Delays in presentation and treatment of breast cancer in Enugu ...

African Journals Online (AJOL)

To assess the delays and define the causes of delay in presentation and treatment of breast cancer patients inEnugu,Nigeria. Across-sectional survey of breast cancer patients using a semi structured questionnaire. SurgicalOncology unit,University ofNigeriaTeachingHospitalEnugu, (UNTH-E),Nigeria. 164 consecutively ...

Factors affecting professional delay in diagnosis and treatment of oral cancer in Iran.

Science.gov (United States)

Esmaelbeigi, Farhad; Hadji, Maryam; Harirchi, Iraj; Omranipour, Ramesh; vand Rajabpour, Mojtaba; Zendehdel, Kazem

2014-04-01

Oral cancer is the most common malignant tumor among head and neck cancers. Delay in diagnosis affects the treatment and prognosis of oral cancer. We measured the professional delay in the diagnosis and its attributes in the Cancer Institute of Iran, the largest referral center for oral cancer patients in the country.  We interviewed oral cancer patients to measure the delay and used case-control approach to study association of various prognostic factors with professional delay and tumor stage. Out of 206 patients, 71.4% were diagnosed at the advanced stage. The median of the patient, professional and total delays were 45, 86 and 140 day, receptively. In the univariate model, prescription of medicines like analgesics (OR = 5.3, 95% CI 2.2-12.9) and history of dental procedure (OR=6.8, 95% CI 1.7-26.9) were associated with higher risk of delay compared to patient who were biopsied from the beginning. History of loose teeth increased risk of delay 4 times (OR = 4.0, 95% CI 1.6-9.8). Patients with primary education had 70% lower risk of delay compared to the illiterate patients (OR = 0.3, 95% CI 0.1-0.7) and the risk was lower among patients who had diploma (OR = 0.04, 95% CI 0-0.7) and college education (OR = 0.1, 95% CI 0-0.4). The delayed patients were diagnosed in more advanced stage compared to the patients without delay (OR = 2.1, 95% CI 1.0-4.4). Development of a national guideline for follow-up of oral lesions, training and awareness of health care professionals about oral cancer diagnosis may decrease the delay and improve the oral cancer outcome in Iran.

Preventing delayed diagnosis of cancer: clinicians’ views on main problems and solutions

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Car, Lorainne Tudor; Papachristou, Nikolaos; Urch, Catherine; Majeed, Azeem; El–Khatib, Mona; Aylin, Paul; Atun, Rifat; Car, Josip; Vincent, Charles

2016-01-01

Background Delayed diagnosis is a major contributing factor to the UK’s lower cancer survival compared to many European countries. In the UK, there is a significant national variation in early cancer diagnosis. Healthcare providers can offer an insight into local priorities for timely cancer diagnosis. In this study, we aimed to identify the main problems and solutions relating to delay cancer diagnosis according to cancer care clinicians. Methods We developed and implemented a new priority–setting approach called PRIORITIZE and invited North West London cancer care clinicians to identify and prioritize main causes for and solutions to delayed diagnosis of cancer care. Results Clinicians identified a number of concrete problems and solutions relating to delayed diagnosis of cancer. Raising public awareness, patient education as well as better access to specialist care and diagnostic testing were seen as the highest priorities. The identified suggestions focused mostly on the delays during referrals from primary to secondary care. Conclusions Many identified priorities were feasible, affordable and converged around common themes such as public awareness, care continuity and length of consultation. As a timely, proactive and scalable priority–setting approach, PRIORITZE could be implemented as a routine preventative system for determining patient safety issues by frontline staff. PMID:28028437

Delayed breast reconstruction with implants after invasive breast cancer does not impair prognosis

DEFF Research Database (Denmark)

Holmich, L.R.; During, M.; Henriksen, T.F.

2008-01-01

We investigated if delayed breast implant reconstruction after breast cancer impairs prognosis. Using data from the Danish Breast Cancer Cooperative Group register, we identified all women......We investigated if delayed breast implant reconstruction after breast cancer impairs prognosis. Using data from the Danish Breast Cancer Cooperative Group register, we identified all women...

Health system delay and its effect on clinical stage of breast cancer: Multicenter study.

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Unger-Saldaña, Karla; Miranda, Alfonso; Zarco-Espinosa, Gelasio; Mainero-Ratchelous, Fernando; Bargalló-Rocha, Enrique; Miguel Lázaro-León, Jesús

2015-07-01

The objective of this study was to determine the correlation between health system delay and clinical disease stage in patients with breast cancer. This was a cross-sectional study of 886 patients who were referred to 4 of the largest public cancer hospitals in Mexico City for the evaluation of a probable breast cancer. Data on time intervals, sociodemographic factors, and clinical stage at diagnosis were retrieved. A logistic regression model was used to estimate the average marginal effects of delay on the probability of being diagnosed with advanced breast cancer (stages III and IV). The median time between problem identification and the beginning of treatment was 7 months. The subinterval with the largest delay was that between the first medical consultation and diagnosis (median, 4 months). Only 15% of the patients who had cancer were diagnosed with stage 0 and I disease, and 48% were diagnosed with stage III and IV disease. Multivariate analyses confirmed independent correlations for the means of problem identification, patient delay, health system delay, and age with a higher probability that patients would begin cancer treatment in an advanced stage. In the sample studied, the majority of patients with breast cancer began treatment after a delay. Both patient delays and provider delays were associated with advanced disease. Research aimed at identifying specific access barriers to medical services is much needed to guide the design of tailored health policies that go beyond the promotion of breast care awareness and screening participation to include improvements in health services that facilitate access to timely diagnosis and treatment. © 2015 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Rapid Disease Progression With Delay in Treatment of Non-Small-Cell Lung Cancer

International Nuclear Information System (INIS)

Mohammed, Nasiruddin; Kestin, Larry Llyn; Grills, Inga Siiner; Battu, Madhu; Fitch, Dwight Lamar; Wong, Ching-yee Oliver; Margolis, Jeffrey Harold; Chmielewski, Gary William; Welsh, Robert James

2011-01-01

Purpose: To assess rate of disease progression from diagnosis to initiation of treatment for Stage I-IIIB non-small-cell lung cancer (NSCLC). Methods and Materials: Forty patients with NSCLC underwent at least two sets of computed tomography (CT) and 18-fluorodeoxyglucose positron emission tomography (PET) scans at various time intervals before treatment. Progression was defined as development of any new lymph node involvement, site of disease, or stage change. Results: Median time interval between first and second CT scans was 13.4 weeks, and between first and second PET scans was 9.0 weeks. Median initial primary maximum tumor dimension (MTD) was 3.5 cm (0.6-8.5 cm) with a median standardized uptake value (SUV) of 13.0 (1.7-38.5). The median MTD increased by a median of 1.0 cm (mean, 1.6 cm) between scans for a median relative MTD increase of 35% (mean, 59%). Nineteen patients (48%) progressed between scans. Rate of any progression was 13%, 31%, and 46% at 4, 8, and 16 weeks, respectively. Upstaging occurred in 3%, 13%, and 21% at these intervals. Distant metastasis became evident in 3%, 13%, and 13% after 4, 8, and 16 weeks, respectively. T and N stage were associated with progression, whereas histology, grade, sex, age, and maximum SUV were not. At 3 years, overall survival for Stage III patients with vs. without progression was 18% vs. 67%, p = 0.05. Conclusions: With NSCLC, treatment delay can lead to disease progression. Diagnosis, staging, and treatment initiation should be expedited. After 4-8 weeks of delay, complete restaging should be strongly considered.

Cytotoxic effects of ultra-diluted remedies on breast cancer cells.

