to developing basal-like breast cancers with high metastasis and poor prognosis. Yet, how BRCA1 suppresses formation of basal-like breast cancers is still obscure. Deletion of p18(Ink4c) (p18), an inhibitor of CDK4 and CDK6, functionally inactivates the RB pathway, stimulates mammary luminal stem cell (LSC) proliferation, and leads to spontaneous luminal tumor development. Alternately, germline mutation of Brca1 shifts the fate of luminal cells to cause luminal-to-basal mammary tumor transformation. Here, we report that disrupting Brca1 by either germline or epithelium-specific mutation in p18-deficient mice activates epithelial-to-mesenchymal transition (EMT) and induces dedifferentiation of LSCs, which associate closely with expansion of basal and cancer stem cells and formation of basal-like tumors. Mechanistically, BRCA1 bound to the TWIST promoter, suppressing its activity and inhibiting EMT in mammary tumor cells. In human luminal cancer cells, BRCA1 silencing was sufficient to activate TWIST and EMT and increase tumor formation. In parallel, TWIST expression and EMT features correlated inversely with BRCA1 expression in human breast cancers. Together, our findings showed that BRCA1 suppressed TWIST and EMT, inhibited LSC dedifferentiation, and repressed expansion of basal stem cells and basal-like tumors. Thus, our work offers the first genetic evidence that Brca1 directly suppresses EMT and LSC dedifferentiation during breast tumorigenesis. PMID:25239453

Bai, Feng; Chan, Ho Lam; Scott, Alexandria; Smith, Matthew D; Fan, Cheng; Herschkowitz, Jason I; Perou, Charles M; Livingstone, Alan S; Robbins, David J; Capobianco, Anthony J; Pei, Xin-Hai

2014-11-01

284

Role of prolactin in induction of mammary tumors in rats with low dose radiations or of a chemical carcinogen  

International Nuclear Information System (INIS)

Synergy of prolactin with x-ray, fast neutron, N-nitrosobutylurea (NBU), in an induction of mammary tumors was discussed, and the following results were obtained. Conversion of mammary epithelium to malignant tumors was induced in rats which were exposed to x-ray of a dose estimated to be below carcinogenic dose or which were given chemical substances. Cells converted to malignant tumors by carcinogenetic treatment survived for a fairly long term without proliferation, responded to proper stimulations, and formed macroscopical tumors. The effect of prolactin was showed at maximum under the presence of normal function of the ovary. RBE of 14.1 MeV fast neutron in an induction of mammary tumor in rats was about 1.3 - 1.5 times of 180 kVp x-ray. From the above-mentioned results, the author would like to point out and emphasize that at present, radiation used frequently for diagnosis and therapy although in small dose incurs the danger of inducing tumors under the specific circumstances where the host lives, and especially that easy treatments for atomic bomb survivors would bring double misfortunes to them in future. (Ueda, J.)

285

Versican G3 Promotes Mouse Mammary Tumor Cell Growth, Migration, and Metastasis by Influencing EGF Receptor Signaling  

OpenAIRE

Increased versican expression in breast tumors is predictive of relapse and has negative impact on survival rates. The C-terminal G3 domain of versican influences local and systemic tumor invasiveness in pre-clinical murine models. However, the mechanism(s) by which G3 influences breast tumor growth and metastasis is not well characterized. Here we evaluated the expression of versican in mouse mammary tumor cell lines observing that 4T1 cells expressed highest levels while 66c14 cells express...

Du, William Weidong; Yang, Burton B.; Shatseva, Tatiana A.; Yang, Bing L.; Deng, Zhaoqun; Shan, Sze Wan; Lee, Daniel Y.; Seth, Arun; Yee, Albert J.

2010-01-01

286

Loss of STAT1 from Mouse Mammary Epithelium Results in an Increased Neu-Induced Tumor Burden1  

OpenAIRE

Type I and type II classes of interferons (IFNs) signal through the JAK/STAT1 pathway and are known to be important in adaptive and innate immune responses and in protection against tumors. Although STAT1 is widely considered a tumor suppressor, it remains unclear, however, if this function occurs in tumor cells (cell autonomous) or if STAT1 acts primarily through immune cells. Here, the question of whether STAT1 has a cell autonomous role in mammary tumor formation was addressed in a mouse m...

Klover, Peter J.; Muller, William J.; Robinson, Gertraud W.; Pfeiffer, Ruth M.; Yamaji, Daisuke; Hennighausen, Lothar

2010-01-01

287

Tumor cell-macrophage interactions increase angiogenesis through secretion of EMMPRIN  

Directory of Open Access Journals (Sweden)

Full Text Available Tumor macrophages are generally considered to be alternatively/M2 activated to induce secretion of pro-angiogenic factors such as VEGF and MMPs. EMMPRIN (CD147, basigin is overexpressed in many tumor types, and has been shown to induce fibroblasts and endothelial cell expression of MMPs and VEGF. We first show that tumor cell interactions with macrophages resulted in increased expression of EMMPRIN and induction of MMP-9 and VEGF. Human A498 renal carcinoma or MCF-7 breast carcinoma cell lines were co-cultured with the U937 monocytic-like cell line in the presence of TNFalpha (1 ng/ml. Membranal EMMPRIN expression was increased in the co-cultures (by 3-4 folds, p<0.01, as was the secretion of MMP-9 and VEGF (by 2-5 folds for both MMP-9 and VEGF, p<0.01, relative to the single cultures with TNFalpha. Investigating the regulatory mechanisms, we show that EMMPRIN was post-translationally regulated by miR-146a, as no change was observed in the tumoral expression of EMMPRIN mRNA during co-culture, expression of miR-146a was increased and its neutralization by its antagomir inhibited EMMPRIN expression. The secretion of EMMPRIN was also enhanced (by 2-3 folds, p<0.05, only in the A498 co-culture via shedding off of the membranal protein by a serine protease that is yet to be identified, as demonstrated by the use of wide range protease inhibitors. Finally, soluble EMMPRIN enhanced monocytic secretion of MMP-9 and VEGF, as inhibition of its expression levels by neutralizing anti-EMMPRIN or siRNA in the tumor cells lead to subsequent decreased induction of these two pro-angiogenic proteins. These results reveal a mechanism whereby tumor cell-macrophage interactions promote angiogenesis via an EMMPRIN-mediated pathway.

MichalAmitRahat

2013-07-01

288

Mammary hamartomas  

International Nuclear Information System (INIS)

Five cases of mammary hamartoma are described, with special reference to the radiographic features. Hamartomas are well circumscribed lesions composed of normal or dysplastic mammary tissue. They are probably more common than has been anticipated from the literature and are important because they may be confused with other well circumscribed tumors, such as cystosarcoma phyllodes. The radiographic characteristics of hamartoma allows a tentative diagnosis in most cases. (Auth.)

289

Maternal metabolic perturbations elicited by high-fat diet promote Wnt-1-induced mammary tumor risk in adult female offspring via long-term effects on mammary and systemic phenotypes.  

Science.gov (United States)

Many adult chronic diseases are thought to be influenced during early life by maternal nutrition; however, the underlying mechanisms remain largely unknown. Obesity-related diseases may be due partly to high fat consumption. Herein, we evaluated mammary tumor risk in female mouse mammary tumor virus-Wnt-1 transgenic (Tg) offspring exposed to high-fat diet (HFD) or control diet (CD) (45% and 17% kcal from fat, respectively) during gestation and lactation, with CD provided to progeny at weaning. In Tg offspring, maternal HFD exposure increased mammary tumor incidence and decreased tumor latency without affecting tumor volume. Tumor risk was associated with higher tumor necrosis factor-? and insulin and altered oxidative stress biomarkers in sera and with early changes in mammary expression of genes linked to tumor promotion [interleukin 6 (Il6)] or inhibition [phosphatase and tensin homolog deleted on chromosome 10 (Pten), B-cell lymphoma 2 (Bcl2)]. Corresponding wild-type progeny exposed to maternal HFD displayed accelerated mammary development, higher mammary adiposity, increased insulin resistance and early changes in Pten, Bcl2 and Il6, than CD-exposed offspring. Dams-fed HFD showed higher serum glucose and oxidative stress biomarkers but comparable adiposity compared with CD-fed counterparts. In human breast cancer MCF-7 cells, sera from maternal HFD-exposed Tg offspring elicited changes in PTEN, BCL2 and IL6 gene expression, mimicking in vivo exposure; increased cell viability and mammosphere formation and induced measures [insulin receptor substrate-1 (IRS-1), IRS-2] of insulin sensitivity. Serum effects on IRS-1 were recapitulated by exogenous insulin and the PTEN-specific inhibitor SF1670. Hyperinsulinemia and PTEN loss-of-function may thus, couple maternal HFD exposure to enhanced insulin sensitivity via increased mammary IRS-1 expression in progeny, to promote breast cancer risk. PMID:24832086

Montales, Maria Theresa E; Melnyk, Stepan B; Simmen, Frank A; Simmen, Rosalia C M

2014-09-01

290

Synthesis of Specific Nanoparticles for Targeting and Imaging Tumor Angiogenesis Using Electron-Beam Irradiation  

International Nuclear Information System (INIS)

We have succeeded to synthesize PVDF nanoparticles by nanoemulsion polymerization and their functionalization with a peptide that presents an anti-angiogenic activity. Resulted nanoparticles present a radius of 60 nm. From FESEM images and light scattering measurements, we deduced that they were spherical and monodisperse. The alkyl radicals induced from electron beam irradiation combine immediately with the oxygen to form peroxide radicals. Because of a high specific area and small crystallite size, the radical decay with time is evidenced from EPR measurements. Despite this radical decay, electron beam irradiation allows us to graft PAA by radical polymerization onto freshly irradiated PVDF nanoparticles and then to immobilize CBO-P11 by click chemistry via a spacer arm. Evidences of grafting were shown using HRMAS NMR and MALDI-TOF mass spectrometry. Nanoparticles functionalized with an angiogenesis-targeting agent are an attractive option for anti-tumor therapy

291

Nuclear localization of long-VEGF is associated with hypoxia and tumor angiogenesis  

International Nuclear Information System (INIS)

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that has a pivotal role in normal and pathological angiogenesis. VEGF has a long 5' untranslated region harboring an open reading frame (ORF) initiated by a CUG codon that is in-frame with the VEGF coding region. The ORF translation leads to the expression of a long isoform termed L-VEGF that is extended by an additional 180 amino acids. In this communication, we provide evidence that L-VEGF is subjected to proteolytic cleavage leading to the detachment of the 180 aa extension from the VEGF moiety. Using immunofluorescence staining, we show that upon hypoxia this 180 aa extension translocates to the nuclei of expressing cells. Accordingly, immunohistochemical staining of both normal and tumor tissue samples demonstrated restricted nuclear localization of the ORF, which was correlated with cytoplasmic localization of VEGF. This suggests that the 180 aa ORF is involved in VEGF-mediated angiogenic processes

292

Silencing HoxA1 by intraductal injection of siRNA lipidoid nanoparticles prevents mammary tumor progression in mice.  

Science.gov (United States)

With advances in screening, the incidence of detection of premalignant breast lesions has increased in recent decades; however, treatment options remain limited to surveillance or surgical removal by lumpectomy or mastectomy. We hypothesized that disease progression could be blocked by RNA interference (RNAi) therapy and set out to develop a targeted therapeutic delivery strategy. Using computational gene network modeling, we identified HoxA1 as a putative driver of early mammary cancer progression in transgenic C3(1)-SV40TAg mice. Silencing this gene in cultured mouse or human mammary tumor spheroids resulted in increased acinar lumen formation, reduced tumor cell proliferation, and restoration of normal epithelial polarization. When the HoxA1 gene was silenced in vivo via intraductal delivery of nanoparticle-formulated small interfering RNA (siRNA) through the nipple of transgenic mice with early-stage disease, mammary epithelial cell proliferation rates were suppressed, loss of estrogen and progesterone receptor expression was prevented, and tumor incidence was reduced by 75%. This approach that leverages new advances in systems biology and nanotechnology offers a novel noninvasive strategy to block breast cancer progression through targeted silencing of critical genes directly within the mammary epithelium. PMID:24382894

Brock, Amy; Krause, Silva; Li, Hu; Kowalski, Marek; Goldberg, Michael S; Collins, James J; Ingber, Donald E

2014-01-01

293

Inhibition of 7,12-dimethylbenzanthracene-induced rat mammary tumor growth by 2,3,7,8-tetrachlorodibenzo-p-dioxin.  

Science.gov (United States)

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds inhibit diverse estrogen-induced responses in the rodent uterus and human breast cancer cells. The effects of a single non-toxic dose of TCDD (10 micrograms/kg) on the development of mammary tumors was investigated in female Sprague-Dawley rats treated with an oral dose of 7,12-dimethylbenzanthracene (DMBA) (20 mg). In rats which developed mammary tumors, subsequent treatment with corn oil (vehicle) resulted in a 3.9-fold increase in mammary tumor volume after 21 days. In contrast, a second group of rats with mammary tumors were treated with a non-toxic dose of TCDD (10 micrograms/kg) and after 21 days, the mean tumor volumes decreased from 89.7 +/- 53 mm3 to 24.9 +/- 28.5 mm3. Moreover, these results demonstrate the antitumorigenic activity of TCDD in female Sprague-Dawley rats. PMID:8033067

Holcomb, M; Safe, S

1994-07-15

294

T cell-mediated delay of spontaneous mammary tumor onset: increased efficacy with in vivo versus in vitro activation.  