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Frenkel, Moshe; Mishra, Bal Mukund; Sen, Subrata; Yang, Peiying; Pawlus, Alison; Vence, Luis; Leblanc, Aimee; Cohen, Lorenzo; Banerji, Pratip; Banerji, Prasanta

2010-02-01

The use of ultra-diluted natural products in the management of disease and treatment of cancer has generated a lot of interest and controversy. We conducted an in vitro study to determine if products prescribed by a clinic in India have any effect on breast cancer cell lines. We studied four ultra-diluted remedies (Carcinosin, Phytolacca, Conium and Thuja) against two human breast adenocarcinoma cell lines (MCF-7 and MDA-MB-231) and a cell line derived from immortalized normal human mammary epithelial cells (HMLE). The remedies exerted preferential cytotoxic effects against the two breast cancer cell lines, causing cell cycle delay/arrest and apoptosis. These effects were accompanied by altered expression of the cell cycle regulatory proteins, including downregulation of phosphorylated Rb and upregulation of the CDK inhibitor p27, which were likely responsible for the cell cycle delay/arrest as well as induction of the apoptotic cascade that manifested in the activation of caspase 7 and cleavage of PARP in the treated cells. The findings demonstrate biological activity of these natural products when presented at ultra-diluted doses. Further in-depth studies with additional cell lines and animal models are warranted to explore the clinical applicability of these agents.

Diet, Stem Cells, and Breast Cancer Prevention

Science.gov (United States)

2011-01-01

pepper [39], flavonoids such as hesperetin and naringenin in citrus fruits and tomatoes [40], isoflavones (e.g., GEN, daidzein) from legumes and red...Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices. Nutr Cancer 1996;26:167–81. [41...38], capsaicin from chili pepper [39], flavonoids such as hesperetin and naringenin in citrus fruits and tomatoes [40], isoflavones (e.g., GEN

Oral and pharyngeal cancer : Analysis of patient delay at different tumor stages

NARCIS (Netherlands)

Brouha, XDR; Tromp, DM; Hordijk, GJ; Winnubst, JAM; de Leeuw, JRJ

2005-01-01

Background. The aim of this study was to examine which factors are related to patient delay in a cohort of consecutive patients with pharyngeal cancer and oral cancer and to determine whether the different stages of patient delay (ie, appraisal, illness, behavioral, and scheduling) were related to

Factors that influence treatment delay in patients with colorectal cancer

Science.gov (United States)

Zarcos-Pedrinaci, Irene; Fernández-López, Alberto; Téllez, Teresa; Rivas-Ruiz, Francisco; Rueda A, Antonio; Suarez-Varela, María Manuela Morales; Briones, Eduardo; Baré, Marisa; Escobar, Antonio; Sarasqueta, Cristina; de Larrea, Nerea Fernández; Aguirre, Urko; Quintana, José María; Redondo, Maximino

2017-01-01

A prospective study was performed of patients diagnosed with colorectal cancer (CRC), distinguishing between colonic and rectal location, to determine the factors that may provoke a delay in the first treatment (DFT) provided. 2749 patients diagnosed with CRC were studied. The study population was recruited between June 2010 and December 2012. DFT is defined as time elapsed between diagnosis and first treatment exceeding 30 days. Excessive treatment delay was recorded in 65.5% of the cases, and was more prevalent among rectal cancer patients. Independent predictor variables of DFT in colon cancer patients were a low level of education, small tumour, ex-smoker, asymptomatic at diagnosis and following the application of screening. Among rectal cancer patients, the corresponding factors were primary school education and being asymptomatic. We conclude that treatment delay in CRC patients is affected not only by clinicopathological factors, but also by sociocultural ones. Greater attention should be paid by the healthcare provider to social groups with less formal education, in order to optimise treatment attention. PMID:27888636

Delay in the diagnosis of cancer

DEFF Research Database (Denmark)

Hansen, Rikke Pilegaard

for a detailed description of the patients' diagnostic pathways, allowing the researchers to draw the time line from symptom onset to treatment start, and to describe the characteristics of the patients and the GPs. Existing scales were used whenever possible; otherwise, ad hoc questions were constructed....... Chaper 1 introduces the concept of delay in the diagnosis of cancer. The chapter aims to provide insight into the time interval from symptom to treatment and into the patient and GP characteristics that potentially influence this interval. In addition, the chapter gives a brief overview of cancer...

Zebularine exerts its antiproliferative activity through S phase delay and cell death in human malignant mesothelioma cells.

Science.gov (United States)

Takemura, Yukitoshi; Satoh, Motohiko; Hatanaka, Kenichi; Kubota, Shunichiro

2018-04-24

Malignant mesothelioma is an asbestos-related aggressive tumor and current therapy remains ineffective. Zebularine as a DNA methyltransferase (DNMT) inhibitor has an anti-tumor effect in several human cancer cells. The aim of the present study was to investigate whether zebularine could induce antiproliferative effect in human malignant mesothelioma cells. Zebularine induced cell growth inhibition in a dose-dependent manner. In addition, zebularine dose-dependently decreased expression of DNMT1 in all malignant mesothelioma cells tested. Cell cycle analysis indicated that zebularine induced S phase delay. Zebularine also induced cell death in malignant mesothelioma cells. In contrast, zebularine did not induce cell growth inhibition and cell death in human normal fibroblast cells. These results suggest that zebularine has a potential for the treatment of malignant mesothelioma by inhibiting cell growth and inducing cell death.

Disparities in breast cancer surgery delay: the lingering effect of race.

Science.gov (United States)

Sheppard, Vanessa B; Oppong, Bridget A; Hampton, Regina; Snead, Felicia; Horton, Sara; Hirpa, Fikru; Brathwaite, Echo J; Makambi, Kepher; Onyewu, S; Boisvert, Marc; Willey, Shawna

2015-09-01

Delays to surgical breast cancer treatment of 90 days or more may be associated with greater stage migration. We investigated racial disparities in time to receiving first surgical treatment in breast cancer patients. Insured black (56 %) and white (44 %) women with primary breast cancer completed telephone interviews regarding psychosocial (e.g., self-efficacy) and health care factors (e.g., communication). Clinical data were extracted from medical charts. Time to surgery was measured as the days between diagnosis and definitive surgical treatment. We also examined delays of more than 90 days. Unadjusted hazard ratios (HRs) examined univariate relationships between delay outcomes and covariates. Cox proportional hazard models were used for multivariate analyses. Mean time to surgery was higher in blacks (mean 47 days) than whites (mean 33 days; p = .001). Black women were less likely to receive therapy before 90 days compared to white women after adjustment for covariates (HR .58; 95 % confidence interval .44, .78). Health care process factors were nonsignificant in multivariate models. Women with shorter delay reported Internet use (vs. not) and underwent breast-conserving surgery (vs. mastectomy) (p interventions to address delay are needed.

Gompertzian stochastic model with delay effect to cervical cancer growth

International Nuclear Information System (INIS)

Mazlan, Mazma Syahidatul Ayuni binti; Rosli, Norhayati binti; Bahar, Arifah

2015-01-01

In this paper, a Gompertzian stochastic model with time delay is introduced to describe the cervical cancer growth. The parameters values of the mathematical model are estimated via Levenberg-Marquardt optimization method of non-linear least squares. We apply Milstein scheme for solving the stochastic model numerically. The efficiency of mathematical model is measured by comparing the simulated result and the clinical data of cervical cancer growth. Low values of Mean-Square Error (MSE) of Gompertzian stochastic model with delay effect indicate good fits

Gompertzian stochastic model with delay effect to cervical cancer growth

Energy Technology Data Exchange (ETDEWEB)

Mazlan, Mazma Syahidatul Ayuni binti; Rosli, Norhayati binti [Faculty of Industrial Sciences and Technology, Universiti Malaysia Pahang, Lebuhraya Tun Razak, 26300 Gambang, Pahang (Malaysia); Bahar, Arifah [Department of Mathematical Sciences, Faculty of Science, Universiti Teknologi Malaysia, 81310 Johor Bahru, Johor and UTM Centre for Industrial and Applied Mathematics (UTM-CIAM), Universiti Teknologi Malaysia, 81310 Johor Bahru, Johor (Malaysia)

2015-02-03

In this paper, a Gompertzian stochastic model with time delay is introduced to describe the cervical cancer growth. The parameters values of the mathematical model are estimated via Levenberg-Marquardt optimization method of non-linear least squares. We apply Milstein scheme for solving the stochastic model numerically. The efficiency of mathematical model is measured by comparing the simulated result and the clinical data of cervical cancer growth. Low values of Mean-Square Error (MSE) of Gompertzian stochastic model with delay effect indicate good fits.