Science.gov (United States)

Peripheral tolerance to shared Ags expressed on both tumors and normal self-tissues presents a major barrier to T cell-based immunotherapy as a treatment for cancer. To assess the activity of tumor-specific T cells against spontaneously arising carcinomas in the context of shared Ag expression, we developed a model system whereby an identified tumor Ag, tumor ERK (tERK), is expressed transgenically on both normal mammary tissue and spontaneous mammary carcinomas. Transfer of in vitro-activated, tERK-specific DUC18 T cells delayed spontaneous tumor development in tERK-expressing mice when T cells were given before the development of palpable carcinomas. However, antitumor activity mediated by in vitro-activated DUC18 T cells, as measured by responsiveness against a transplanted tERK-expressing fibrosarcoma challenge, was lost within days of transfer. This loss was due to expression of tERK as a self-Ag on normal tissues and was independent of the presence of mammary tumors. In contrast, transferred naive DUC18 T cells maintained a long-term protective function in tERK-expressing mice. Ten-fold fewer naive T cells activated in vivo were able to replicate the delay in spontaneous tumor development achieved by in vitro-activated T cells. These results are in contrast to our earlier studies using transplanted tumors alone, in which in vitro-activated DUC18 T cells were more efficacious than naive DUC18 T cells and highlight the need to perform tumor studies in the presence of tumor Ag expression on normal self-tissue. PMID:15814690

O'Mara, Leigh A; Norian, Lyse A; Kreamalmeyer, Darren; White, J Michael; Allen, Paul M

2005-04-15

295

Visualization of Tumor Angiogenesis Using MR Imaging Contrast Agent Gd-DTPA-anti-VEGF Receptor 2 Antibody Conjugate in a Mouse Tumor Model  

International Nuclear Information System (INIS)

To visualize tumor angiogenesis using the MRI contrast agent, Gd- DTPA-anti-VEGF receptor 2 antibody conjugate, with a 4.7-Tesla MRI instrument in a mouse model. We designed a tumor angiogenesis-targeting T1 contrast agent that was prepared by the bioconjugation of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) and an anti-vascular endothelial growth factor receptor-2 (VEGFR2) antibody. The specific binding of the agent complex to cells that express VEGFR2 was examined in cultured murine endothelial cells (MS-1 cells) with a 4.7-Tesla magnetic resonance imaging scanner. Angiogenesis-specific T1 enhancement was imaged with the Gd-DTPA-anti-VEGFR2 antibody conjugate using a CT-26 adenocarcinoma tumor model in eight mice. As a control, the use of the Gd-DTPA-anti-rat immunoglobulin G (Gd-DTPA-anti-rat IgG) was imaged with a tumor model in eight mice. Statistical significance was assessed using the Mann-Whitney test. Tumor tissue was examined by immunohistochemical analysis. The Gd-DTPA-anti-VEGFR2 antibody conjugate showed predominant binding to cultured endothelial cells that expressed a high level of VEGFR2. Signal enhancement was approximately three-fold for in vivo T1-weighted MR imaging with the use of the Gd-DTPA-anti-VEGFR2 antibody conjugate as compared with the Gd-DTPA-rat IgG in the mouse tumor model (p < 0.05). VEGFR2 expression in CT-26 tumor vessels was demonstrated using immunohistochemical staining. MR imaging using the Gd-DTPA-anti-VEGFR2 antibodging using the Gd-DTPA-anti-VEGFR2 antibody conjugate as a contrast agent is useful in visualizing noninvasively tumor angiogenesis in a murine tumor model

296

Distinct ErbB-2 coupled signaling pathways promote mammary tumors with unique pathologic and transcriptional profiles.  

Science.gov (United States)

ErbB-2 overexpression and amplification occurs in 15% to 30% of human invasive breast carcinomas associated with poor clinical prognosis. Previously, we have shown that four ErbB-2/Neu tyrosine-autophosphorylation sites within the cytoplasmic tail of the receptor recruit distinct adaptor proteins and are sufficient to mediate transforming signals in vitro. Two of these sites, representing the growth factor receptor binding protein 2 (Grb2; Neu-YB) and the Src homology and collagen (Shc; Neu-YD) binding sites, can induce mammary tumorigenesis and metastasis. Here, we show that transgenic mice bearing the two other ErbB-2 autophosphorylation sites (Neu-YC and Neu-YE) develop metastatic mammary tumors. A detailed comparison of biological profiles among all Neu mutant mouse models revealed that Neu-YC, Neu-YD, and Neu-YE mammary tumors shared similar pathologic and transcriptional features. By contrast, the Neu-YB mouse model displayed a unique pathology with a high metastatic potential that correlates with a distinct transcriptional profile, including genes that promote malignant tumor progression such as metalloproteinases and chemokines. Furthermore, Neu-YB tumor epithelial cells showed abundant intracellular protein level of the chemokine CXCL12/SDF-1alpha, which may reflect the aggressive nature of this Neu mutant mouse model. Taken together, these findings indicate that activation of distinct Neu-coupled signaling pathways has an important impact on the biological behavior of Neu-induced tumors. PMID:17699761

Schade, Babette; Lam, Sonya H L; Cernea, Daniela; Sanguin-Gendreau, Virginie; Cardiff, Robert D; Jung, Boonim L; Hallett, Michael; Muller, William J

2007-08-15

297

The relationship of blood vessel proximity and time after radiolabeled thymidine administration to tumor cell population kinetics in a transplanted mouse mammary tumor.  

OpenAIRE

The relation between the time of administration of tritiated thymidine and the proximity of cells to blood vessels and their labeling index, grain density per labeled cells, mitotic index, and growth fraction have been determined autoradiographically in a transplanted mammary tumor of mice. The tumor was rich in blood vessels, and the cells were densely packed, showing a few glandular structures. Shortly after tritiated thymidine administration, cells closer to the blood vessels (0-70 mu) sho...

Pavelic, Z. P.; Allen, L. M.; Mihich, E.

1981-01-01

298

A preliminary study of the relationship between helical CT enhancement and tumor angiogenesis in gastric carcinoma  

International Nuclear Information System (INIS)

Objective: The aim of the study is to investigate the relationship between CT enhancement and tumor angiogenesis in gastric carcinoma (GC) and seek for a noninvasive and efficient way to predict the malignancy and prognosis of GC. Methods: The study included 27 histopathologically proven GC patients. Plain scan and triphasic incremental helical CT were performed in all cases. Hypotonic agent and water-filling method were used in 27 patients. Nonionic contrast medium was administrated with a power injector at the flow rate of 3 ml/s. The triphasic spiral scans were obtained at 25 s( arterial-dominant phase), 80 s (portal venous-dominant slides were carefully prepared for the monoclonal antibody phase) and 180 s (equilibrium phase) after the start of intravenous injection. The CT attenuation was measured both before and after enhancement. Histopathological anti-human factor VIII related antigen (F8RA) and polyclonal antibody anti-human vascular endothelial growth factor (VEGF ) were used for immunohistochemical staining, and calculation of tumormicrovessel density (MVD) and VEGF expression rate of tumor cells was performed. The contrast-enhancement imaging features of GC lesions were correlatively studied with tumor MVD and VEGF expression. Results: The accuracy of helical CT in determining T, N and M staging of GC was 77.8%, 74.1% and 100% respectively, and the accuracy of the total TNM staging was 81.5%. Peak attenuation (PA) of CT enhancement in GC lesions was 40-80 of CT enhancement in GC lesions was 40-80 HU (mean 62.83), MVD was 4-27 (mean 15.35). VEGF expression rate was 5%-65%. There was significant correlation between PA and MVD (r=0.708, t=5.015). MVD and PA of strong positive VEGF expression group (expression percentage >30%) were evidently higher than those of negative (expression percentage <10%) and weak positive (10 < expression percentage < 20%) groups (0.02 < P < 0.05 and 0.025 < P < 0.05 respectively). The histological differentiation of GC was also positively correlated with VEGF expression rate. Conclusion: The peak attenuation of CT enhancement reflects VEGF-related tumor angiogenesis in gastric carcinoma, therefore the malignancy and prognosis of GC is possible to be predicted preoperatively in CT images. (authors)

299

Increasing the thermosensitivity of a mammary tumor (CA755) through dietary modification.  

Science.gov (United States)

Disruption of the integrity of tumor cellular membranes has been proposed as an initiating event in hyperthermic cell death. Thermosensitivity measured by the shift in the harmonic mean of tumor regrowth delay of CA755 mammary adenocarcinomas grown in the hind legs of male BDF1, mice increased 22% when the hosts were fed a diet enriched in polyunsaturated fatty acids. Although the diet elicited the anticipated increase in tumor membrane phospholipid polyunsaturated fatty acids, the proportion of total unsaturated fatty acids decreased and the proportion of membrane-rigidifying saturated fatty acids increased. Concomitantly, the concentrations of cholesterol and phospholipid phosphorus increased and the ratio of phosphatidylethanolamine to phosphatidylcholine decreased, presumably to counter the effect of the change in the fatty acid pattern. In host liver membranes, the diet-mediated increase in proportion of polyunsaturated fatty acids was not accompanied by an increase in the proportion of rigidifying saturated fatty acids. Instead, the homeoviscous adaptation consisted of decreases in monounsaturated fatty acids and cholesterol concentration and an increase in the phosphatidylethanolamine-phosphatidylcholine ratio. Addition of a natural inhibitor of cholesterol biosynthesis to the polyunsaturated fatty acid enriched-diet reversed the diet-mediated increase in the phosphatidylethanolamine-phosphatidylcholine ratio of host liver membranes. Tumor membrane lipids from hosts fed the combined dietary factors were characterized by the formentioned rigidifying increase in saturated fatty acids and compensatory decrease in the phosphatidylethanolamine-phosphatidylcholine ratio. The inhibitor reversed the compensatory increases in cholesterol and phospholipid phosphorus concentrations. As a consequence the thermosensitivity of tumors bearing this perturbed membrane was increased. PMID:3770032

Elegbede, J A; Elson, C E; Qureshi, A; Dennis, W H; Yatvin, M B

1986-05-01

300

Moscatilin, a bibenzyl derivative from the India orchid Dendrobrium loddigesii, suppresses tumor angiogenesis and growth in vitro and in vivo.  

Science.gov (United States)

Attacking angiogenesis is considered an effective strategy for controls the expansion and metastasis of tumors and other related-diseases. The aim of this study was to assess the effects of moscatilin, a bibenzyl derivative, on VEGF and bFGF-induced angiogenesis in cultured human umbilical vein endothelial cells (HUVECs) in vitro and in vivo. Moscatilin significantly inhibited growth of lung cancer cell line A549 (NSCLC) and suppressed growth factor-induced neovascularization. In addition, VEGF- and bFGF-induced cell proliferation, migration, and tube formation of HUVECs was markedly inhibited by moscatilin. Western blotting analysis of cell signaling molecules indicated that moscatilin inhibited ERK1/2, Akt, and eNOS signaling pathways in HUVECs. These results suggest that inhibition of angiogenesis by moscatilin may be a major mechanism in cancer therapy. PMID:20056528

Tsai, An-Chi; Pan, Shiow-Lin; Liao, Cho-Hwa; Guh, Jih-Hwa; Wang, Shih-Wei; Sun, Hui-Lung; Liu, Yi-Nan; Chen, Chien-Chih; Shen, Chien-Chang; Chang, Ya-Ling; Teng, Che-Ming

2010-06-28

301

Repeated exposure of C3H/HeJ mice to ultra-wideband electromagnetic pulses: lack of effects on mammary tumors.  

Science.gov (United States)

It has been suggested that chronic, low-level exposure to radiofrequency (RF) radiation may promote the formation of tumors. Previous studies, however, showed that low-level, long-term exposure of mammary tumor-prone mice to 435 MHz or 2450 MHz RF radiation did not affect the incidence of mammary tumors. In this study, we investigated the effects of exposure to a unique type of electromagnetic energy: pulses composed of an ultra-wideband (UWB) of frequencies, including those in the RF range. One hundred C3H/HeJ mice were exposed to UWB pulses (rise time 176 ps, fall time 3.5 ns, pulse width 1.9 ns, peak E-field 40 kV/m, repetition rate 1 kHz). Each animal was exposed for 2 min once a week for 12 weeks. One hundred mice were used as sham controls. There were no significant differences between groups with respect to incidence of palpated mammary tumors, latency to tumor onset, rate of tumor growth, or animal survival. Histopathological evaluations revealed no significant differences between the two groups in numbers of neoplasms in all tissues studied (lymphoreticular tissue, thymus, respiratory, digestive and urinary tracts, reproductive, mammary and endocrine systems, and skin). Our major finding was the lack of effects of UWB-pulse exposure on promotion of mammary tumors in a well-established animal model of mammary cancer. PMID:11175673

Jauchem, J R; Ryan, K L; Frei, M R; Dusch, S J; Lehnert, H M; Kovatch, R M

2001-02-01

302

Evidence that tumor necrosis factor-related apoptosis inducing ligand (TRAIL) inhibits angiogenesis by inducing vascular endothelial cell apoptosis  

International Nuclear Information System (INIS)

Tumor necrosis factor (TNF) and its related ligands TNF-related apoptosis inducing ligand (TRAIL) and Fas ligand (FasL) play roles in the regulation of vascular responses, but their effect on the formation of new blood vessels (angiogenesis) is unclear. Therefore, we have examined the effects of these ligands on angiogenesis modeled with primary cultures of human umbilical vein endothelial cells (HUVEC). To examine angiogenesis in the context of the central nervous system, we have also modeled cerebral angiogenesis with the human brain endothelial cell line hCMEC/D3. Parameters studied were bromodeoxyuridine (BrdU) incorporation and cell number (MTT) assay (to assess endothelial proliferation), scratch assay (migration) and networks on Matrigel (tube formation). In our hands, neither TRAIL nor FasL (1, 10, and 100 ng/ml) had an effect on parameters of angiogenesis in the HUVEC model. In hCMEC/D3 cells by contrast, TRAIL inhibited all parameters (10-100 ng/ml, 24 h). This was due to apoptosis, since its action was blocked by the pan-caspase inhibitor zVADfmk (5 x 10-5 mol/l) and TRAIL increased caspase-3 activity 1 h after application. However FasL (100 ng/ml) increased BrdU uptake without other effects. We conclude that TRAIL has different effects on in vitro angiogenesis depending on which model is used, but that FasL is generally ineffective when applied in vitro. The data suggest that TRAIL primarily influences angiogenesis by the induction of vascular endothelial apoptosis, leading to vessel regression.

303

The isoflavone metabolite 6-methoxyequol inhibits angiogenesis and suppresses tumor growth  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background Increased consumption of plant-based diets has been linked to the presence of certain phytochemicals, including polyphenols such as flavonoids. Several of these compounds exert their protective effect via inhibition of tumor angiogenesis. Identification of additional phytochemicals with potential antiangiogenic activity is important not only for understanding the mechanism of the preventive effect, but also for developing novel therapeutic interventions. Results In an attempt to identify phytochemicals contributing to the well-documented preventive effect of plant-based diets on cancer incidence and mortality, we have screened a set of hitherto untested phytoestrogen metabolites concerning their anti-angiogenic effect, using endothelial cell proliferation as an end point. Here, we show that a novel phytoestrogen, 6-methoxyequol (6-ME, inhibited VEGF-induced proliferation of human umbilical vein endothelial cells (HUVE cells, whereas VEGF-induced migration and survival of HUVE cells remained unaffected. In addition, 6-ME inhibited FGF-2-induced proliferation of bovine brain capillary endothelial (BBCE cells. In line with its role in cell proliferation, 6-ME inhibited VEGF-induced phosphorylation of ERK1/2 MAPK, the key cascade responsible for VEGF-induced proliferation of endothelial cells. In this context, 6-ME inhibited in a dose dependent manner the phosphorylation of MEK1/2, the only known upstream activator of ERK1/2. 6-ME did not alter VEGF-induced phosphorylation of p38 MAPK or AKT, compatible with the lack of effect on VEGF-induced migration and survival of endothelial cells. Peri-tumor injection of 6-ME in A-431 xenograft tumors resulted in reduced tumor growth with suppressed neovasularization compared to vehicle controls (P? Conclusions 6-ME inhibits VEGF- and FGF2-induced proliferation of ECs by targeting the phosphorylation of MEK1/2 and it downstream substrate ERK1/2, both key components of the mitogenic MAPK pathway. Injection of 6-ME in mouse A-431 xenograft tumors results to tumors with decreased neovascularization and reduced tumor volume suggesting that 6-ME may be developed to a novel anti-angiogenic agent in cancer treatment.

Bellou Sofia

2012-05-01

304

Solitary fibrous tumor: is there a molecular relationship with cellular angiofibroma, spindle cell lipoma, and mammary-type myofibroblastoma?  

Science.gov (United States)

Solitary fibrous tumor (SFT) is a mesenchymal tumor characterized by ovoid cells, branching blood vessels, stromal hyalinization, and CD34 immunoreactivity. Studies have shown loss of 13q in a group of morphologically similar entities, including cellular angiofibroma, mammary-type myofibroblastoma, and spindle cell lipoma. The histologic and immunophenotypic overlap between SFT and the latter group of tumors suggests that these tumors may be genetically linked. We tested a group of 40 SFTs to assess for loss of RB1 (13q14) by fluorescence in situ hybridization (FISH). All 38 SFTs with evaluable signals failed to show loss of RB1 (13q14) by FISH. All cases of cellular angiofibroma (1/1), spindle cell lipoma (6/6), and mammary-type myofibroblastoma (4/4), which were used as a control group, showed monoallelic or biallelic loss of RB1. The absence of RB1 loss in SFTs suggests that they are not related to cellular angiofibroma, mammary-type myofibroblastoma, or spindle cell lipoma. PMID:22586056

Fritchie, Karen J; Carver, Paula; Sun, Yang; Batiouchko, Galina; Billings, Steven D; Rubin, Brian P; Tubbs, Raymond R; Goldblum, John R

2012-06-01

305

Menhaden, coconut, and corn oils and mammary tumor incidence in BALB/c virgin female mice treated with DMBA.  

Science.gov (United States)

Omega-3 fatty (n-3) acids are believed to inhibit the rate of occurrence and the growth of mammary tumors in rats treated with 7,12-dimethylbenz[a]anthracene (DMBA). Linoleic acid, on the other hand, has been shown to promote mammary tumorigenesis. This study was undertaken to see whether replacing 18% of the corn oil (high in linoleic acid) in a 20% fat diet with menhaden oil (high in n-3 fatty acids, low in linoleic acid) or coconut oil (low in n-3 fatty acids, low in linoleic acid), while keeping constant the cholesterol, antioxidant, and total fat content, would affect tumor incidence in virgin female BALB/c mice dosed with DMBA. Dietary treatment had no effect on body weight, feed intake, or survival to 44 weeks of age (36 wks after the first of 6 DMBA doses). Mammary tumor incidence was the same in the menhaden oil and coconut oil diet groups but was significantly higher in the 20% corn oil diet group. The protective effect of menhaden oil and coconut oil may be due, at least in part, to the decreased linoleic acid content of these diets relative to the corn oil diet. We conclude that n-3 fatty acids per se do not seem to inhibit tumor formation. PMID:8233985

Craig-Schmidt, M; White, M T; Teer, P; Johnson, J; Lane, H W

1993-01-01

306

Selective photothermal laser-tissue interaction with augmentation of immunoadjuvants in treatment of DMBA-4 metastatic mammary tumors in rats  

Science.gov (United States)

Induced anti-tumor immunity can be the most effective and long-term cure for cancers, particularly for metastatic tumors. Laser immunotherapy has been developed to induce such immunological responses in rats bearing DMBA-4 metastatic mammary tumors. It involves an intratumoral administration of a laser-absorbing dye (indocyanine green) and a specially formulated immunoadjuvant (glycated chitosan), followed by an irradiation of a near-infrared laser (805-nm diode laser). To understand the immunity induced in this tumor model, immunization using freeze-thaw cell lysates against the DMBA-4 tumors was performed, followed by the tumor challenge twenty-one days later. Also performed is the surgical removal of the primary tumors of the rats before the observation of metastatic tumors. The immunization only delayed the emergence of the primary and metastases in the rats but did not provide immunity against the tumor challenge. After surgical removal of the primary tumors, the tumors re-emerged at the primary sites and the metastases developed at multiple remote sites. In contrast, laser immunotherapy cured rats experienced tumor regression and eradication. Our research has provided strong support for the working mechanism of laser immunotherapy. The experimental results showed that selective photothermal laser-tissue interaction with a complementary use of immunoadjuvant could be a potential therapy for treatment of metastatic tumors by inducing a tumor-specific, long-lasting immunity.

Chen, Wei R.; Liu, Hong; Wolf, Roman F.; Lucroy, Michael D.; Nordquist, Robert E.

2002-09-01

307

Cyclin D3 compensates for the loss of Cyclin D1 during ErbB2-induced mammary tumor initiation and progression  

OpenAIRE

Cyclin D1 regulates cell proliferation and is a candidate molecular target for breast cancer therapy. The current work addresses whether Cyclin D1 is indispensable for ErbB2-associated mammary tumor initiation and progression using a breast cancer model in which this cell cycle regulator can be genetically ablated prior to or after neoplastic transformation. Deficiency in Cyclin D1 delayed tumor onset but did not prevent the occurrence of mammary cancer in mice overexpressing wildtype ErbB2. ...

Zhang, Qian; Sakamoto, Kazuhito; Liu, Chengbao; Triplett, Aleata A.; Lin, Wan-chi; Rui, Hallgeir; Wagner, Kay-uwe

2011-01-01

308

Rosiglitazone inhibits metastasis development of a murine mammary tumor cell line LMM3  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background Activation of peroxisome proliferator-activated receptors ? (PPAR? induces diverse effects on cancer cells. The thiazolidinediones (TZDs, such as troglitazone and ciglitazone, are PPAR? agonists exhibiting antitumor activities; however, the underlying mechanism remains inconclusive. Rosiglitazone (RGZ, a synthetic ligand of PPAR? used in the treatment of Type 2 diabetes, inhibits growth of some tumor cells and is involved in other processes related to cancer progression. Opposing results have also been reported with different ligands on tumor cells. The purpose of this study was to determine if RGZ and 15d-PGJ2 induce antitumor effects in vivo and in vitro on the murine mammary tumor cell line LMM3. Methods The effect on LMM3 cell viability and nitric oxide (NO production of different doses of RGZ, 15-dPGJ2, BADGE and GW9662 were determined using the MTS colorimetric assay and the Griess reaction respectively. In vivo effect of orally administration of RGZ on tumor progression was evaluated either on s.c. primary tumors as well as on experimental metastasis. Cell adhesion, migration (wound assay and invasion in Transwells were performed. Metalloproteinase activity (MMP was determined by zymography in conditioned media from RGZ treated tumor cells. PPAR? expression was detected by inmunohistochemistry in formalin fixed tumors and by western blot in tumor cell lysates. Results RGZ orally administered to tumor-bearing mice decreased the number of experimental lung metastases without affecting primary s.c. tumor growth. Tumor cell adhesion and migration, as well as metalloproteinase MMP-9 activity, decreased in the presence of 1 ?M RGZ (non-cytotoxic dose. RGZ induced PPAR? protein expression in LMM3 tumors. Although metabolic activity -measured by MTS assay- diminished with 1–100 ?M RGZ, 1 ?M-treated cells recovered their proliferating capacity while 100 ?M treated cells died. The PPAR? antagonist Biphenol A diglicydyl ether (BADGE did not affect RGZ activity. On the contrary, the specific antagonist GW9662 completely abrogated RGZ-induced decrease in cell viability. A decrease in NO levels was detected in the presence of either 1 or 100 ?M RGZ. The natural ligand 15d-PGJ2 did not affect metabolic activity although it induced a significant decrease in NO production. Conclusion A significant decrease in the number of experimental LMM3 lung metastasis, but not on primary tumor growth, after oral RGZ administration was observed. In vitro, 100 ?MRGZ also reduced cell viability and NO production, while no changes were observed in the presence of 15d-PGJ2. BADGE did not reverse RGZ effect while the antagonist GW9662 completely abrogated it, suggesting a PPAR?- dependent mechanism. Inhibition of lung metastatic nodules by RGZ administered in vivo, might be associated with the observed decrease in MMP-9 expression, in cell adhesion, migration and invasion. RGZ augmented its expression. PPAR? was detected in cell lysates by western blot and by immunohistochemistry in tumors from RGZ-treated mice. In summary we can suggest that RGZ or any other TZDs might be possible future approaches in the treatment of metastasis of PPAR?-expressing cells.

Rolando Romina

2008-02-01

309

Talin regulates moesin-NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis.  

Science.gov (United States)

Invadopodia are actin-rich protrusions that degrade the extracellular matrix and are required for stromal invasion, intravasation, and metastasis. The role of the focal adhesion protein talin in regulating these structures is not known. Here, we demonstrate that talin is required for invadopodial matrix degradation and three-dimensional extracellular matrix invasion in metastatic breast cancer cells. The sodium/hydrogen exchanger 1 (NHE-1) is linked to the cytoskeleton by ezrin/radixin/moesin family proteins and is known to regulate invadopodium-mediated matrix degradation. We show that the talin C terminus binds directly to the moesin band 4.1 ERM (FERM) domain to recruit a moesin-NHE-1 complex to invadopodia. Silencing talin resulted in a decrease in cytosolic pH at invadopodia and blocked cofilin-dependent actin polymerization, leading to impaired invadopodium stability and matrix degradation. Furthermore, talin is required for mammary tumor cell motility, intravasation, and spontaneous lung metastasis in vivo. Thus, our findings provide a novel understanding of how intracellular pH is regulated and a molecular mechanism by which talin enhances tumor cell invasion and metastasis. PMID:24891603

Beaty, Brian T; Wang, Yarong; Bravo-Cordero, Jose Javier; Sharma, Ved P; Miskolci, Veronika; Hodgson, Louis; Condeelis, John

2014-06-01

310

Contrast enhanced maximum intensity projection ultrasound imaging for assessing angiogenesis in murine glioma and breast tumor models: A comparative study.  

Science.gov (United States)

The purpose of this study was to prospectively compare noninvasive, quantitative measures of vascularity obtained from four contrast enhanced ultrasound (US) techniques to four invasive immunohistochemical markers of tumor angiogenesis in a large group of murine xenografts. Glioma (C6) or breast cancer (NMU) cells were implanted in 144 rats. The contrast agent Optison (GE Healthcare, Princeton, NJ) was injected in a tail vein (dose: 0.4ml/kg). Power Doppler imaging (PDI), pulse-subtraction harmonic imaging (PSHI), flash-echo imaging (FEI), and Microflow imaging (MFI; a technique creating maximum intensity projection images over time) was performed with an Aplio scanner (Toshiba America Medical Systems, Tustin, CA) and a 7.5MHz linear array. Fractional tumor neovascularity was calculated from digital clips of contrast US, while the relative area stained was calculated from specimens. Results were compared using a factorial, repeated measures ANOVA, linear regression and z-tests. The tortuous morphology of tumor neovessels was visualized better with MFI than with the other US modes. Cell line, implantation method and contrast US imaging technique were significant parameters in the ANOVA model (p0.05). In conclusion, the largest study of contrast US of murine xenografts to date has been conducted and quantitative contrast enhanced US measures of tumor neovascularity in glioma and breast cancer xenograft models appear to provide a noninvasive marker for angiogenesis; although the best method for monitoring angiogenesis was not conclusively established. PMID:21144542

Forsberg, Flemming; Ro, Raymond J; Fox, Traci B; Liu, Ji-Bin; Chiou, See-Ying; Potoczek, Magdalena; Goldberg, Barry B

2011-04-01

311

Effect of thyroid hormone-nitric oxide interaction on tumor growth, angiogenesis, and aminopeptidase activity in mice.  

Science.gov (United States)

This study evaluated the effects of thyroid hormone-NO interaction on tumor development, vascularization, vascular endothelial growth factor (VEGF), and aminopeptidase (AP) activity in a murine model of implanted Lewis's carcinoma. Experiments were performed in male CBA-C57 mice. Animals were untreated (controls) or treated with: T4, the antithyroid drug methimazole, the NO inhibitor L-NAME, T4+L-NAME, methimazole+NAME, the ?vß3 integrin antagonist tetrac, T4+tetrac, the iNOS inhibitor aminoguanidine (AG), and T4 + AG; all treatments were for 6 weeks except for tetrac, administered for the last 11 days. Mice were subcutaneously inoculated with 1 × 10(6) exponentially growing Lewis carcinoma 3LL cells into the dorsum. Study variables 9 days later were tumor weight (TW), Hb content, an index of tumor vascularization, VEGF, and AP activity. T4 produced parallel increases in TW and angiogenesis. L-NAME reduced TW and angiogenesis in control, hyperthyroid, and hypothyroid mice, whereas AG had no effect on these variables. Tetrac arrested TW in normal and T4-treated mice but did not decrease angiogenesis in T4-treated animals. Negative correlations were found between TW and AP activity in tumors from control hyper- and hypothyroid groups and an inverse relationship was observed between TW and AP activities in tetrac-treated mice. T4 enhances TW and angiogenesis, in which NO participates, but requires activation of integrin ?vß3 to promote carcinogenesis. NO blockade reduces TW, regardless of the thyroid status. Thyroid hormone negatively modulates AP activity in the tumor. Accordingly, blockade of the membrane TH receptor ?vß3 integrin reduces TW associated with an increase in AP activity. PMID:24549786

Carmona-Cortés, Javier; Rodríguez-Gómez, Isabel; Wangensteen, Rosemary; Banegas, Inmaculada; García-Lora, Ángel M; Quesada, Andrés; Osuna, Antonio; Vargas, Félix

2014-06-01

312

Mouse mammary tumors express elevated levels of RNA encoding the murine homology of SKY, a putative receptor tyrosine kinase.  