Transfer between hospitals as a predictor of delay in diagnosis and treatment of patients with Non-Small Cell Lung Cancer

DEFF Research Database (Denmark)

Iachina, Maria; Jakobsen, Erik; Fallesen, Anne Kudsk

2017-01-01

with treatment facilities during the care pathway. We wanted to investigate whether this organizational set-up influenced the time that patients wait for the diagnosis and treatment. Therefore, the objective of this study was to uncover the impact of transfer between hospitals on the delay in the diagnosis......BACKGROUND: Lung cancer is the second most frequent cancer diagnosis in Denmark. Although improved during the last decade, the prognosis of lung cancer is still poor with an overall 5-year survival rate of approximately 12%. Delay in diagnosis and treatment of lung cancer has been suggested...... and incomplete data on the dates of referral, diagnosis and treatment were excluded. RESULTS: A total of 11 273 patients were included for further analyses. Transfer patients waited longer for treatment after the diagnosis, (Hazard ratio (HR) 0.81 (0.68-0.96)) and in total time from referral to treatment (HR 0...

Diagnosis delay of breast cancer and its associated factors in Malaysian women

Directory of Open Access Journals (Sweden)

Naing Nyi N

2011-04-01

Full Text Available Abstract Background Breast cancer is the leading cause of cancer mortality among women in Malaysia. Delayed diagnosis is preventable and has major effects on patients' prognosis and survival. The objectives of our study were to identify the magnitude of delayed diagnosis and its associated factors in women with breast cancer in Malaysia. Methods This study had a cross-sectional design. Respondents had histologically confirmed breast cancer and were registered at five medical centres between 2005 and 2007. All breast cancer patients who attended hospital clinics at the East Coast were included. Patients at Kuala Lumpur hospitals were selected by systematic sampling. A standardised questionnaire was developed to interview respondents. We measured the time from the first recognition of symptoms to the first general practitioners' consultation and to the histological diagnosis of breast cancer. Diagnosis delay was defined when there was more than 6 months from the recognition of symptoms to the histological diagnosis. Multiple logistic regression was used for analysis. Results In total, 328 respondents were included. The mean (standard deviation age was 47.9 (9.4 years. Most respondents were of Malay ethnicity, were married housewives with a median family income of RM1500 a month. Most respondents had ductal carcinoma (89.3% and the stage distribution was as follows: 5.2% stage I, 38.7% stage II, 44.8% stage III and 11.3% stage IV. The median time to consultation was 2 months and the median time to diagnosis was 5.5 months. The frequency of diagnosis delay of more than 3 months was 72.6% and delay of more than 6 months occurred in 45.5% of the cases. The factors associated with diagnosis delay included the use of alternative therapy (odds ratio (OR 1.77; 95% confidence interval (CI: 1.06, 2.94, breast ulcer (OR 5.71; 95% CI: 1.59, 20.47, palpable axillary lymph nodes (OR 2.19; 95% CI: 1.23, 3.90, false-negative diagnostic test (OR 5.32; 95% CI: 2

Diagnosis delay of breast cancer and its associated factors in Malaysian women

International Nuclear Information System (INIS)

Norsa'adah, Bachok; Rampal, Krishna G; Rahmah, Mohd A; Naing, Nyi N; Biswal, Biswa M

2011-01-01

Breast cancer is the leading cause of cancer mortality among women in Malaysia. Delayed diagnosis is preventable and has major effects on patients' prognosis and survival. The objectives of our study were to identify the magnitude of delayed diagnosis and its associated factors in women with breast cancer in Malaysia. This study had a cross-sectional design. Respondents had histologically confirmed breast cancer and were registered at five medical centres between 2005 and 2007. All breast cancer patients who attended hospital clinics at the East Coast were included. Patients at Kuala Lumpur hospitals were selected by systematic sampling. A standardised questionnaire was developed to interview respondents. We measured the time from the first recognition of symptoms to the first general practitioners' consultation and to the histological diagnosis of breast cancer. Diagnosis delay was defined when there was more than 6 months from the recognition of symptoms to the histological diagnosis. Multiple logistic regression was used for analysis. In total, 328 respondents were included. The mean (standard deviation) age was 47.9 (9.4) years. Most respondents were of Malay ethnicity, were married housewives with a median family income of RM1500 a month. Most respondents had ductal carcinoma (89.3%) and the stage distribution was as follows: 5.2% stage I, 38.7% stage II, 44.8% stage III and 11.3% stage IV. The median time to consultation was 2 months and the median time to diagnosis was 5.5 months. The frequency of diagnosis delay of more than 3 months was 72.6% and delay of more than 6 months occurred in 45.5% of the cases. The factors associated with diagnosis delay included the use of alternative therapy (odds ratio (OR) 1.77; 95% confidence interval (CI): 1.06, 2.94), breast ulcer (OR 5.71; 95% CI: 1.59, 20.47), palpable axillary lymph nodes (OR 2.19; 95% CI: 1.23, 3.90), false-negative diagnostic test (OR 5.32; 95% CI: 2.32, 12.21), non-cancer interpretation

Delayed esophageal perforation from stereotactic body radiation therapy for locally recurrent central nonsmall cell lung cancer

Directory of Open Access Journals (Sweden)

Sandeep Sainathan

2014-01-01

Full Text Available Stereotactic body radiation therapy (SBRT is a novel form of external beam radiation therapy. It is used to treat early and locally recurrent nonsmall cell lung cancer (NSLC in medically inoperable patients. It uses high dose, hypofractionated radiotherapy, with targeting of the tumor by precise spatial localization, thus minimizing injury to surrounding tissues. It can be safely used to ablate NSLC in both central and peripheral locations. We present two cases of delayed esophageal perforation after SBRT for locally recurrent central NSLC. The perforations occurred several months after the therapy. They were treated with covered esophageal stents, with mortality, due to the perforation in one of the patients. SBRT should be judiciously used to ablate centrally located NSLC and patients who develop episodes of esophagitis during or after SBRT, need to be closely followed with endoscopy to look for esophageal ulcerations. These ulcers should be closely followed for healing as these may degenerate into full thickness perforations several months after SBRT.

System delays in breast cancer | Dalwai | South African Journal of ...

African Journals Online (AJOL)

Background: Centralised multidisciplinary management of breast cancer occurs in KwaZulu-Natal, South Africa, and requires a diagnostic and staging pathway at the referring hospital. Delays in this pathway are unknown. This study, conducted at a referring hospital, R K Khan (RKK), quantifies and analyses these delays.

[Prognostic factors of advanced stage non-small-cell lung cancer].

Science.gov (United States)

Kwas, H; Guermazi, E; Khattab, A; Hrizi, C; Zendah, I; Ghédira, H

2017-09-01

Primary lung cancer is the leading cause of cancer death in men in the world. Although the introduction of new drugs, new therapeutic strategies and despite therapeutic advances, the prognosis is relatively improved during the last years. To evaluate the prognosis of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) and to identify prognostic factors at these stages. A retrospective study, including 140 cases of locally advanced or metastatic NSCLC diagnosed in our department between 2003 and 2013. The average age was 61±10 years (35 to 90 years). Sex ratio was 18. The delays management were 80±25 days for presentation, 45±20 days for the diagnostic, while the treatment delay was 8±2.33 days. The cancer was at stage IIIA in 14%, IIIB in 27% and IV in 59%. Six months and one-year survival was between 50 and 74% and between 9 and 25%, respectively. Better survival was observed in patients with NSCLC on stage III, having better performance status, having comorbid conditions, with prolonged delays management, a short therapeutic delay and patients who received specific antitumor treatment. The prognostic factors in locally advanced and metastatic NSCLC in our patients were: stage of cancer, performance status, comorbid conditions, delay of management and specific antitumoral treatment. These factors should be considered in the management of patients with advanced NSCLC. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Phytochemicals radiosensitize cancer cells by inhibiting DNA repair

International Nuclear Information System (INIS)

Singh, Rana P.