Science.gov (United States)

To gain insight into the signal transduction pathways utilized by the Wnt-1-responsive mammary epithelial cell line C57MG, we screened for non-src family member tyrosine kinases expressed in these cells using a polymerase chain reaction-based technique. We identified five cDNA clones encoding receptor tyrosine kinases for which the ligand is known (fibroblast growth factor receptor, platelet-derived growth factor receptor, epithelial growth factor receptor, insulin receptor, and insulin-like growth factor receptor), two putative receptor tyrosine kinases for which the ligand remains to be identified (the products of ryk and the mouse klg homolog), and a novel tyrosine kinase. We cloned cDNAs encoding both the murine and human homologs of this kinase, the sequences of which were subsequently published under the names sky (Ohashi, K., Mizuno, K., Kuma, K., Miyata, T., and Nakamura, T. (1994) Oncogene 9, 699-705) and rse (Mark, M. R., Scadden, D. T., Wang, Z., Gu, Q., Goddard, A., and Godowski, P. J. (1994) J. Biol. Chem. 269, 10720-10728). Mouse sky RNA levels are abundant in mammary tumors derived from transgenic mice that express wnt-1, fgf-3, or both oncogenes in their mammary glands. However, little or no expression of sky is detected in mammary glands from virgin animals or in preneoplastic mammary glands from wnt-1 transgenic mice. Moreover, we find that the human homolog of sky is expressed at elevated levels when normal human mammary epithelial cells are rendered tumorigenic by the introduction of two viral oncogenes. Transient transfection of the human SKY cDNA into the quail fibrosarcoma cell line QT6 reveals that SKY is an active tyrosine kinase that augments the level of cellular phosphotyrosine. Introduction of murine Sky into RatB1a fibroblasts by retrovirus-mediated gene transfer results in morphological transformation, growth in soft agar, and the formation of tumors in nude mice. These data raise the possibility that the Sky tyrosine kinase is involved in the development and/or progression of mammary tumors. PMID:7896835

Taylor, I C; Roy, S; Yaswen, P; Stampfer, M R; Varmus, H E

1995-03-24

313

Inhibition of growth of human mammary tumor cells by potent antagonists of luteinizing hormone-releasing hormone.  

OpenAIRE

Various studies support the view that analogs of luteinizing hormone-releasing hormone (LH-RH) exert some direct effects on mammary tumor cells. Recently, new LH-RH antagonists [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Trp3,D-Hci6,D-Ala10]-LH-RH (SB-29) and [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Trp3,D-Cit6,D-Ala10]LH-RH (SB-30), which are devoid of edematogenic effects, were synthesized. In this study, we examined whether these LH-RH antagonists inhibit the proliferation of MDA-MB-231 human mammary tumor cells in cu...

Sharoni, Y.; Bosin, E.; Miinster, A.; Levy, J.; Schally, A. V.

1989-01-01

314

Three-dimensional imaging of the metabolic state of c-MYC-induced mammary tumor with the cryo-imager  

Science.gov (United States)

This study imaged the metabolic state of a growing tumor and the relationship between energy metabolism and the ability of glucose uptake in whole tumor tissue with cryo-imaging at 77° K. A MTB/TOM mouse model, bearing c-MYC-induced mammary tumor, was very rapidly freeze-trapped 2 hrs post Pyro-2DG injection. The fluorescence signals of oxidized flavoprotein (Fp), reduced pyridine nucleotide (PN), pyro-2DG, and the reflection signal of deoxy-hemoglobin were imaged every 100 ?m from the top surface to the bottom of the tumor sequentially, 9 sections in total. Each of the four signals was constructed into 3D images with Amira software. Both Fp and PN signals could be detected in the growing tumor regions, and a higher reduction state where was shown in the ratio images. The necrotic tumor regions displayed a very strong Fp signal and weak PN signal. In the bloody extravasation regions, Fp and PN signals were observably diminished. Therefore, the regions of high growth and necrosis in the tumor could be determined according to the Fp and PN signals. The content of deoxy-hemoglobin (Hb) in the tumor was positively correlated with the reduced PN signal. Pyro-2DG signal was only evident in the growing condition region in the tumor. Normalized 3D cross-correlation showed that Pyro-2DG signal was similar to the redox ratio. The results indicated that glucose uptake in the tumor was consistent with the redox state of the tumor. And both Pyro-2DG and mitochondrial NADH fluorescence showed bimodal histograms suggesting that the two population of c-MYC induced mammary tumor, one of which could be controlled by c-MYC transgene.

Zhang, Zhihong; Liu, Qian; Luo, Qingming; Zhang, Min Z.; Blessington, Dana M.; Zhou, Lanlan; Chodosh, Lewis A.; Zheng, Gang; Chance, Britton

2003-07-01

315

Correlation of Hypoxia-Inducible Factor 1? with Angiogenesis in Liver Tumors After Transcatheter Arterial Embolization in an Animal Model  

International Nuclear Information System (INIS)

This study sought to determine the expression of hypoxia-inducible factor 1? (HIF-1?) and its relation to angiogenesis in liver tumors after transcatheter arterial embolization (TAE) in an animal model. A total of 20 New Zealand White rabbits were implanted with VX2 tumor in liver. TAE-treated group animals (n = 10) received TAE with polyvinyl alcohol particles. Control group animals (n = 10) received sham embolization with distilled water. Six hours or 3 days after TAE, animals were humanely killed, and tumor samples were collected. Immunohistochemical staining was performed to evaluate HIF-1? and vascular endothelial growth factor (VEGF) protein expression and microvessel density (MVD). Real-time polymerase chain reaction was performed to examine VEGF mRNA levels. The levels of HIF-1? protein were significantly higher in TAE-treated tumors than those in the control tumors (P = 0.001). HIF-1? protein was expressed in viable tumor cells that were located predominantly at the periphery of necrotic tumor regions. The levels of VEGF protein and mRNA, and mean MVD were significantly increased in TAE-treated tumors compared with the control tumors (P = 0.001, 0.000, and 0.001, respectively). HIF-1? protein level was significantly correlated with VEGF mRNA (r = 0.612, P = 0.004) and protein (r = 0.554, P = 0.011), and MVD (r = 0.683, P = 0.001). We conclude that HIF-1? is overexpressed in VX2 tumors treated with TAE as a result of intratumoral hypoxia generated by thntratumoral hypoxia generated by the procedure and involved in activation of the TAE-associated tumor angiogenesis. HIF-1? might represent a promising therapeutic target for antiangiogenesis in combination with TAE against liver tumors.

316

Comparison of angiogenesis-related factor expression in primary tumor cultures under normal and hypoxic growth conditions  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background A localized hypoxic environment occurs during tumor growth necessitating an angiogenic response or tumor necrosis results. Novel cancer treatment strategies take advantage of tumor-induced vascularisation by combining standard chemotherapeutic agents with angiogenesis-inhibiting agents. This has extended the progression-free interval and prolonged survival in patients with various types of cancer. We postulated that the expression levels of angiogenesis-related proteins from various primary tumor cultures would be greater under hypoxic conditions than under normoxia. Methods Fifty cell sources, including both immortalized cell lines and primary carcinoma cells, were incubated under normoxic conditions for 48 hours. Then, cells were either transferred to a hypoxic environment (1% O2 or maintained at normoxic conditions for an additional 48 hours. Cell culture media from both conditions was collected and analyzed via an ELISA-based assay to determine expression levels of 11 angiogenesis-related factors: VEGF, PDGF-AA, PDGF-AA/BB, IL-8, bFGF/FGF-2, EGF, IP-10/CXCL10, Flt-3 ligand, TGF-?1, TGF-?2, and TGF-?3. Results A linear correlation between normoxic and hypoxic growth conditions exists for expression levels of eight of eleven angiogenesis-related proteins tested including: VEGF, IL-8, PDGF-AA, PDGF-AA/BB, TGF-?1, TGF-?2, EGF, and IP-10. For VEGF, the target of current therapies, this correlation between hypoxia and higher cytokine levels was greater in primary breast and lung carcinoma cells than in ovarian carcinoma cells or tumor cell lines. Of interest, patient cell isolates differed in the precise pattern of elevated cytokines. Conclusion As linear correlations exist between expression levels of angiogenic factors under normoxic and hypoxic conditions in vitro, we propose that explanted primary cells may be used to probe the in vivo hypoxic environment. Furthermore, differential expression levels for each sample across all proteins examined suggests it may be possible to build a predictor for angiogenesis-related anticancer agents, as each sample has a unique expression profile. Further studies should be performed to correlate in vitro protein expression levels of angiogenesis-related factors with in vivo patient response.

Brower Stacey L

2008-07-01

317

Dietary intake of a plant phospholipid/lipid conjugate reduces lung cancer growth and tumor angiogenesis.  

Science.gov (United States)

It is well recognized that early detection and cancer prevention are significant armaments in the 'war against cancer'. Changes in lifestyle and diet have significant impact on the global incidence of cancer. For over 30 years, many investigators have studied the concept of chemoprevention. More recently, with the demonstration that antiangiogenic activity reduces tumor growth, the concept of angioprevention has emerged as a novel strategy in the deterrence of cancer development (carcinogenesis). In this study, we utilized a fast growing, highly aggressive murine Lewis lung cancer model to examine the in vivo antitumor effects of a novel, dietary supplement, known as plant phospholipid/lipid conjugate (pPLC). Our goal was to determine if pPLC possessed direct antitumor activity with relatively little toxicity that could be developed as a chemoprevention therapy. We used pPLC directly in this in vivo model due to the lack of aqueous solubility of this novel formulation, which precludes in vitro experimentation. pPLC contains known antioxidants, ferulic acid and lipoic acid, as well as soy sterols, formulated in a unique aqueous-insoluble matrix. The pPLC dietary supplement was shown to suppress in vivo growth of this tumor model by 30%. We also demonstrated a significant decrease in tumor angiogenesis accompanied by increased apoptosis and present preliminary evidence of enhanced expression of the hypoxia-related genes pentraxin-3 and metallothionein-3, by 24.9-fold and 10.9-fold, respectively, compared with vehicle control. These findings lead us to propose using this plant phosolipid/lipid conjugate as a dietary supplement that may be useful in cancer prevention. PMID:24510111

Shuman Moss, Laurie A; Jensen-Taubman, Sandra; Rubinstein, Danielle; Viole, Gary; Stetler-Stevenson, William G

2014-07-01

318

Distribution studies with 17B(16a-(125-I)iodo-estradiol) in rats bearing mammary tumors  

International Nuclear Information System (INIS)

The tissue distribution of 125-iodine in rats bearing transplanted dimethylbenzanthracene (DMBA) induced mammary tumors after intravenous injection of 17B(16a-(125-I)iodo-estradiol (I-E2) is studied. I-E2 does not appear to be an adequate carrier for in vivo localization of estrogen receptors for therapeutic purposes. Study is underway to design a better estrogen receptor binding pharmaceutical

319

Lipopolysaccharide and dexamethasone induce mouse mammary tumor proviral gene expression and differentiation in B lymphocytes through distinct regulatory pathways.  

OpenAIRE

Endogenous mouse mammary tumor virus (MMTV) proviral transcripts are up regulated during the normal course of B-lymphocyte differentiation. We report here that the regulatory mechanisms which lead to increased levels of MMTV transcripts in differentiating, lipopolysaccharide (LPS)-stimulated normal B cells and in the inducible B-cell lymphoma line CH12 are at least partially distinct from those controlling increases in immunoglobulin and J-chain gene expression. In studies designed to charact...

King, L. B.; Corley, R. B.

1990-01-01

320

Inhibition of Tumor Growth, Angiogenesis, and Microcirculation by the Novel Flk-1 Inhibitor SU5416 as Assessed by Intravital Multi-fluorescence Videomicroscopy  

Directory of Open Access Journals (Sweden)

Full Text Available Vascular endothelial growth factor (VEGF plays a fundamental role in mediating tumor angiogenesis and tumor growth. Here we investigate the direct effect of a novel small molecule inhibitor of the Flk-1-mediated signal transduction pathway of VEGF, SU5416, on tumor angiogenesis and microhemodynamics of an experimental glioblastoma by using intravital multifluorescence videomicroscopy. SU5416 treatment significantly suppressed tumor growth. In parallel, SU5416 demonstrated a potent antiangiogenic activity, resulting in a significant reduction of both the total and functional vascular density of the tumor microvasculature, which indicates an impaired vascularization as well as significant perfusion failure in treated tumors. This malperfusion was not compensated for by changes in vessel diameter or recruitment of nonperfused vessels. Analyses of the tumor microcirculation revealed significant microhemodynamic changes after angiogenesis blockage such as a higher red blood cell velocity and blood flow in remnant tumor vessels when compared with controls. Our results demonstrate that the novel antiangiogenic concept of targeting the tyrosine kinase of Flk-1/KDR by means of a small molecule inhibitor represents an efficient strategy to control growth and progression of angiogenesis-dependent tumors. This study provides insight into microvascular consequences of Flk-1/KDR targeting in vivo and may have important implications for the future treatment of angiogenesis-dependent neoplasms.

Peter Vajkoczy

1999-04-01

321

Subcellular Expression of Mammary Serine Proteinase Inhibitor (MASPIN) in Locally Advance Oral Squamous Cell Carcinoma  

OpenAIRE

Objectives: Mammary serine protease inhibitor (MASPIN) has numerous interactions with tumor pathogenesis and progression. Its relationships with apoptosis and angiogenesis have proven the impact on prognosis. However, its exact role is not known and needs further work in relation to various human cancers. Current study was planned to investigate the subcellular expression of MASPIN in oral squamous cell carcinoma (OSCC) and to observe its relation with tumor grade. Methods: It was a descr...

Samina Zaheer; Abdul Hannan Nagi

2014-01-01

322

Overexpression of inhibitor of DNA-binding (ID)-1 protein related to angiogenesis in tumor advancement of ovarian cancers  

OpenAIRE

Abstract Background The inhibitor of DNA-binding (ID) has been involved in cell cycle regulation, apoptosis and angiogenesis. This prompted us to study ID functions in tumor advancement of ovarian cancers. Methods Sixty patients underwent surgery for ovarian cancers. In ovarian cancers, the levels of ID-1, ID-2 and ID-3 mRNAs were determined by real-time reverse transcription-polymerase chain reaction. The histoscore with the localization of ID-1 was determined by immunohistochemistry. Patien...

Tamaya Teruhiko; Fujimoto Jiro; Maw Min

2009-01-01

323

Endothelial Wnt/?-catenin signaling inhibits glioma angiogenesis and normalizes tumor blood vessels by inducing PDGF-B expression  

OpenAIRE

Endothelial Wnt/?-catenin signaling is necessary for angiogenesis of the central nervous system and blood–brain barrier (BBB) differentiation, but its relevance for glioma vascularization is unknown. In this study, we show that doxycycline-dependent Wnt1 expression in subcutaneous and intracranial mouse glioma models induced endothelial Wnt/?-catenin signaling and led to diminished tumor growth, reduced vascular density, and normalized vessels with increased mural cell attachment. These f...

Reis, Marco; Czupalla, Cathrin J.; Ziegler, Nicole; Devraj, Kavi; Seidel, Sascha; Heck, Rosario; Thom, Sonja; Macas, Jadranka; Bockamp, Ernesto; Fruttiger, Marcus; M Taketo, Makoto; Dimmeler, Stefanie; Plate, Karl H.; Liebner, Stefan

2012-01-01

324

Contrast Enhanced Maximum Intensity Projection Ultrasound Imaging for Assessing Angiogenesis in Murine Glioma and Breast Tumor Models: A Comparative Study  

OpenAIRE

The purpose of this study was to prospectively compare noninvasive, quantitative measures of vascularity obtained from 4 contrast enhanced ultrasound (US) techniques to 4 invasive immunohistochemical markers of tumor angiogenesis in a large group of murine xenografts. Glioma (C6) or breast cancer (NMU) cells were implanted in 144 rats. The contrast agent Optison (GE Healthcare, Princeton, NJ) was injected in a tail vein (dose: 0.4ml/kg). Power Doppler imaging (PDI), pulse-subtraction harmonic...

Forsberg, Flemming; Ro, Raymond J.; Fox, Traci B.; Liu, Ji-bin; Chiou, See-ying; Potoczek, Magdalena; Goldberg, Barry B.

2010-01-01

325

The alternative medicine pawpaw and its acetogenin constituents suppress tumor angiogenesis via the HIF-1/VEGF pathway.  

Science.gov (United States)

Products that contain twig extracts of pawpaw (Asimina triloba) are widely consumed anticancer alternative medicines. Pawpaw crude extract (CE) and purified acetogenins inhibited hypoxia-inducible factor-1 (HIF-1)-mediated hypoxic signaling pathways in tumor cells. In T47D cells, pawpaw CE and the acetogenins 10-hydroxyglaucanetin (1), annonacin (2), and annonacin A (3) inhibited hypoxia-induced HIF-1 activation with IC(50) values of 0.02 microg/mL, 12 nM, 13 nM, and 31 nM, respectively. This inhibition correlates with the suppression of the hypoxic induction of HIF-1 target genes VEGF and GLUT-1. The induction of secreted VEGF protein represents a key event in hypoxia-induced tumor angiogenesis. Both the extract and the purified acetogenins blocked the angiogenesis-stimulating activity of hypoxic T47D cells in vitro. Pawpaw extract and acetogenins inhibited HIF-1 activation by blocking the hypoxic induction of nuclear HIF-1alpha protein. The inhibition of HIF-1 activation was associated with the suppression of mitochondrial respiration at complex I. Thus, the inhibition of HIF-1 activation and hypoxic tumor angiogenesis constitutes a novel mechanism of action for these anticancer alternative medicines. PMID:20423107

Coothankandaswamy, Veena; Liu, Yang; Mao, Shui-Chun; Morgan, J Brian; Mahdi, Fakhri; Jekabsons, Mika B; Nagle, Dale G; Zhou, Yu-Dong

2010-05-28

326

Dopamine D2 receptor agonists inhibit lung cancer progression by reducing angiogenesis and tumor infiltrating myeloid derived suppressor cells.  

Science.gov (United States)

We sought to determine whether Dopamine D2 Receptor (D2R) agonists inhibit lung tumor progression and identify subpopulations of lung cancer patients that benefit most from D2R agonist therapy. We demonstrate D2R agonists abrogate lung tumor progression in syngeneic (LLC1) and human xenograft (A549) orthotopic murine models through inhibition of tumor angiogenesis and reduction of tumor infiltrating myeloid derived suppressor cells. Pathological examination of human lung cancer tissue revealed a positive correlation between endothelial D2R expression and tumor stage. Lung cancer patients with a smoking history exhibited greater levels of D2R in lung endothelium. Our results suggest D2R agonists may represent a promising individualized therapy for lung cancer patients with high levels of endothelial D2R expression and a smoking history. PMID:25226814

Hoeppner, Luke H; Wang, Ying; Sharma, Anil; Javeed, Naureen; Van Keulen, Virginia P; Wang, Enfeng; Yang, Ping; Roden, Anja C; Peikert, Tobias; Molina, Julian R; Mukhopadhyay, Debabrata

2015-01-01

327

Lack of c-kit receptor promotes mammary tumors in N-nitrosomethylurea-treated Ws/Ws rats  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background c-kit is expressed in various cell types during development and it has been linked to the promotion of cellular migration, proliferation and/or survival of melanoblasts, hematopoietic progenitors and primordial germ cells. Several reports have proposed a role for the c-kit gene on carcinogenesis. Gain-of-function mutations are associated with diseases such as mastocytosis and gastrointestinal stromal tumors among others. However, very little is known about pathologies associated with loss-of-function mutations. Regarding breast cancer, c-kit protein and mRNA are highly expressed in normal breast but their expression decreases or is absent in the presence of breast cancer. We studied the role of c-kit in mammary carcinogenesis in the Ws/Ws rats carrying spontaneous lack-of-function mutation in the c-kit gene. Fifty day-old virgin female Ws/Ws rats and their wild type counterparts were injected with either 50 mg/kg body weight of the chemical carcinogen N-nitrosomethylurea or with vehicle. The animals were followed-up for 6 months. Fisher 344 rats were used as positive controls for tumor development. Results Eleven weeks after treatment, palpable tumors were detected in the Ws/Ws rats. The tumor incidence was 80% in Ws/Ws rats, while no tumors were observed in the wild type rats (p = 0.006. Our data show that the lack of c-kit is permissive for the development of mammary tumor in Ws/Ws rats treated with carcinogen. Conclusion We conclude that the lack of c-kit may contribute to an imbalanced homeostatic state in the mammary gland either by affecting signaling between stroma and epithelium, or through the lack of mast cells.

Papadopoulos Nikoletta

2008-04-01

328

The PARP inhibitors, veliparib and olaparib, are effective chemopreventive agents for delaying mammary tumor development in BRCA1-deficient mice.  

Science.gov (United States)

Poly-ADP ribose polymerase (PARP) inhibitors are effective for the treatment of BRCA-deficient tumors. Women with these mutations have an increased risk of developing breast cancer and would benefit from effective chemoprevention. This study examines whether the PARP inhibitors, veliparib and olaparib, delay mammary gland tumor development in a BRCA1-deficient (BRCA1(Co/Co);MMTV-Cre;p53(+/-)) mouse model. In dose de-escalation studies, mice were fed with control, veliparib (100 mg/kg diet), or olaparib (200, 100, 50, or 25 mg/kg diet) continuously for up to 43 weeks. For intermittent dosing studies, mice cycled through olaparib (200 mg/kg diet) for 2 weeks followed by a 4-week rest period on control diet. To examine biomarkers, mice were fed with olaparib using the intermittent dosing regimen and mammary glands were evaluated by immunohistochemistry. In mice treated with veliparib or olaparib (200 mg/kg diet), the average age of the first detectable tumor was delayed by 2.4 and 6.5 weeks, respectively, compared with controls. Olaparib also increased the average lifespan of mice by 7 weeks. In dose de-escalation studies, lower concentrations of olaparib delayed tumor development but were less effective than the highest dose. When fed intermittently, olaparib delayed the onset of the first palpable tumor by 5.7 weeks and significantly reduced proliferation and induced apoptosis in hyperplastic mammary glands. In summary, veliparib and olaparib are effective for delaying tumor development and extending the lifespan of BRCA1-deficient mice, and intermittent dosing with olaparib was as effective as continuous dosing. These results suggest that the use of PARP inhibitors is a promising chemopreventive option. PMID:24817481

To, Ciric; Kim, Eun-Hee; Royce, Darlene B; Williams, Charlotte R; Collins, Ryan M; Risingsong, Renee; Sporn, Michael B; Liby, Karen T

2014-07-01

329

The analysis of feasibility and effectiveness of vascular targeting radiotherapy based on a model of tumor growth and angiogenesis  

Science.gov (United States)

Targeting cytotoxic agents to tumor angiogenesis, instead of the tumor itself, is an attractive new approach in Radiation Oncology. Unlike tumor cells, endothelial cells are less likely to develop radio-resistance. Investigations have shown that radiation can cause a definite increase in cell permeability. Permeability changes in the tumor capillary endothelium can contribute to circulatory failure and serve as a site for clot formation. Therefore, radiation could initiate platelet aggregation and blood coagulation locally within the tumor vasculature, leading to tumor cell killing through depletion of oxygen and nutrients. In order to analyze the efficacy of a potential 90Y-labeled compound for vascular targeting radiotherapy and to evaluate the factors that may affect targets' absorbed dose, a tumor vasculature model including its angiogenesis process as a function of time and tumor growth are adopted and improved from the Liotta model. Its output is used to estimate targets' absorbed doses by Monte Carlo simulation. The results show that the effectiveness of vascular targeting therapy depends on the existence of available tumor endothelial cells and target expression. The alphavbeta3 antagonist model compound is less effective in the early stage tumors, which have very few vessels. Although a high administered dose, such as injecting of 2.1 mCi/kg to saturate all available binding sites, can destroy tumor endothelium network, the toxicity to bone marrow makes it impossible to inject such a dose. To a vascularized tumor, after giving one maximum allowable administered activity, 0.83 mCi/kg for the 90Y-labeled model compound, an average of 9.8%, 27.3%, 34.7% and 37.8% of endothelial cells would be killed when treatment starts at day 4, 7, 9 and 12 after tumor development, respectively. Therefore, recurrent treatment by vascular targeting therapy to well-vascularized tumor has the potential to slow down tumor growth or may even cause tumor regression at the primary site. Using an alternative radionuclide, 177Lu (0.498 MeV) to replace high-energy 90Y (2.282 MeV) in the model compound to treat small size tumors is also discussed. The low absorbed dose to tumor endothelium from 177Lu suggests that it is not an ideal choice for vascular targeting radiotherapy.

Ding, Yihong

330

Expression of angiogenesis-related genes in canine cortisol-secreting adrenocortical tumors.  

Science.gov (United States)

The aim of this study was to evaluate the expression of angiogenesis-related genes in canine cortisol-secreting adrenocortical tumors (ATs). Quantitative RT-PCR analysis revealed mRNA encoding for vascular endothelial growth factor, vascular endothelial growth factor receptors 1 and 2, angiopoietin 1 and 2 (ANGPT1 and ANGPT2), the splice variant ANGPT2443, the ANGPT-receptor Tie2, and basic fibroblast growth factor in 38 canine cortisol-secreting ATs (26 carcinomas and 12 adenomas) and 15 normal adrenals. The relative expression of both ANGPT2 and ANGPT2443 was higher in adenomas (P = 0.020 for ANGPT2 and P = 0.002 for ANGPT2443) and carcinomas (P = 0.003 for ANGPT2 and P H295R cortisol-producing adrenocortical carcinoma cell line, we were able to demonstrate that the ANGPT2 expression was stimulated by cyclic adenosine monophosphate and progesterone but not by cortisol. In conclusion, canine cortisol-secreting ATs have enhanced ANGPT2 expression with a concomitant shift toward a proangiogenic state. On the basis of this information, treatment modalities may be developed that interfere with ANGPT2 expression, including inhibition of the cyclic adenosine monophosphate/protein kinase A pathway, or of the effect of ANGPT2, by using specific ANGPT2 inhibitors. PMID:24377872

Kool, M M J; Galac, S; Kooistra, H S; Mol, J A

2014-04-01

331

pRb Inactivation in Mammary Cells Reveals Common Mechanisms for Tumor Initiation and Progression in Divergent Epithelia  

Directory of Open Access Journals (Sweden)

Full Text Available Retinoblastoma 1 (pRb and the related pocket proteins, retinoblastoma-like 1 (p107 and retinoblastoma-like 2 (p130 (pRbf, collectively, play a pivotal role in regulating eukaryotic cell cycle progression, apoptosis, and terminal differentiation. While aberrations in the pRb-signaling pathway are common in human cancers, the consequence of pRbf loss in the mammary gland has not been directly assayed in vivo. We reported previously that inactivating these critical cell cycle regulators in divergent cell types, either brain epithelium or astrocytes, abrogates the cell cycle restriction point, leading to increased cell proliferation and apoptosis, and predisposing to cancer. Here we report that mouse mammary epithelium is similar in its requirements for pRbf function; Rbf inactivation by T121, a fragment of SV40 T antigen that binds to and inactivates pRbf proteins, increases proliferation and apoptosis. Mammary adenocarcinomas form within 16 mo. Most apoptosis is regulated by p53, which has no impact on proliferation, and heterozygosity for a p53 null allele significantly shortens tumor latency. Most tumors in p53 heterozygous mice undergo loss of the wild-type p53 allele. We show that the mechanism of p53 loss of heterozygosity is not simply the consequence of Chromosome 11 aneuploidy and further that chromosomal instability subsequent to p53 loss is minimal. The mechanisms for pRb and p53 tumor suppression in the epithelia of two distinct tissues, mammary gland and brain, are indistinguishable. Further, this study has produced a highly penetrant breast cancer model based on aberrations commonly observed in the human disease.