2017-01-01

Solid tumors are mostly treated with radiotherapy. Radiotherapy is toxic to normal tissues and also promote the invasiveness and radioresistance in cancer cells. The resistance against radiotherapy and adverse effects to normal cells reduce the overall therapeutic effects of the treatment. Radiosensitizing agents usually show limited success during clinical trials. Therefore, the search and development of new radiosensitizers showing selective response to only cancer cells is desirable. We analyzed the radiosensitizing effects including cell death effect of silibinin, a phytochemical on prostate cancer cells. Silibinin enhanced gamma radiation (2.5-10 Gy) induced inhibition in colony formation selectively in prostate cancer cells. In cell cycle progression, G2/M phase is the most sensitive phase for radiation-induced damage which was delayed by the compound treatment in radiation exposed cells. The lower concentrations of silibinin substantially enhanced radiation-induced apoptosis. A prolonged reactive oxygen species production was also observed in these treatments EGFR signaling pathway can contribute to radiation-induced pro-survival mechanisms and to the therapeutic resistance. Agent treatment reduced the IR-induced EGFR phosphorylation and consequently reversed the resistance mediating mechanisms within the cancer cell. Thus, inhibiting DNA repair in cancer cells would enhance therapeutic response of radiation in cancer cells. Silibinin affected the localization of EGFR and DNA-dependent protein kinase, the DNA-PK is known to be an important mediator of DSB repair in human cells, and showed increased number of pH2AX (ser139) foci, and thus indicating lower DNA repair in these cancer cells. This was also confirmed in the tumor xenograft study. Our findings suggest that a combination of silibinin with radiation could be an effective treatment of radioresistant human prostate cancer and warrants further investigation. (author)

Advanced gastric cancer. The findings of delayed phase dynamic CT and radiologic-histopathologic correlation

International Nuclear Information System (INIS)

Monzawa, Shuichi; Omata, Kosaku; Nakazima, Hiroto; Yokosuka, Noriko; Ito, Atuko; Araki, Tsutomu

2000-01-01

The aim of this study was to describe delayed phase dynamic CT findings of advanced (T2-T4) gastric cancer and to correlate with histopathologic findings. Quadruple phase dynamic CT including delayed imaging taken five minutes after the start of injection of contrast material was performed in 43 patients with 45 advanced gastric cancer and 20 control subjects with no gastric lesions. On delayed phase CT scans, the attenuation of the gastric wall was equal to or lower than that of the liver parenchyma in the control subjects, therefore, the presence of higher attenuation in the gastric wall was considered to be abnormal and defined as delayed enhancement. Histopathologic findings in the tumors showing delayed enhancement were compared with those in the tumors without this feature. Delayed enhancement was seen in 26 (57%) of the 45 tumors. Eleven of 25 differentiated-type tumors and 15 of 20 undifferentiated-type tumors showed delayed enhancement (p<.05). Delayed enhancement was seen in one of five medullary type tumors, in 11 of 25 intermediate-type tumors, and in 14 of 15 scirrhous-type tumors (p<.005). Delayed enhancement was frequently seen in the tumors with abundant fibrous tissue stroma. Delayed phase dynamic CT may be useful for the characterization of advanced gastric cancer. (author)

Cell cycle delays induced by heavy ion irradiation of synchronous mammalian cells

International Nuclear Information System (INIS)

Scholz, M.; Kraft-Weyrather, W.; Ritter, S.; Kraft, G.

1994-01-01

Cell cycle delays in V79 Chinese hamster cells induced by heavy ion exposure have been investigated using flow cytometry. Synchronous cell populations in G 1 -, S- and late-S/G 2 M-phase were used. Cells were irradiated with particles from Z = 10 (neon) up to Z = 96 (uranium) in the energy range from 2.4 to 17.4 MeV/u and the LET range from 415 to 16225 keV/μm at the UNILAC at GSI, Darmstadt. For comparison, experiments with 250 kV X-rays were performed. For light particles like neon, cell cycle perturbations comparable to those after X-ray irradiation were found, and with increasing LET an increasing delay per particle traversal was observed. For the highest LET-values, extended delays in G 1 -, S- and G 2 M-phase were detected immediately after irradiation. A large fraction of the cells remained in S-phase or G 2 M-phase up to 48 h or longer after irradiation. No significant cell age dependence of cycle delays was detected for the very high LET values. In addition to cell cycle delays, two effects related to the DNA-content as determined by flow cytometry were found after irradiation with very high LET particles, which were attributed to cell fusion and to drastic morphological changes of the cells. Estimations based on the dose deposited by a single particle hit in the cell nucleus and the actual number of hits show, that the basic trend of the experimental results can be explained by the stochastic properties of particle radiation. (orig.)

Delayed cell death, giant cell formation and chromosome instability induced by X-irradiation in human embryo cells

International Nuclear Information System (INIS)

Roy, K.; Kodama, Seiji; Suzuki, Keiji; Watanabe, Masami

1999-01-01

We studied X-ray-induced delayed cell death, delayed giant cell formation and delayed chromosome aberrations in normal human embryo cells to explore the relationship between initial radiation damage and delayed effect appeared at 14 to 55 population doubling numbers (PDNs) after X-irradiation. The delayed effect was induced in the progeny of X-ray survivors in a dose-dependent manner and recovered with increasing PDNs after X-irradiation. Delayed plating for 24 h post-irradiation reduced both acute and delayed lethal damage, suggesting that potentially lethal damage repair (PLDR) can be effective for relieving the delayed cell death. The chromosome analysis revealed that most of the dicentrics (more than 90%) observed in the progeny of X-ray survivors were not accompanied with fragments, in contrast with those observed in the first mitosis after X-irradiation. The present results indicate that the potentiality of genetic instability is determined during the repair process of initial radiation damage and suggest that the mechanism for formation of delayed chromosome aberrations by radiation might be different from that of direct radiation-induced chromosome aberrations. (author)

Cell cycle delays in synchronized cell populations following irradiation with heavy ions

International Nuclear Information System (INIS)

Scholz, M.

1992-11-01

Mammalian cells subjected to irradiation with heavy ions were investigated for cell cycle delays. The ions used for this purpose included Ne ions in the LET range of 400 keV/μm just as well as uranium ions of 16225 keV/μm. The qualitative changes in cell cycle progression seen after irradiation with Ne ions (400 keV/μm) were similar to those observed in connection with X-rays. Following irradiation with extremely heavy ions (lead, uranium) the majority of cells were even at 45 hours still found to be in the S phase or G 2 M phase of the first cycle. The delay cross section 'σ-delay' was introduced as a quantity that would permit quantitative comparisons to be carried out between the changes in cell progression and other effects of radiation. In order to evaluate the influence of the number of hits on the radiation effect observed, the size of the cell nucleus was precisely determined with reference to the cycle phase and local cell density. A model to simulate those delay effects was designed in such a way that account is taken of this probability of hit and that the results can be extrapolated from the delay effects after X-irradiation. On the basis of the various probabilities of hit for cells at different cycle stages a model was developed to ascertain the intensified effect following fractionated irradiation with heavy ions. (orig./MG) [de

Novel Hsp90 inhibitor NVP-AUY922 radiosensitizes prostate cancer cells.

Science.gov (United States)

Gandhi, Nishant; Wild, Aaron T; Chettiar, Sivarajan T; Aziz, Khaled; Kato, Yoshinori; Gajula, Rajendra P; Williams, Russell D; Cades, Jessica A; Annadanam, Anvesh; Song, Danny; Zhang, Yonggang; Hales, Russell K; Herman, Joseph M; Armour, Elwood; DeWeese, Theodore L; Schaeffer, Edward M; Tran, Phuoc T

2013-04-01

Outcomes for poor-risk localized prostate cancers treated with radiation are still insufficient. Targeting the "non-oncogene" addiction or stress response machinery is an appealing strategy for cancer therapeutics. Heat-shock-protein-90 (Hsp90), an integral member of this machinery, is a molecular chaperone required for energy-driven stabilization and selective degradation of misfolded "client" proteins, that is commonly overexpressed in tumor cells. Hsp90 client proteins include critical components of pathways implicated in prostate cancer cell survival and radioresistance, such as androgen receptor signaling and the PI3K-Akt-mTOR pathway. We examined the effects of a novel non-geldanamycin Hsp90 inhibitor, AUY922, combined with radiation (RT) on two prostate cancer cell lines, Myc-CaP and PC3, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γ-H2AX foci kinetics and client protein expression in pathways important for prostate cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined treatment (RT-AUY922) on the PI3K-Akt-mTOR and AR pathways in a hind-flank tumor graft model. We observed that AUY922 caused supra-additive radiosensitization in both cell lines at low nanomolar doses with enhancement ratios between 1.4-1.7 (p < 0.01). RT-AUY922 increased apoptotic cell death compared with either therapy alone, induced G 2-M arrest and produced marked changes in client protein expression. These results were confirmed in vivo, where RT-AUY922 combination therapy produced supra-additive tumor growth delay compared with either therapy by itself in Myc-CaP and PC3 tumor grafts (both p < 0.0001). Our data suggest that combined RT-AUY922 therapy exhibits promising activity against prostate cancer cells, which should be investigated in clinical studies.