Simin Karl

2004-01-01

332

DNA supercoiling in proliferating and quiescent 67 murine mammary tumor cells  

International Nuclear Information System (INIS)

The nucleoid sedimentation assay, which is a measure of DNA ''compactness'' or supercoiling, was used to evaluate the supercoiling state of proliferating (P) and quiescent (Q) murine mammary tumor cells. Two day old cultures are referred to as P cells, whereas 7 day old cultures maintained without media replenishment are referred to as Q cells (>95% arrested in G/sub 1/). Q nucleoids sedimented significantly less far into neutral sucrose gradients than P nucleoids, suggesting a less compact DNA structure. This was further confirmed by the utilization of two other probes of DNA supercoiling: ionizing radiation and sedimentation through gradients containing the intercalator ethidium bromide (EtBr). Whereas nucleoids from P cells showed a decrease in sedimentation following ionizing radiation and an initial decrease, followed by an increase, in sedimentation through gradients containing increasing concentrations of EtBr, the sedimentation of nucleoids from Q cells did not change following either treatment. These data indicate that the DNA of nucleoids isolated from Q cells is in a ''relaxed'' state. The potential significance of these results is discussed

333

Expression of human sequences related to those of mouse mammary tumor virus  

International Nuclear Information System (INIS)

Sequences related to those of the mouse mammary tumor virus (MuMTV) genome have been cloned from human DNA by screening a library prepared from the DNA of a human breast cancer cell line with MuMTV gag-pol DNA. Nine distinct groups of (MuMTV-related) sequences were identified among 100 lambda recombinants by cross-hybridization experiments with subcloned fragments containing gag-pol-related DNA. The largest group, of 64 recombinants, contains the MuMTV-related sequences cloned by others. The other eight groups contain MuMTV-related sequences that have not been described previously. The gag-pol regions of one recombinant from each of the nine groups were hybridized to RNA prepared from five human breast cancer cell lines, from placenta, and from two cell lines derived from other malignancies. RNAs were detected by probes for several of the groups. The RNAs ranged in size from 1.2 to 12 kilobases. Probes for six of the groups detected large RNAs that could represent transcripts of full-length proviral DNA. Two of the probes detected RNA in one breast cancer cell line only. Most of the RNAs were detected in more than one cell line

334

Expression of human sequences related to those of mouse mammary tumor virus  

Energy Technology Data Exchange (ETDEWEB)

Sequences related to those of the mouse mammary tumor virus (MuMTV) genome have been cloned from human DNA by screening a library prepared from the DNA of a human breast cancer cell line with MuMTV gag-pol DNA. Nine distinct groups of (MuMTV-related) sequences were identified among 100 lambda recombinants by cross-hybridization experiments with subcloned fragments containing gag-pol-related DNA. The largest group, of 64 recombinants, contains the MuMTV-related sequences cloned by others. The other eight groups contain MuMTV-related sequences that have not been described previously. The gag-pol regions of one recombinant from each of the nine groups were hybridized to RNA prepared from five human breast cancer cell lines, from placenta, and from two cell lines derived from other malignancies. RNAs were detected by probes for several of the groups. The RNAs ranged in size from 1.2 to 12 kilobases. Probes for six of the groups detected large RNAs that could represent transcripts of full-length proviral DNA. Two of the probes detected RNA in one breast cancer cell line only. Most of the RNAs were detected in more than one cell line.

Franklin, G.C.; Hanson, I.M.; May, F.E.B.; Westley, B.R. (Royal Victoria Infirmary, Newcastle upon Tyne (England)); Chretien, S.; Rochefort, H. (Institut National de la Sante et de la Recherche Medicale, Montpellier (France))

1988-04-01

335

Kinetically directed combination therapy with adriamycin and x-irradiation in a mammary tumor model  

International Nuclear Information System (INIS)

In the present studies, the interaction of adriamycin (A) and x-irradiation (X) in T1699 mouse mammary tumors was evaluated. Mitotic indices and thymidine labeling indices were determined at various intervals after A or X alone, and after A + X given in combination. The results with A (1.0 mg/kg) and X(200 R) alone suggest that those quantities of each agent induce a G2 progression delay of 9 to 12 h. The kinetic results after A + X in combination indicated increased S phase transit time and G2 progression delay. Recovery kinetics after A + X were used to predict optimum sequence intervals for subsequent A + X fractions. Sequential A + X treatment schedules, up to 4 fractions, were designed and evaluated by regrowth delay measurements. The results indicated that the interaction was additive when A and X were given together in combination. Fractionation of A + X to minimize proliferative recovery between fractions resulted in an enhanced antitumor effect

336

E-cadherin expression and in vitro invasion of canine mammary tumor cells.  

Science.gov (United States)

E-cadherin is considered to be an invasion suppressor molecule. We have studied the expression and function of E-cadherin in three cell lines derived from a dog mammary tumor, namely SH15, SH24, and SH27. In monolayer culture the cell lines can be distinguished by their morphotype: epithelioid (SH15), fibroblast-like (SH24) and intermediate type (SH27). SH27 was unable to form colonies in collagen gel in contrast to SH15 and SH24. All three cell lines expressed the E-cadherin antigen, as evident from immunocytochemistry, and alpha-, beta-, and gamma-catenins as evident from immunoprecipitation with E-cadherin antibody. Only SH27 showed E-cadherin-dependent aggregation, and little invasion into collagen type 1 gels, in contrast to SH15 and SH24 cells. However, in the precultured embryonic chick heart assay all three cell lines were invasive, demonstrating that invasion depends upon the microenvironment. We assume that in the embryonic chick heart, factors were present or were induced by the SH27 cells, interfering with the function of E-cadherin. PMID:8690022

Spieker, N; Mareel, M; Bruyneel, E A; Nederbragt, H

1995-12-01

337

Nitric oxide mediates angiogenesis induced in vivo by platelet-activating factor and tumor necrosis factor-alpha.  

Science.gov (United States)

We evaluated the role of an endogenous production of nitric oxide (NO) in the in vitro migration of endothelial cells and in the in vivo angiogenic response elicited by platelet-activating factor (PAF), tumor necrosis factor-alpha (TNF), and basic fibroblast growth factor (bFGF). The NO synthase inhibitor, N omega-nitro-L-arginine-methyl ester (L-NAME), but not its enantiomer D-NAME, prevented chemotaxis of endothelial cells induced in vitro by PAF and by TNF. The motogenic activity of TNF was also inhibited by WEB 2170, a specific PAF-receptor antagonist. In contrast, chemotaxis induced by bFGF was not prevented by L-NAME or by WEB 2170. Angiogenesis was studied in vivo in a murine model in which Matrigel was used as a vehicle for the delivery of mediators. In this model, the angiogenesis induced by PAF and TNF was inhibited by WEB 2170 and L-NAME but not by D-NAME. In contrast, angiogenesis induced by bFGF was not affected by L-NAME or by WEB 2170. TNF, but not bFGF, induced PAF synthesis within Matrigel. These results suggest that NO mediates the angiogenesis induced by PAF as well as that induced by TNF, which is dependent on the production of PAF. In contrast, the angiogenic effect of bFGF appears to be both PAF and NO independent. Images Figure 3 Figure 4 PMID:9250168

Montrucchio, G.; Lupia, E.; de Martino, A.; Battaglia, E.; Arese, M.; Tizzani, A.; Bussolino, F.; Camussi, G.

1997-01-01

338

Synergism of diethylstilbestrol and other carcinogens in concurrent development of hepatic, mammary, and pituitary tumors in castrated male rats  

International Nuclear Information System (INIS)

Castrated male WF rats, given implants of pellets containing 5.0 mg diethylstilbestrol (DES), were given N-butyl-N-nitrosourea (NBU) in small amounts, which alone produced no mammary tumors in intact female rats. Treatment resulted in the high yield of hepatic tumors (HT), mammary tumors (MT), and pituitary tumors (PT) concurrently in each rat. If animals were further tested with prolactin, the development of HT and MT was accelerated, whereas that of PT was suppressed. None of the intact or castrated rats receiving NBU and/or prolactin developed tumors in any tissues if DES treatment was omitted. Exposure of male rats, preconditioned similarly to NBU treatment, to 200 rads of 14.1-MeV fast-neutron radiation also elicited HT, MT, and PT with an efficiency comparable to that of NBU-treated rats. These findings indicate that DES played an essential role in the whole carcinogenic process in each tissue and that castrated male rats, if conditioned properly with estrogens, are useful for the study of the carcinogenesis mechanism in these tissues

339

Estudo retrospectivo de 207 casos de tumores mamários em gatas / A retrospective study of 207 cases of mammary tumors in queens  

Scientific Electronic Library Online (English)

Full Text Available SciELO Brazil | Language: Portuguese Abstract in portuguese Este estudo teve como objetivos determinar os tumores mais prevalentes em gatos e relacionar os tumores mamários a alguns de seus fatores prognósticos. Os arquivos do Laboratório de Patologia Veterinária (LPV) da Universidade Federal de Santa Maria (UFSM) foram revisados e um total de 1.427 protocol [...] os de biopsias e necropsias de felinos, entre 2000 e 2011, foi encontrado. Com base nas informações dos arquivos, foi estabelecida a relação entre os tumores e alguns fatores como sexo, idade, raça, estado reprodutivo, uso de contraceptivos, número e localização das glândulas afetadas, ulcerações, tamanho do neoplasma, metástases distantes e para os linfonodos. Assim, observou-se que os tumores de mama foram o segundo diagnóstico mais prevalente, após os tumores de pele. Todos os gatos com tumores mamários eram fêmeas, sendo os sem raça definida e os idosos os mais afetados. Os neoplasmas malignos foram diagnosticados com maior frequência, seguidos pelos tumores não neoplásicos e pelos neoplasmas benignos. Os tumores menores eram, na sua maioria, carcinomas. Ulcerações estavam presentes não só em neoplasmas malignos, mas também em alterações não neoplásicas. Metástases distantes foram encontradas principalmente nos pulmões e na pele. Abstract in english This study aimed to determine the most prevalent mammary tumors in cats and associate them to some prognostic factors. The files from the Laboratório de Patologia Veterinária (LPV) of the Universidade Federal de Santa Maria (UFSM) were reviewed, and 1.427 feline biopsies and autopsy protocols betwee [...] n the years 2000 and 2011 were found. Based on the information retrieved from the files, a relationship was established among the tumors and some prognostic factors such as sex, age, breed, reproductive status, use of contraceptives, number and location of affected glands, ulcers, size of the neoplasm, distant metastases, and affected lymph nodes. Thus, it was observed that mammary cancer is the second most prevalent diagnosis, following skin tumors. All cats with mammary tumors were female, being the elderly and mixed breed the most affected. Malignant neoplasms were the most frequently diagnosed, followed by non-neoplastic tumors, and benign neoplasms. Smaller tumors were mostly carcinomas. Ulcerations were present not only in malignant neoplasms but also in non-neoplastic changes. Distant metastases were found mainly to the lungs and skin.

Monique, Togni; Eduardo K., Masuda; Glaucia D., Kommers; Rafael A., Fighera; Luiz Francisco, Irigoyen.

2013-03-01

340

Overexpression of Dimethylarginine Dimethylaminohydrolase Enhances Tumor Hypoxia: An Insight into the Relationship of Hypoxia and Angiogenesis In Vivo  

Directory of Open Access Journals (Sweden)

Full Text Available The oxygenation status of tumors derived from wild-type C6 glioma cells and clone D27 cells overexpressing dimethylarginine dimethylaminohydrolase (DDAH was assessed in vivo using a variety of direct and indirect assays of hypoxia. Clone D27 tumors exhibit a more aggressive and better-vascularized phenotype compared to wild-type C6 gliomas. Immunohistochemical analyses using the 2-nitroimidazole hypoxia marker pimonidazole, fiber optic OxyLite measurements of tumor pO2, and localized 31P magnetic resonance spectroscopy measurements of tumor bioenergetic status and pH clearly demonstrated that the D27 tumors were more hypoxic compared to C6 wild type. In the tumor extracts, only glucose concentrations were significantly lower in the D27 tumors. Elevated Glut-1 expression, a reliable functional marker for hypoxia-inducible factor-1-mediated metabolic adaptation, was observed in the D27 tumors. Together, the data show that overexpression of DDAH results in C6 gliomas that are more hypoxic compared to wild-type tumors, and point strongly to an inverse relationship of tumor oxygenation and angiogenesis in vivo-a concept now being supported by the enhanced understanding of oxygen sensing at the molecular level.

Vassiliki Kostourou

2004-07-01

341

Proteínas de fase aguda em cadelas com neoplasia mamária / Acute phase proteins in female dogs with mammary tumors  

Scientific Electronic Library Online (English)

Full Text Available As proteínas de fase aguda (PFA) apresentam concentrações séricas alteradas mediante processos infecciosos, inflamatórios e neoplásicos. Objetivou-se com este trabalho avaliar as variações séricas das PFA em cadelas portadoras de neoplasia mamária, comparando com a avaliação histológica e leucograma [...] . As PFA foram avaliadas em 45 cadelas com tumor de mama, distribuídas nos grupos neoplasia benigna (n=13), maligna não ulcerada (n=24) e maligna ulcerada (n=8). O grupo controle foi composto por 20 cadelas saudáveis. Foram realizados o teste de eletroforese em gel de poliacrilamida contendo dodecil sulfato de sódio (SDS-PAGE) para identificar as PFA (albumina, ceruloplasmina, transferrina, haptoglobina Hp, ?-1 antitripsina e ?-1 glicoproteina ácida) e o teste ultrassensível para proteína C reativa (PCR). As pacientes com neoplasia mamária maligna ulcerada apresentaram elevações sérica para PCR e Hp e redução da albumina (P Abstract in english Acute phase proteins (APPs) are serum proteins whose concentrations change after infectious and inflammatory disease, and cancer. The aims of this study were to evaluate changes in APPs concentration and to correlate these findings with histological classification and WBC in female dogs with mammary [...] tumors. APPs were studied in 45 female dogs with mammary tumor distributed in the following groups: benign (n=13), malignant without tumor ulceration (n=24), and malignant with tumor ulceration (n=8). SDS-polyacrylamide gel (SDS-PAGE) electrophoresis was used to measure APPs concentrations (albumin, ceruloplasmin, transferrin, haptoglobinHp, ?-1-acid glycoprotein and ?-1-antitrypsin) and ultrasensitive assay was used to evaluate serum C-reactive protein (CRP). Patients with malignant mammary neoplasia plus ulceration had significant increase of CRP and Hp, and had decreased levels of albumin (P

Michelly Kheidy Borges, Battisti; Daniella Matos da, Silva; Mhayara Samile de Oliveira, Reusing; Olair Carlos, Beltrame; Elizabeth Moreira dos Santos, Schmidt; José Jurandir, Fagliari; Rosângela Locatelli, Dittrich; Simone Domit, Guérios.

2013-05-01

342

Docosahexaenoic acid is neither synthesized nor retroconverted by the normal and tumor mouse mammary epithelial cells in primary culture.  