The epigenetic agents suberoylanilide hydroxamic acid and 5‑AZA‑2' deoxycytidine decrease cell proliferation, induce cell death and delay the growth of MiaPaCa2 pancreatic cancer cells in vivo.

Science.gov (United States)

Susanto, Johana M; Colvin, Emily K; Pinese, Mark; Chang, David K; Pajic, Marina; Mawson, Amanda; Caldon, C Elizabeth; Musgrove, Elizabeth A; Henshall, Susan M; Sutherland, Robert L; Biankin, Andrew V; Scarlett, Christopher J

2015-05-01

Despite incremental advances in the diagnosis and treatment for pancreatic cancer (PC), the 5‑year survival rate remains <5%. Novel therapies to increase survival and quality of life for PC patients are desperately needed. Epigenetic thera-peutic agents such as histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) have demonstrated therapeutic benefits in human cancer. We assessed the efficacy of these epigenetic therapeutic agents as potential therapies for PC using in vitro and in vivo models. Treatment with HDACi [suberoylanilide hydroxamic acid (SAHA)] and DNMTi [5‑AZA‑2' deoxycytidine (5‑AZA‑dc)] decreased cell proliferation in MiaPaCa2 cells, and SAHA treatment, with or without 5‑AZA‑dc, resulted in higher cell death and lower DNA synthesis compared to 5‑AZA‑dc alone and controls (DMSO). Further, combination treatment with SAHA and 5‑AZA‑dc significantly increased expression of p21WAF1, leading to G1 arrest. Treatment with epigenetic agents delayed tumour growth in vivo, but did not decrease growth of established pancreatic tumours. In conclusion, these data demonstrate a potential role for epigenetic modifier drugs for the management of PC, specifically in the chemoprevention of PC, in combination with other chemotherapeutic agents.

Polyphenol-rich extract of Pimenta dioica berries (Allspice) kills breast cancer cells by autophagy and delays growth of triple negative breast cancer in athymic mice

Science.gov (United States)

Zhang, Lei; Shamaladevi, Nagarajarao; Jayaprakasha, Guddadarangavvanahally K.; Patil, Bhimu S.; Lokeshwar, Bal L.

2015-01-01

Bioactive compounds from edible plants have limited efficacy in treating advanced cancers, but they have potential to increase the efficacy of chemotherapy drugs in a combined treatment. An aqueous extract of berries of Pimenta dioica (Allspice) shows promise as one such candidate for combination therapy or chemoprevention. An aqueous extract of Allspice (AAE) was tested against human breast cancer (BrCa) cells in vitro and in vivo. AAE reduced the viability and clonogenic growth of several types of BrCa cells (IC50 ≤ 100 μg/ml) with limited toxicity in non-tumorigenic, quiescent cells (IC50 >200 μg/ml). AAE induced cytotoxicity in BrCa was inconsistent with apoptosis, but was associated with increased levels of autophagy markers LC3B and LC3B-positive puncta. Silencing the expression of autophagy related genes (ATGs) prevented AAE-induced cell death. Further, AAE caused inhibition of Akt/mTOR signaling, and showed enhanced cytotoxicity when combined with rapamycin, a chemotherapy drug and an inhibitor of mTOR signaling. Oral administration (gavage) of AAE into athymic mice implanted with MDA-MB231 tumors inhibited tumor growth slightly but not significantly (mean decrease ~ 14%, p ≥ 0.20) if mice were gavaged post-tumor implant. Tumor growth showed a significant delay (38%) in tumor palpability and growth rate (time to reach tumor volume ≥ 1,000 mm3) when mice were pre-dosed with AAE for two weeks. Analysis of tumor tissues showed increased levels of LC3B in AAE treated tumors, indicating elevated autophagic tumor cell death in vivo in treated mice. These results demonstrate antitumor and chemo-preventive activity of AAE against BrCa and potential for adjuvant to mTOR inhibition. PMID:25945840

Delay in Diagnosis of Testicular Cancer; A Need for Awareness Programs

NARCIS (Netherlands)

Ozturk, Cigdem; Fleer, Joke; Hoekstra, Harald J.; Hoekstra-Weebers, Josette E. H. M.

2015-01-01

Background Aim To gain insight into patient and doctor delay in testicular cancer (TC) and factors associated with delay. Materials and Methods Sixty of the 66 eligible men; median age 26 (range 17-45) years, diagnosed with TC at the University Medical Center Groningen completed a questionnaire on

Delayed airway stenosis after radiotherapy for head and neck cancer

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Yuta, Atsushi; Tatematsu, Masanori; Ishinaga, Hajime; Harada, Teruhiko; Majima, Yuichi [Mie Univ., Tsu (Japan). School of Medicine

2002-03-01

Seven cases of delayed airway stenosis after radiotherapy for early staged head and neck cancers during 1989 and 1999 were evaluated (aged 54-77 yrs, 6 male and a female). The cases included five glottic laryngeal cancers (T1a, T1b, and three T2), a subglottic laryngeal cancer, and an unknown origin, but strongly suspected laryngeal cancer, with neck metastasis. Radio injury was found from 3 months to 47 months after radiotherapy. {sup 60}Co for radiotherapy was used in all seven cases, although {sup 60}Co radionuclide was changed to Liniac in 1997. The total dose was 60 Gy for 3 cases, and 70 Gy for 4 cases. Tracheostomy was performed in 3 cases due to bilateral vocal cord impairment. Background, treatment, and response to radiotherapy were compared to those of 90 patients of a control group with early staged laryngeal cancer who did not fail radiation injury during the same period. As a result, radionuclide ({sup 60}Co), total dose, cervical surgery, antiinflammatory drugs, laryngeal edema during radiotherapy were risk factors. The intensity and the period of mucositis by radiotherapy was important for indicating delayed airway stenosis. (author)

Delayed airway stenosis after radiotherapy for head and neck cancer

International Nuclear Information System (INIS)

Yuta, Atsushi; Tatematsu, Masanori; Ishinaga, Hajime; Harada, Teruhiko; Majima, Yuichi

2002-01-01

Seven cases of delayed airway stenosis after radiotherapy for early staged head and neck cancers during 1989 and 1999 were evaluated (aged 54-77 yrs, 6 male and a female). The cases included five glottic laryngeal cancers (T1a, T1b, and three T2), a subglottic laryngeal cancer, and an unknown origin, but strongly suspected laryngeal cancer, with neck metastasis. Radio injury was found from 3 months to 47 months after radiotherapy. 60 Co for radiotherapy was used in all seven cases, although 60 Co radionuclide was changed to Liniac in 1997. The total dose was 60 Gy for 3 cases, and 70 Gy for 4 cases. Tracheostomy was performed in 3 cases due to bilateral vocal cord impairment. Background, treatment, and response to radiotherapy were compared to those of 90 patients of a control group with early staged laryngeal cancer who did not fail radiation injury during the same period. As a result, radionuclide ( 60 Co), total dose, cervical surgery, antiinflammatory drugs, laryngeal edema during radiotherapy were risk factors. The intensity and the period of mucositis by radiotherapy was important for indicating delayed airway stenosis. (author)

Factors Responsible for the Diagnostic Delay in Oral Cancer Patients: A Hospital Based Sociodemographic Study in Kolkata

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Pramitasri Bhattacharyya

2016-12-01

Full Text Available Introduction Oral cancer is a challenging health problem globally. Delay in diagnosis is an important factor in determining the outcome of the disease. It is a major determinant of mortality and morbidity of oral cancer patients. Present observational study was conducted with the objective of finding the factors responsible for delay in diagnosis of oral cancer in patients. Materials and Methods Hospital based observational study where patient register was used as data source from 15th Nov, 2013-15th Jan, 2014. Results Among the causes for delay in reporting to hospital, financial constraint (84% and illiteracy (56.5% have been found to contribute the most. The risk of primary delay is 3.53 times more among illiterate in comparison with literate. Age, gender, stage of cancer, religion, caste, tobacco use and delayed referral from the first physician were the other factors found to be significant in relation to primary delay. Discussion Early diagnosis is a major factor for favorable outcome of a disease and several factors hinder early diagnosis. Some of these factors can be easily modified through Information, Education and Communication (IEC. Conclusion Some important factors that lead to delay are identified and some of them are preventable. So, IEC regarding cancer among general population will not only provide knowledge to them, but also will break myths regarding cancer and reduce the burden of disease. These identified predictors of delay may be used for designing an educational intervention program for patients with oral cancers.

Radiation cell survival and growth delay studies in multicellular spheroids of small-cell lung carcinoma

International Nuclear Information System (INIS)

Duchesne, G.M.; Peacock, J.H.

1987-01-01

The radiation sensitivity of two small-cell lung carcinoma cell lines growing as multicellular spheroids in static culture was determined using clonogenic cell survival and growth delay as endpoints. Growth delay determination suggested that clonogenic cell kill was less than was obtained by direct assay of cell survival. Recovery from potentially lethal damage was assayed in one line (HC12) but was not demonstrable, and clonogenic cell survival decreased with time in treated spheroids with diameters greater than 300 μm which contained a hypoxic cell population. Microscopic examination of the treated spheroids showed the emergence of an abnormal giant-cell population, and the progressive clonogenic cell loss that occurred after treatment was thought to be due to oxygen and nutrient deprivation of the remaining viable cells by this doomed cell population. Correction of the growth delay measurements for changes in cell size and clonogenic cell population allowed correlation of the growth delay and cell survival data. (author)

[Determinants of patient and health system delays for women with breast cancer in Morocco, 2013].

Science.gov (United States)

Benbakhta, B; Tazi, M; Benjaafar, N; Khattabi, A; Maaroufi, A

2015-06-01

In Morocco, breast cancer is the first most common cancer in women. It is diagnosed in most cases at an advanced stage. Delay in diagnosis and access to treatment for breast cancer increases morbidity and mortality. The objective of this study was to determine the consultation delay (patient delay), diagnosis delay and access to treatment delay (health system delays) of women with breast cancer admitted at the National Institute of Oncology in Rabat. Factors associated with these delays were analyzed. We conducted a cross-sectional study from December 2012 to May 2013 at the National Institute of Oncology in Rabat. Two hundred eligible and consenting women were interviewed using a structured and pre-tested questionnaire. Stages I and II were identified as "early stages" and III and IV as "advanced stages". In our population, 54% were diagnosed at an early stage of breast cancer and 46% at an advanced stage. The median total delay was 120 days (interquartile interval [IIQ]=81-202 days). The patient delay (median=65 days, IIQ=31-121) was longer than the health system delay (median=50 days, IIQ=29-77). High risk for a long total delay (more than 4 months) was observed for women who were aged over 65 years (OR=1.30, 95% CI 1.10-4.20), illiterate (OR=4.50, 95% CI 2.10-6.20), rural residents (OR=3.40, 95% CI 1.23-8.13), in a lower socioeconomic category (OR=4.75, 95% CI 1.45-15.60), without knowledge about breast self-examination (OR=5.67, 95% CI 2.65-12.15) and seen more than 2 times before diagnosis (OR=7.70, 95% CI 2.88-20.50). A long total delay increased the risk of being diagnosed at an advanced stage (OR=5.62, 95% CI 3.03-10.45). Efforts should be directed to providing good information to the population at risk, better access to screening and continuing medical training to enable diagnosis and early treatment. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Inhibition of phosphatidylinositol 3-kinase promotes tumor cell resistance to chemotherapeutic agents via a mechanism involving delay in cell cycle progression

International Nuclear Information System (INIS)

McDonald, Gail T.; Sullivan, Richard; Pare, Genevieve C.; Graham, Charles H.

2010-01-01

Approaches to overcome chemoresistance in cancer cells have involved targeting specific signaling pathways such as the phosphatidylinositol 3-kinase (PI3K) pathway, a stress response pathway known to be involved in the regulation of cell survival, apoptosis and growth. The present study determined the effect of PI3K inhibition on the clonogenic survival of human cancer cells following exposure to various chemotherapeutic agents. Treatment with the PI3K inhibitors LY294002 or Compound 15e resulted in increased survival of MDA-MB-231 breast carcinoma cells after exposure to doxorubicin, etoposide, 5-fluorouracil, and vincristine. Increased survival following PI3K inhibition was also observed in DU-145 prostate, HCT-116 colon and A-549 lung carcinoma cell lines exposed to doxorubicin. Increased cell survival mediated by LY294002 was correlated with a decrease in cell proliferation, which was linked to an increase in the proportion of cells in the G 1 phase of the cell cycle. Inhibition of PI3K signaling also resulted in higher levels of the cyclin-dependent kinase inhibitors p21 Waf1/Cip1 and p27 Kip1 ; and knockdown of p27 kip1 with siRNA attenuated resistance to doxorubicin in cells treated with LY294002. Incubation in the presence of LY294002 after exposure to doxorubicin resulted in decreased cell survival. These findings provide evidence that PI3K inhibition leads to chemoresistance in human cancer cells by causing a delay in cell cycle; however, the timing of PI3K inhibition (either before or after exposure to anti-cancer agents) may be a critical determinant of chemosensitivity.

Stability Analysis of Nonlinear Time–Delayed Systems with Application to Biological Models

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Kruthika H.A.

2017-03-01

Full Text Available In this paper, we analyse the local stability of a gene-regulatory network and immunotherapy for cancer modelled as nonlinear time-delay systems. A numerically generated kernel, using the sum-of-squares decomposition of multivariate polynomials, is used in the construction of an appropriate Lyapunov–Krasovskii functional for stability analysis of the networks around an equilibrium point. This analysis translates to verifying equivalent LMI conditions. A delay-independent asymptotic stability of a second-order model of a gene regulatory network, taking into consideration multiple commensurate delays, is established. In the case of cancer immunotherapy, a predator–prey type model is adopted to describe the dynamics with cancer cells and immune cells contributing to the predator–prey population, respectively. A delay-dependent asymptotic stability of the cancer-free equilibrium point is proved. Apart from the system and control point of view, in the case of gene-regulatory networks such stability analysis of dynamics aids mimicking gene networks synthetically using integrated circuits like neurochips learnt from biological neural networks, and in the case of cancer immunotherapy it helps determine the long-term outcome of therapy and thus aids oncologists in deciding upon the right approach.

Thalidomide for control delayed vomiting in cancer patients receiving chemotherapy

International Nuclear Information System (INIS)

Han, Z.; Sun, X.; Du, X.

2016-01-01

To explore the efficacy and safety of thalidomide for the treatment of delayed vomiting, induced by chemotherapy in cancer patients. Study Design: Randomized, double-blind controlled study. Place and Duration of Study: The Oncology Department of Affiliated Hospital of Xuzhou Medical University, Jiangsu Xuzhou, China, from January 2012 to January 2014. Methodology: A total of 78 cancer patients, who had delayed vomiting observed from 24 hours to 1 week after chemotherapy, were included in the study. Patients were divided in a treatment group (40 patients, 51.28%) and a control group (38 patients, 48.71%). The treatment group received thalidomide at an oral dose of 100 mg per night; 50 mg was added daily up to a dose of 200 mg per night, if the curative effect was suboptimal and the medicine was tolerated. Both the treatment and the control groups received a drip of 10 mg azasetron 30 minutes before chemotherapy. The control group only proportions of antiemetic effects and adverse reactions were compared using the ?2 test. Antiemetic effects and adverse reactions were assessed from Odds Ratios (OR) with 95% Confidence Intervals(95% CI). Results: The effective control rate of delayed vomiting in the treatment group was significantly higher than that in the control group (?2=5.174, p=0.023). No significant difference was found between the two groups in other adverse effects of chemotherapy. Karnofsky scores or the overall self-evaluation of the patients (p>0.05). Conclusion: Thalidomide can effectively control the delayed vomiting of cancer patients receiving chemotherapy and the adverse reactions of the agent can be tolerated.

Cancer stem cells, cancer cell plasticity and radiation therapy.