Science.gov (United States)

Metabolism of 1-14C-[18:3(n-3)] and 1-14C-[22:6(n-3)] were investigated in the primary cultures of normal and tumor mouse mammary epithelial cells. Analysis of endogenous fatty acid composition indicated a decreased proportion of total (n-6) PUFA in the cultured tumor cells compared to normal cells. These cells can synthesize significant amount of 20:5 (n-3) and 22:5 (n-3) but not 22:6 (n-3), from 18:3 (n-3). There was very little or no retroconversion of 22:6 (n-3) by these cells. It has been concluded that mammary epithelial cells may be deficient in 4-desaturase activity and also that exogenous 22:6 (n-3), instead of serving as a source of 20:5 (n-3), may actually counter the effects of both 20:4 (n-6) and 20:5 (n-3) in the mammary tissue. PMID:2522001

Bandyopadhyay, G K; Mckenzie, K E; Imagawa, W; Nandi, S

1989-02-15

343

Global Tumor RNA Expression in Early Establishment of Experimental Tumor Growth and Related Angiogenesis following Cox-Inhibition Evaluated by Microarray Analysis  

Directory of Open Access Journals (Sweden)

Full Text Available Altered expression of COX-2 and overproduction of prostaglandins, particularly prostaglandin E2, are common in malignant tumors. Consequently, non-steroidal anti-inflammatory drugs (NSAIDs attenuate tumor net growth, tumor related cachexia, improve appetite and prolong survival. We have also reported that COX-inhibition (indomethacin interfered with early onset of tumor endothelial cell growth, tumor cell proliferation and apoptosis. It is however still unclear whether such effects are restricted to metabolic alterations closely related to eicosanoid pathways and corresponding regulators, or whether a whole variety of gene products are involved both up- and downstream effects of eicosanoids. Therefore, present experiments were performed by the use of an in vivo, intravital chamber technique, where micro-tumor growth and related angiogenesis were analyzed by microarray to evaluate for changes in global RNA expression caused by indomethacin treatment. Indomethacin up-regulated 351 and down-regulated 1852 genes significantly (p < 0.01; 1066 of these genes had unknown biological function. Genes with altered expression occurred on all chromosomes. Our results demonstrate that indomethacin altered expression of a large number of genes distributed among a variety of processes in the carcinogenic progression involving angiogenesis, apoptosis, cell-cycling, cell adhesion, inflammation as well as fatty acid metabolism and proteolysis. It remains a challenge to distinguish primary key alterations from secondary adaptive changes in transcription of genes altered by cyclooxygenase inhibition.

Kent Lundholm

2007-01-01

344

Dysregulation of MicroRNA-34a Expression in Head and Neck Squamous Cell Carcinoma Promotes Tumor Growth and Tumor Angiogenesis  

Science.gov (United States)

Background MicroRNAs (miRs) are small non-coding RNAs that play an important role in cancer development where they can act as oncogenes or as tumor-suppressors. miR-34a is a tumor-suppressor that is frequently downregulated in a number of tumor types. However, little is known about the role of miR-34a in head and neck squamous cell carcinoma (HNSCC). Methods and Results miR-34a expression in tumor samples, HNSCC cell lines and endothelial cells was examined by real time PCR. Lipofectamine-2000 was used to transfect miR-34a in HNSCC cell lines and human endothelial cells. Cell-proliferation, migration and clonogenic survival was examined by MTT, Xcelligence system, scratch assay and colony formation assay. miR-34a effect on tumor growth and tumor angiogenesis was examined by in vivo SCID mouse xenograft model. Our results demonstrate that miR-34a is significantly downregulated in HNSCC tumors and cell lines. Ectopic expression of miR-34a in HNSCC cell lines significantly inhibited tumor cell proliferation, colony formation and migration. miR-34a overexpression also markedly downregulated E2F3 and survivin levels. Rescue experiments using microRNA resistant E2F3 isoforms suggest that miR-34a-mediated inhibition of cell proliferation and colony formation is predominantly mediated by E2F3a isoform. In addition, tumor samples from HNSCC patients showed an inverse relationship between miR-34a and survivin as well as miR-34a and E2F3 levels. Overexpression of E2F3a completely rescued survivin expression in miR-34a expressing cells, thereby suggesting that miR-34a may be regulating survivin expression via E2F3a. Ectopic expression of miR-34a also significantly inhibited tumor growth and tumor angiogenesis in a SCID mouse xenograft model. Interestingly, miR-34a inhibited tumor angiogenesis by blocking VEGF production by tumor cells as well as directly inhibiting endothelial cell functions. Conclusions Taken together, these findings suggest that dysregulation of miR-34a expression is common in HNSCC and modulation of miR34a activity might represent a novel therapeutic strategy for the treatment of HNSCC. PMID:22629428

Kumar, Bhavna; Yadav, Arti; Lang, James; Teknos, Theodoros N.; Kumar, Pawan

2012-01-01

345

PET imaging of tumor angiogenesis in mice with VEGF-A-targeted (86)Y-CHX-A?-DTPA-bevacizumab.  

Science.gov (United States)

Bevacizumab is a humanized monoclonal antibody that binds to tumor-secreted vascular endothelial growth factor (VEGF)-A and inhibits tumor angiogenesis. In 2004, the antibody was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic colorectal carcinoma in combination with chemotherapy. This report describes the preclinical evaluation of a radioimmunoconjugate, (86)Y-CHX-A?-DTPA-bevacizumab, for potential use in Positron Emission Tomography (PET) imaging of VEGF-A tumor angiogenesis and as a surrogate marker for (90)Y-based radioimmunotherapy. Bevacizumab was conjugated to CHX-A?-DTPA and radiolabeled with (86)Y. In vivo biodistribution and PET imaging studies were performed on mice bearing VEGF-A-secreting human colorectal (LS-174T), human ovarian (SKOV-3) and VEGF-A-negative human mesothelioma (MSTO-211H) xenografts. Biodistribution and PET imaging studies demonstrated highly specific tumor uptake of the radioimmunoconjugate. In mice bearing VEGF-A-secreting LS-174T, SKOV-3 and VEGF-A-negative MSTO-211H tumors, the tumor uptake at 3 days postinjection was 13.6 ± 1.5, 17.4 ± 1.7 and 6.8 ± 0.7 % ID/g, respectively. The corresponding tumor uptake in mice coinjected with 0.05 mg cold bevacizumab were 5.8 ± 1.3, 8.9 ± 1.9 and 7.4 ± 1.0 % ID/g, respectively at the same time point, demonstrating specific blockage of the target in VEGF-A-secreting tumors. The LS-174T and SKOV3 tumors were clearly visualized by PET imaging after injecting 1.8-2.0 MBq (86)Y-CHX-A?-DTPA-bevacizumab. Organ uptake quantified by PET closely correlated (r(2) = 0.87, p = 0.64, n = 18) to values determined by biodistribution studies. This preclinical study demonstrates the potential of the radioimmunoconjugate, (86)Y-CHX-A?-DTPA-bevacizumab, for noninvasive assessment of the VEGF-A tumor angiogenesis status and as a surrogate marker for (90)Y-CHX-A?-DTPA-bevacizumab radioimmunotherapy. PMID:20473899

Nayak, Tapan K; Garmestani, Kayhan; Baidoo, Kwamena E; Milenic, Diane E; Brechbiel, Martin W

2011-02-15

346

Angiogenesis in advanced colorectal adenocarcinoma with special reference to tumoral invasion / Angiogênese no adenocarcinoma colorretal avançado com especial referência à invasão tumoral  

Scientific Electronic Library Online (English)

Full Text Available Racional- A angiogênse é uma etapa fundamental no crescimento e progressão tumoral. Sua quantificação, através da contagem microvascular, apresenta valor prognóstico em muitas neoplasias malignas e, recentemente, tem sido avaliada em tumores gastrointestinais. Objetivos - Avaliar a significância pro [...] gnóstica da contagem microvascular no carcinoma colorretal, estudando sua associação com metástases hematogênicas, sobrevida e variáveis clinicopatológicas, tais como tamanho, diferenciação histológica e profundidade de invasão tumoral. Pacientes/Métodos - Foram incluídos 48 pacientes com adenocarcinoma colorretal. Secções histológicas contendo a margem tumoral invasiva (4 mm) foram analisadas e os microvasos foram identificados através de imunohistoquímica utilizando o anticorpo monoclonal anti-FVIII (Von Willebrand Factor - mouse). A contagem microvascular foi realizada através da identificação de áreas com maior densidade microvascular - hot spots - e resulta da média entre cinco destas áreas. Resultados - A contagem microvascular mediana foi de 14 microvasos/0,785 mm², dividindo a amostra em grupos hipo e hipervascular. Enquanto 2/8 (25%) tumores com invasão da muscular própria foram classificados como hipervasculares, 11/15 (73%) tumores com invasão da serosa ou tecidos peri-colônicos foram classificados como hipervasculares. No entanto, associação não significativa foi encontrada entre a quantificação angiogênica e metástases hematogênicas, sobrevida e variáveis clinicopatológicas, tais como o tamanho tumoral e diferenciação histológica. Conclusões - O achado de aumento significativo na contagem microvascular em conformidade com a maior profundidade de invasão tumoral suporta a teoria que a progressão tumoral possa estar relacionada à angiogênese. Embora a angiogênese seja etapa importante no crescimento tumoral e durante a metastatização à distância, outros fatores podem estar implicados em tais processos. Abstract in english Background - Angiogenesis is a crucial step in tumor growth and progression. Its quantification by microvessel counting has a prognostic value in several types of malignancies and recently has been appraised in gastrointestinal tumors. Aim - To assess the prognostisc significance of microvessel quan [...] tification in colorectal carcinomas, studying its association with hematogenous metastases, survival and clinicopathological variables such as size, histologic differentiation and depth of tumoral invasion. Patients/Methods - Forty eight patients with colorectal adenocarcinoma were included in this study. Histologic sections of invasion tumoral margin (4 µm) were analyzed and endothellined microvessels were immunostained with monoclonal mouse Von Willebrand Factor (anti-FVIII). The microvessel count was performed from the identification of the area with increased microvessel density - hot spots - and results of the mean in five of these fields. Results- The cut-off microvessel count was 14 microvessels/0,785 mm² , which divided the sample into hypovascular and hypervascular groups. While 2/8 (25%) tumors with muscularis propria invasion were classified as hypervascular, 11/15 (73%) tumors with serosa or perivisceral fat were classified as hypervascular. However, a non-significant statistical association was found between the angiogenesis quantification, hematogenous metastases, survival and clinicopathological variables such as size and histologic differentiation of the tumor. Conclusions - The findings of significantly increase of microvessel count in conformity with tumoral invasion depth supports the hypothesis that tumor progression might be related to angiogenesis. Although angiogenesis is an important step in the tumoral growth and during the metastatization process, other factors can be implicated.

Cláudio, TARTA; Cláudio Rolim, TEIXEIRA; Shinji, TANAKA; Ken, HARUMA; César, CHIELE-NETO; Vinícius Duval da, SILVA.

2002-03-01

347

Angiogenesis in advanced colorectal adenocarcinoma with special reference to tumoral invasion Angiogênese no adenocarcinoma colorretal avançado com especial referência à invasão tumoral  

Directory of Open Access Journals (Sweden)

Full Text Available Background - Angiogenesis is a crucial step in tumor growth and progression. Its quantification by microvessel counting has a prognostic value in several types of malignancies and recently has been appraised in gastrointestinal tumors. Aim - To assess the prognostisc significance of microvessel quantification in colorectal carcinomas, studying its association with hematogenous metastases, survival and clinicopathological variables such as size, histologic differentiation and depth of tumoral invasion. Patients/Methods - Forty eight patients with colorectal adenocarcinoma were included in this study. Histologic sections of invasion tumoral margin (4 µm were analyzed and endothellined microvessels were immunostained with monoclonal mouse Von Willebrand Factor (anti-FVIII. The microvessel count was performed from the identification of the area with increased microvessel density - hot spots - and results of the mean in five of these fields. Results- The cut-off microvessel count was 14 microvessels/0,785 mm² , which divided the sample into hypovascular and hypervascular groups. While 2/8 (25% tumors with muscularis propria invasion were classified as hypervascular, 11/15 (73% tumors with serosa or perivisceral fat were classified as hypervascular. However, a non-significant statistical association was found between the angiogenesis quantification, hematogenous metastases, survival and clinicopathological variables such as size and histologic differentiation of the tumor. Conclusions - The findings of significantly increase of microvessel count in conformity with tumoral invasion depth supports the hypothesis that tumor progression might be related to angiogenesis. Although angiogenesis is an important step in the tumoral growth and during the metastatization process, other factors can be implicated.Racional- A angiogênse é uma etapa fundamental no crescimento e progressão tumoral. Sua quantificação, através da contagem microvascular, apresenta valor prognóstico em muitas neoplasias malignas e, recentemente, tem sido avaliada em tumores gastrointestinais. Objetivos - Avaliar a significância prognóstica da contagem microvascular no carcinoma colorretal, estudando sua associação com metástases hematogênicas, sobrevida e variáveis clinicopatológicas, tais como tamanho, diferenciação histológica e profundidade de invasão tumoral. Pacientes/Métodos - Foram incluídos 48 pacientes com adenocarcinoma colorretal. Secções histológicas contendo a margem tumoral invasiva (4 mm foram analisadas e os microvasos foram identificados através de imunohistoquímica utilizando o anticorpo monoclonal anti-FVIII (Von Willebrand Factor - mouse. A contagem microvascular foi realizada através da identificação de áreas com maior densidade microvascular - hot spots - e resulta da média entre cinco destas áreas. Resultados - A contagem microvascular mediana foi de 14 microvasos/0,785 mm², dividindo a amostra em grupos hipo e hipervascular. Enquanto 2/8 (25% tumores com invasão da muscular própria foram classificados como hipervasculares, 11/15 (73% tumores com invasão da serosa ou tecidos peri-colônicos foram classificados como hipervasculares. No entanto, associação não significativa foi encontrada entre a quantificação angiogênica e metástases hematogênicas, sobrevida e variáveis clinicopatológicas, tais como o tamanho tumoral e diferenciação histológica. Conclusões - O achado de aumento significativo na contagem microvascular em conformidade com a maior profundidade de invasão tumoral suporta a teoria que a progressão tumoral possa estar relacionada à angiogênese. Embora a angiogênese seja etapa importante no crescimento tumoral e durante a metastatização à distância, outros fatores podem estar implicados em tais processos.