Science.gov (United States)

Vlashi, Erina; Pajonk, Frank

2015-04-01

Since the first prospective identification of cancer stem cells in solid cancers the cancer stem cell hypothesis has reemerged as a research topic of increasing interest. It postulates that solid cancers are organized hierarchically with a small number of cancer stem cells driving tumor growth, repopulation after injury and metastasis. They give rise to differentiated progeny, which lack these features. The model predicts that for any therapy to provide cure, all cancer stem cells have to be eliminated while the survival of differentiated progeny is less critical. In this review we discuss recent reports challenging the idea of a unidirectional differentiation of cancer cells. These reports provide evidence supporting the idea that non-stem cancer cells exhibit a remarkable degree of plasticity that allows them to re-acquire cancer stem cell traits, especially in the context of radiation therapy. We summarize conditions under which differentiation is reversed and discuss the current knowledge of the underlying mechanisms. Copyright © 2014 Elsevier Ltd. All rights reserved.

Cell cycle related /sup 125/IUDR-induced-division delay

International Nuclear Information System (INIS)

Scheniderman, M.H.; Hofer, K.G.

1987-01-01

A series of experiments were run to determine if /sup 125/I-decays, in /sup 125/IUdR labeled DNA, specifically accumulated at 1, 3, 5, 7 and 9 hours after plating labeled mitotic cells caused a change in the rate or time of cell entry into mitosis. To accomplish this, a pool of labeled mitotic cells was selected in mitosis and plated in replicate flasks. /sup 125/I decays were accumulated in groups of cells by cooling (4 0 C) for 2 hours starting at the designated times. After rewarding, colcemid was added to arrest cells in mitosis. The rate of cell progression into mitosis for each cell cycle time of accumulation was determined by scoring the mitotic index of cells sampled as a function of time after addition of the colcemid. The results are summarized: (1) Decays from /sup 125/I in /sup 125/I(UdR) labeled DNA reduced the rate of cell progression into mitosis and delayed the time of initiation of mitosis. (2) The reduced rate of progression and the delayed time of initiation of mitosis were independent of the cell cycle time that /sup 125/I-decays were accumulated. (3) The reduced rate of progression after cell cycle accumulation of /sup 125/I decay was statistically indistinguishable from the corresponding controls. (4) The delayed initiation of mitosis after specific cell cycle accumulation of /sup 125/I- decays was greater than the corresponding control. The relationship of these data to DNA and non-DNA division delay target(s) is emphasized

Influence of distributed delays on the dynamics of a generalized immune system cancerous cells interactions model

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Piotrowska, M. J.; Bodnar, M.

2018-01-01

We present a generalisation of the mathematical models describing the interactions between the immune system and tumour cells which takes into account distributed time delays. For the analytical study we do not assume any particular form of the stimulus function describing the immune system reaction to presence of tumour cells but we only postulate its general properties. We analyse basic mathematical properties of the considered model such as existence and uniqueness of the solutions. Next, we discuss the existence of the stationary solutions and analytically investigate their stability depending on the forms of considered probability densities that is: Erlang, triangular and uniform probability densities separated or not from zero. Particular instability results are obtained for a general type of probability densities. Our results are compared with those for the model with discrete delays know from the literature. In addition, for each considered type of probability density, the model is fitted to the experimental data for the mice B-cell lymphoma showing mean square errors at the same comparable level. For estimated sets of parameters we discuss possibility of stabilisation of the tumour dormant steady state. Instability of this steady state results in uncontrolled tumour growth. In order to perform numerical simulation, following the idea of linear chain trick, we derive numerical procedures that allow us to solve systems with considered probability densities using standard algorithm for ordinary differential equations or differential equations with discrete delays.

Controlling flow time delays in flexible manufacturing cells

NARCIS (Netherlands)

Slomp, J.; Caprihan, R.; Bokhorst, J. A. C.

2009-01-01

Flow time delays in Flexible Manufacturing Cells (FMCs) are caused by transport and clamping/reclamping activities. This paper shows how dynamic scheduling parameters may control the flow times of jobs and the available task windows for flow time delays.

P38 delta MAPK promotes breast cancer progression and lung metastasis by enhancing cell proliferation and cell detachment.

Science.gov (United States)

Wada, M; Canals, D; Adada, M; Coant, N; Salama, M F; Helke, K L; Arthur, J S; Shroyer, K R; Kitatani, K; Obeid, L M; Hannun, Y A

2017-11-23

The protein p38 mitogen-activated protein kinase (MAPK) delta isoform (p38δ) is a poorly studied member of the MAPK family. Data analysis from The Cancer Genome Atlas database revealed that p38δ is highly expressed in all types of human breast cancers. Using a human breast cancer tissue array, we confirmed elevation in cancer tissue. The breast cancer mouse model, MMTV-PyMT (PyMT), developed breast tumors with lung metastasis; however, mice deleted in p38δ (PyMT/p38δ -/- ) exhibited delayed primary tumor formation and highly reduced lung metastatic burden. At the cellular level, we demonstrate that targeting of p38δ in breast cancer cells, MCF-7 and MDA-MB-231 resulted in a reduced rate of cell proliferation. In addition, cells lacking p38δ also displayed an increased cell-matrix adhesion and reduced cell detachment. This effect on cell adhesion was molecularly supported by the regulation of the focal adhesion kinase by p38δ in the human breast cell lines. These studies define a previously unappreciated role for p38δ in breast cancer development and evolution by regulating tumor growth and altering metastatic properties. This study proposes MAPK p38δ protein as a key factor in breast cancer. Lack of p38δ resulted in reduced primary tumor size and blocked the metastatic potential to the lungs.

Relation between delay and survival in 596 patients with breast cancer.

Science.gov (United States)

Machiavelli, M; Leone, B; Romero, A; Perez, J; Vallejo, C; Bianco, A; Rodriguez, R; Estevez, R; Chacon, R; Dansky, C

1989-01-01

To evaluate the influence of delay between first symptom and first treatment upon survival the medical records of 596 patients with breast cancer were reviewed. The following intervals were considered: less than 3 months; 3-6 months and greater than 6 months. Patients in the less than 3 months delay group had a better distribution by clinical stages and a 10-year survival rate higher than those in the longer delay groups (p = 0.034). However, within each stage no statistically significant difference in survival according to delay was observed. A Cox multivariate analysis revealed that performance status and stage of disease were independent predictors of survival, but not delay. Assuming the best prognosis for patients with clinical stages I and II and less than 3 months delay, the group with longer delay times had 15 deaths over what would have been predicted. This adverse effect was observed almost exclusively among patients over age 50 (14/15).

Systemic treatment with CAR-engineered T cells against PSCA delays subcutaneous tumor growth and prolongs survival of mice

International Nuclear Information System (INIS)

Hillerdal, Victoria; Ramachandran, Mohanraj; Leja, Justyna; Essand, Magnus

2014-01-01

Adoptive transfer of T cells genetically engineered with a chimeric antigen receptor (CAR) has successfully been used to treat both chronic and acute lymphocytic leukemia as well as other hematological cancers. Experimental therapy with CAR-engineered T cells has also shown promising results on solid tumors. The prostate stem cell antigen (PSCA) is a protein expressed on the surface of prostate epithelial cells as well as in primary and metastatic prostate cancer cells and therefore a promising target for immunotherapy of prostate cancer. We developed a third-generation CAR against PSCA including the CD28, OX-40 and CD3 ζ signaling domains. T cells were transduced with a lentivirus encoding the PSCA-CAR and evaluated for cytokine production (paired Student’s t-test), proliferation (paired Student’s t-test), CD107a expression (paired Student’s t-test) and target cell killing in vitro and tumor growth and survival in vivo (Log-rank test comparing Kaplan-Meier survival curves). PSCA-CAR T cells exhibit specific interferon (IFN)-γ and interleukin (IL)-2 secretion and specific proliferation in response to PSCA-expressing target cells. Furthermore, the PSCA-CAR-engineered T cells efficiently kill PSCA-expressing tumor cells in vitro and systemic treatment with PSCA-CAR-engineered T cells significantly delays subcutaneous tumor growth and prolongs survival of mice. Our data confirms that PSCA-CAR T cells may be developed for treatment of prostate cancer

Vitamin D compounds inhibit cancer stem-like cells and induce differentiation in triple negative breast cancer.