Cláudio TARTA

2002-03-01

348

Establishment of linear accelerator-based image guided radiotherapy for orthotopic 4T1 mouse mammary tumor model.  

Science.gov (United States)

This study was conducted to assess the feasibility of image guided radiotherapy (IGRT) for orthotopic 4T1 mouse mammary tumor using linear accelerator (LINAC). Eighteen Balb/C mice were inoculated with 4T1 cells on left mammary fat pad and nine of them were irradiated using LINAC. Tumors, planning target volumes (PTV), bowels adjacent to tumors, bones and lungs were delineated on planning CT images. IGRT plans were generated to irradiate prescription dose to at least 90% of the PTV and then compared with conventional 2-dimensional plans with anterior-posterior and posterior-anterior beams with 5 mm margins (2D AP/PA plan). Homemade dose-build-up-cradle was designed to encompass mouse bed for homogeneous dose build up. To confirm the irradiated dose, tumor doses were measured using diode detector placed on the surface of tumors. Plan comparison demonstrated equivalent doses to PTV while sparing more doses to normal tissues including bowel (from 90.9% to 40.5%, median value of mean doses) and bone marrow (from 12.9% to 4.7%, median value of mean doses) than 2D AP/PA plan. Quality assurance using diode detector confirmed that IGRT could deliver 95.3-105.3% of the planned doses to PTV. Tumors grew 505.2-1185.8% (mean 873.3%) in the control group and 436.1-771.8% (mean 615.5%) in the irradiated group. These results demonstrate that LINAC-based IGRT provides a reliable approach with accurate dose delivery in the radiobiological study for orthotropic tumor model maintaining tumor microenvironment. PMID:24999360

Lee, Seung-Heon; Kim, Ji-Young; Lee, Kyu-Chan; Nam, Jeong-Seok; Choi, Jinho; Lee, Seok-Ho; Sung, Ki-Hoon; Ahn, So-Hyun

2014-06-01

349

Tissue-Infiltrating Neutrophils Constitute the Major In Vivo Source of Angiogenesis-Inducing MMP-9 in the Tumor Microenvironment  

Directory of Open Access Journals (Sweden)

Full Text Available According to established notion, one of the major angiogenesis-inducing factors, pro-matrix metalloproteinase-9 (proMMP-9, is supplied to the tumor microenvironment by tumor-associated macrophages (TAMs. Accumulated evidence, however, indicates that tumor-associated neutrophils (TANs are also critically important for proMMP-9 delivery, especially at early stages of tumor development. To clarify how much angiogenic proMMP-9 is actually contributed by TAMs and TANs, we quantitatively evaluated TAMs and TANs from different tumor types, including human xenografts and syngeneic murine tumors grown in wild-type and Mmp9-knockout mice. Whereas host MMP-9 competence was required for full angiogenic potential of both normal and tumor-associated leukocytes, direct comparisons of neutrophils versus macrophages and TANs versus TAMs demonstrated that macrophages and TAMs secrete 40- to 50-fold less proMMP-9 than the same numbers of neutrophils or TANs. Correspondingly, the levels of MMP-9–mediated in vivo angiogenesis induced by neutrophils and TANs substantially exceeded those induced by macrophages and TAMs. MMP-9–delivering TANs were also required for development of metastasis-supporting intratumoral vasculature, characterized by ?11-?m size lumens and partial coverage with stabilizing pericytes. Importantly, MMP-9–producing TAMs exhibit M2-skewed phenotype but do not express tissue inhibitor of metalloproteinases-1 (TIMP-1, a novel characteristic allowing them to secrete TIMP-1–free, neutrophil-like MMP-9 zymogen unencumbered by its natural inhibitor. Together, our findings support the notion whereby TANs, capable of immediate release of their pre-stored cargo, are the major contributors of highly angiogenic MMP-9, whereas tumor-influxing precursors of macrophages require time to differentiate, polarize into M2-skewed TAMs, shut down their TIMP-1 expression, and only then, initiate relatively low-level production of TIMP-free MMP-9 zymogen.

Elena I. Deryugina

2014-10-01

350

Platelets are associated with xenograft tumor growth and the clinical malignancy of ovarian cancer through an angiogenesis-dependent mechanism.  

Science.gov (United States)

Platelets are known to facilitate tumor metastasis and thrombocytosis has been associated with an adverse prognosis in ovarian cancer. However, the role of platelets in primary tumour growth remains to be elucidated. The present study demonstrated that the expression levels of various markers in platelets, endothelial adherence and angiogenesis, including, platelet glycoprotein IIb (CD41), platelet endothelial cell adhesion molecule 1 (CD31), vascular endothelial growth factor (VEGF), lysyl oxidase, focal adhesion kinase and breast cancer anti?estrogen resistance 1, were expressed at higher levels in patients with malignant carcinoma, compared with those with borderline cystadenoma and cystadenoma. In addition, the endothelial markers CD31 and VEGF were found to colocalize with the platelet marker CD41 in the malignant samples. Since mice transplanted with human ovarian cancer cells (SKOV3) demonstrated elevated tumor size and decreased survival rate when treated with thrombin or thrombopoietin (TPO), the platelets appeared to promote primary tumor growth. Depleting platelets using antibodies or by pretreating the cancer cells with hirudin significantly attenuated the transplanted tumor growth. The platelets contributed to late, but not early stages of tumor proliferation, as mice treated with platelet?depleting antibody 1 day prior to and 11 days after tumor transplantation had the same tumor volumes. By contrast, tumor size in the early TPO?injected group was increased significantly compared with the late TPO?injected group. These findings suggested that the interplay between platelets and angiogenesis may contribute to ovarian cancer growth. Therefore, platelets and their associated signaling and adhesive molecules may represent potential therapeutic targets for ovarian cancer. PMID:25502723

Yuan, Lei; Liu, Xishi

2015-04-01

351

Investigation into the cancer protective effect of flaxseed in Tg.NK (MMTV/c-neu) mice, a murine mammary tumor model  

OpenAIRE

The aim of the present study was to investigate whether low flaxseed doses relevant to human dietary exposure can prevent mammary tumors in transgenic Tg.NK mice, a model of breast cancer. Animals were exposed to flaxseed through the diet at human relevant levels. Tumor-related parameters and tumor development were evaluated. Hepatic cytochrome P450 and glutathione S-transferase activities were significantly reduced in animals receiving low flaxseed doses. An incidence of palpable tumors befo...

Birkved, Franziska Kramer; Mortensen, Alicja; Pen?alvo, Jose? L.; Lindecrona, Rikke H.; Sørensen, Ilona Kryspin

2011-01-01

352

Dietary Energy Balance Modulates Epithelial-To-Mesenchymal Transition and Tumor Progression in Murine Claudin-Low and Basal-Like Mammary Tumor Models  

OpenAIRE

Using novel murine models of claudin-low and basal-like breast cancer, we tested the hypothesis that diet-induced obesity (DIO) and calorie restriction (CR) differentially modulate progression of these aggressive breast cancer subtypes. For model development, we characterized two cell lines, “mesenchymal (M)-Wnt” and “epithelial (E)-Wnt,” derived from MMTV-Wnt-1 transgenic mouse mammary tumors. M-Wnt, relative to E-Wnt, cells were tumor-initiating cell (TIC)-enriched (62% vs 2.4% CD44...

Dunlap, Sarah M.; Chiao, Lucia J.; Nogueira, Leticia; Usary, Jerry; Perou, Charles M.; Varticovski, Lyuba; Hursting, Stephen D.

2012-01-01

353

Inhibitory effect of combined treatment with the aromatase inhibitor exemestane and tamoxifen on DMBA-induced mammary tumors in rats.  

Science.gov (United States)

The antitumor effect of exemestane (FCE 24304), an irreversible aromatase inhibitor, given alone or in combination with tamoxifen, was investigated in rats with 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumors. The compounds were given once daily, 6 days a week for 4 weeks. Exemestane, given at the dose of 20 mg/kg/day s.c., induced 26% complete (CR) and 18% partial (PR) tumor regressions, compared to 0% CR and 6% PR observed in controls. Tamoxifen, given at 1 mg/kg/day p.o., induced 16% CR and 13% PR. The combined treatment caused 41% CR and 16% PR, thus resulting in a higher antitumor effect than either single treatment. The appearance of new tumors was reduced by each single treatment and almost totally prevented by the combined treatment. Serum prolactin (PRL) levels, assayed 4 h after the last dose, were unchanged in the group treated with the combination, whereas tamoxifen alone caused a slight increase of serum PRL. These results indicate that estrogen deprivation through aromatase inhibition and estrogen receptor antagonism causes a better inhibition of DMBA-induced mammary tumors than either treatment modality alone. PMID:8476783

Zaccheo, T; Giudici, D; Di Salle, E

1993-03-01

354

Deleted in Malignant Brain Tumors 1 is Present in the Vascular Extracellular Matrix and Promotes Angiogenesis  

DEFF Research Database (Denmark)

OBJECTIVE: Deleted in malignant brain tumors 1 (DMBT1) belongs to the scavenger receptor cysteine-rich superfamily of proteins and is implicated in innate immunity, cell polarity, and differentiation. Here we studied the role of DMBT1 in endothelial cells. METHODS AND RESULTS: DMBT1 was secreted into the extracellular matrix (ECM) by endothelial cells in vitro and in situ and the presence of DMBT1 in the ECM increased endothelial cell adherence. Endothelial cell-derived DMBT1 associated with galectin-3 (coprecipitation), and human recombinant DMBT1 bound EGF, vascular endothelial growth factor and Delta-like (Dll) 4 (specific ELISAs). Compared to cells from wild-type mice, endothelial cells from DMBT1(-/-) mice demonstrated reduced migration, proliferation, and tube formation. In vivo recovery from hindlimb ischemia was attenuated in DMBT1(-/-) animals as was vascular endothelial growth factor -induced endothelial sprouting from isolated aortic rings; the latter response could be rescued by the addition of recombinant DMBT1. The Notch pathway is involved in multiple aspects of vascular development, including arterial-venous differentiation and we found that endothelial cells from DMBT1(-/-) mice expressed more EphrinB2 than cells from wild-type mice. Levels of Dll1, Dll4, Hes1, Hey1, and EphB4, on the other hand, were increased. CONCLUSIONS: Taken together, the results of this study indicate that DMBT1 functions as an important endothelium-derived ECM protein that is able to bind angiogenic factors and promote adhesion, migration, proliferation, and angiogenesis as well as vascular repair. Mechanistically, DMBT1 interacts with galectin-3 and modulates the Notch signaling pathway as well as the differential expression of ephrin-B2 and EphB4.

Müller-Enbergs, Helmut; Hu, Jiong

2012-01-01

355

Detection of different tumor growth kinetics in single transgenic mice with oncogene-induced mammary carcinomas by flat-panel volume computed tomography.  

Science.gov (United States)

Transgenic mouse models offer an excellent opportunity for studying the molecular basis of cancer development and progression. Here we applied flat-panel volume computed tomography (fpVCT) to monitor tumor progression as well as the development of tumor vasculature in vivo in a transgenic mouse model for oncogene-induced mammary carcinogenesis (WAP-T mice). WAP-T mice develop multiple mammary carcinomas on oncogene induction within 3 to 5 months. Following induction, 3-dimensional fpVCT data sets were obtained by serial single scans of entire mice in combination with iodine containing contrast agents and served as basis for precise measurements of tumor volumes. Thereby, we were able to depict tumors within the mammary glands at a very early stage of the development. Tumors of small sizes (0.001 cm(3)) were detected by fpVCT before being palpable or visible by inspection. The capability to determine early tumor onset combined with longitudinal noninvasive imaging identified diverse time points of tumor onset for each mammary carcinoma and different tumor growth kinetics for multiple breast carcinomas that developed in single mice. Furthermore, blood supply to the breast tumors, as well as blood vessels around and within the tumors, were clearly visible over time by fpVCT. Three-dimensional visualization of tumor vessels in high resolution was enhanced by the use of a novel blood pool contrast agent. Here, we demonstrate by longitudinal fpVCT imaging that mammary carcinomas develop at different time points in each WAP-T mouse, and thereafter show divergent growth rates and distinct vascularization patterns. PMID:19384954

Jannasch, Katharina; Dullin, Christian; Heinlein, Christina; Krepulat, Frauke; Wegwitz, Florian; Deppert, Wolfgang; Alves, Frauke

2009-07-01

356

Maternal high fat diet promotion of mammary tumor risk in adult progeny is associated with early expansion of mammary cancer stem-like cells and increased maternal oxidative environment  

Science.gov (United States)

Many adult chronic diseases might be programmed during early life by maternal nutritional history. Here, we evaluated effects of maternal high fat diet on mammary gland development and tumor formation in adult progeny. Female Wnt-1 transgenic mice exposed to high fat (HFD, 45% kcal fat) or control C...

357

FLK-1-based minigene vaccines induce T cell-mediated suppression of angiogenesis and tumor protective immunity in syngeneic BALB/c mice  

OpenAIRE

Angiogenesis is a rate-limiting step in the development of tumors. Here, we demonstrate that oral minigene DNA vaccines against murine vascular endothelial growth factor receptor-2 (FLK-1), a self-antigen overexpressed on proliferating endothelial cells in the tumor vasculature, induced protection against tumors of different origin in syngeneic BALB/c mice. This protection is mediated by CD8 T cells, which specifically kill FLK-1+ endothelial cells, resulting in marked suppression of tumor an...

Luo, Yunping; Markowitz, Dorothy; Xiang, Rong; Zhou, He; Reisfeld, Ralph A.

2006-01-01

358

Detection of mutations within exons 4 to 8 of the p53 tumor suppressor gene in canine mammary glands / Identificação de mutações nos exons 4 a 8 do gene p53 supressor de tumor em glândulas mamárias caninas  

Scientific Electronic Library Online (English)

Full Text Available Para estudar as mutações nos exos 4 a 8 do gene p53, foram utilizados 15 tumores mamários, mamas normais das mesmas cadelas e seis mamas de cadelas normais. O DNA extraído das amostras de tecido foi sequenciado e analisado para a presença de mutações. Em 71,8% das amostras obtidas foram observadas m [...] utações, sendo as "missense" as mais frequentes. Os exons mais comprometidos foram 5, 7 e 8 com 23,4, 31,6 e 23,4% de mutações, respectivamente. O estudo conclui que tumores mamários caninos têm relação com mutações no gene p53 e que as mutações