Science.gov (United States)

Shan, Naing Lin; Wahler, Joseph; Lee, Hong Jin; Bak, Min Ji; Gupta, Soumyasri Das; Maehr, Hubert; Suh, Nanjoo

2017-10-01

Triple-negative breast cancer is one of the least responsive breast cancer subtypes to available targeted therapies due to the absence of hormonal receptors, aggressive phenotypes, and the high rate of relapse. Early breast cancer prevention may therefore play an important role in delaying the progression of triple-negative breast cancer. Cancer stem cells are a subset of cancer cells that are thought to be responsible for tumor progression, treatment resistance, and metastasis. We have previously shown that vitamin D compounds, including a Gemini vitamin D analog BXL0124, suppress progression of ductal carcinoma in situ in vivo and inhibit cancer stem-like cells in MCF10DCIS mammosphere cultures. In the present study, the effects of vitamin D compounds in regulating breast cancer stem-like cells and differentiation in triple-negative breast cancer were assessed. Mammosphere cultures, which enriches for breast cancer cells with stem-like properties, were used to assess the effects of 1α,25(OH) 2 D 3 and BXL0124 on cancer stem cell markers in the triple-negative breast cancer cell line, SUM159. Vitamin D compounds significantly reduced the mammosphere forming efficiency in primary, secondary and tertiary passages of mammospheres compared to control groups. Key markers of cancer stem-like phenotype and pluripotency were analyzed in mammospheres treated with 1α,25(OH) 2 D 3 and BXL0124. As a result, OCT4, CD44 and LAMA5 levels were decreased. The vitamin D compounds also down-regulated the Notch signaling molecules, Notch1, Notch2, Notch3, JAG1, JAG2, HES1 and NFκB, which are involved in breast cancer stem cell maintenance. In addition, the vitamin D compounds up-regulated myoepithelial differentiating markers, cytokeratin 14 and smooth muscle actin, and down-regulated the luminal marker, cytokeratin 18. Cytokeratin 5, a biomarker associated with basal-like breast cancer, was found to be significantly down-regulated by the vitamin D compounds. These results suggest

Pan-Bcl-2 inhibitor obatoclax delays cell cycle progression and blocks migration of colorectal cancer cells.

Directory of Open Access Journals (Sweden)

Bruno Christian Koehler

Full Text Available Despite the fact that new treatment regimes have improved overall survival of patients challenged by colorectal cancer (CRC, prognosis in the metastatic situation is still restricted. The Bcl-2 family of proteins has been identified as promising anti cancer drug target. Even though small molecules targeting Bcl-2 proteins are in clinical trials, little is known regarding their effects on CRC. The aim of this study was to preclinically investigate the value of ABT-737 and Obatoclax as anticancer drugs for CRC treatment. The effects of the BH3-mimetics ABT-737 and Obatoclax on CRC cells were assessed using viability and apoptosis assays. Wound healing migration and boyden chamber invasion assays were applied. 3-dimensional cell cultures were used for long term assessment of invasion and proliferation. Clinically relevant concentrations of pan-Bcl-2 inhibitor Obatoclax did not induce cell death. In contrast, the BH3-mimetic ABT-737 induced apoptosis in a dose dependent manner. Obatoclax caused a cell line specific slowdown of CRC cell growth. Furthermore, Obatoclax, but not ABT-737, recovered E-Cadherin expression and led to impaired migration and invasion of CRC cells. The proliferative capacity and invasiveness of CRC cells was strikingly inhibited by low dose Obatoclax in long term 3-dimensional cell cultures. Obatoclax, but not ABT-737, caused a G1-phase arrest accompanied by a downregulation of Cyclin D1 and upregulation of p27 and p21. Overexpression of Mcl-1, Bcl-xL or Bcl-2 reversed the inhibitory effect of Obatoclax on migration but failed to restore the proliferative capacity of Obatoclax-treated CRC cells. The data presented indicate broad and multifaceted antitumor effects of the pan-Bcl-2 inhibitor Obatoclax on CRC cells. In contrast to ABT-737, Obatoclax inhibited migration, invasion and proliferation in sublethal doses. In summary, this study recommends pan-Bcl-2 inhibition as a promising approach for clinical trials in CRC.

Scan cell design for enhanced delay fault testability

NARCIS (Netherlands)

van Brakel, Gerrit; van Brakel, G.; Xing, Yizi; Xing, Y.; Kerkhoff, Hans G.

1992-01-01

Problems in testing scannable sequential circuits for delay faults are addressed. Modifications to improve circuit controllability and observability for the testing of delay faults are implemented efficiently in a scan cell design. A layout on a gate array is designed and evaluated for this scan

Game theory in the death galaxy: interaction of cancer and stromal cells in tumour microenvironment.

Science.gov (United States)

Wu, Amy; Liao, David; Tlsty, Thea D; Sturm, James C; Austin, Robert H

2014-08-06

Preventing relapse is the major challenge to effective therapy in cancer. Within the tumour, stromal (ST) cells play an important role in cancer progression and the emergence of drug resistance. During cancer treatment, the fitness of cancer cells can be enhanced by ST cells because their molecular signalling interaction delays the drug-induced apoptosis of cancer cells. On the other hand, competition among cancer and ST cells for space or resources should not be ignored. We explore the population dynamics of multiple myeloma (MM) versus bone marrow ST cells by using an experimental microecology that we call the death galaxy, with a stable drug gradient and connected microhabitats. Evolutionary game theory is a quantitative way to capture the frequency-dependent nature of interactive populations. Therefore, we use evolutionary game theory to model the populations in the death galaxy with the gradients of pay-offs and successfully predict the future densities of MM and ST cells. We discuss the possible clinical use of such analysis for predicting cancer progression.

Effect of longer health service provider delays on stage at diagnosis and mortality in symptomatic breast cancer.

Science.gov (United States)

Murchie, P; Raja, E A; Lee, A J; Brewster, D H; Campbell, N C; Gray, N M; Ritchie, L D; Robertson, R; Samuel, L

2015-06-01

This study explored whether longer provider delays (between first presentation and treatment) were associated with later stage and poorer survival in women with symptomatic breast cancer. Data from 850 women with symptomatic breast cancer were linked with the Scottish Cancer Registry; Death Registry; and hospital discharge dataset. Logistic regression and Cox survival analyses with restricted cubic splines explored relationships between provider delays, stage and survival, with sequential adjustment for patient and tumour factors. Although confidence intervals were wide in both adjusted analyses, those with the shortest provider delays had more advanced breast cancer at diagnosis. Beyond approximately 20 weeks, the trend suggests longer delays are associated with more advanced stage, but is not statistically significant. Those with symptomatic breast cancer and the shortest presentation to treatment time (within 4 weeks) had the poorest survival. Longer time to treatment was not significantly associated with worsening mortality. Poor prognosis patients with breast cancer are being triaged for rapid treatment with limited effect on outcome. Prolonged time to treatment does not appear to be strongly associated with poorer outcomes for patients with breast cancer, but the power of this study to assess the effect of very long delays (>25 weeks) was limited. Efforts to reduce waiting times are important from a quality of life perspective, but tumour biology may often be a more important determinant of stage at diagnosis and survival outcome. Copyright © 2015 Elsevier Ltd. All rights reserved.

Stage at diagnosis and delay in seeking medical care among women with breast cancer, delhi, India.

Science.gov (United States)

Pakseresht, Sedigheh; Ingle, Gopal Krishna; Garg, Suneela; Sarafraz, Nahid

2014-12-01

Patients with cancer often delay seeking medical advice in developing countries. It can adversely influence the outcome of disease. The present study was performed to determine the stage at diagnosis and delay in seeking medical care among women with breast cancer in Delhi, India. This was a cross-sectional study based on a census (case series) approach to reach all women (172) diagnosed with primary breast cancer "detected in surgery Out Patient Department (OPD) from January 2007 to December 2009" at Lok Nayak Hospital, Delhi, India. Patients were interviewed using a self-structure questionnaire. Seeking behavior variables were awareness of problem, first consultation, followed physician's advice, detection of problem, system of medicine and gap between knowing the problem and consultation (patient delay). Statistical Analysis was performed using the Microsoft SPSS-pc version 14.0 statistical program. The analytic methods were used (mean, standard deviation, X(2), Fisher's Exact Test, K-S, Kruskal-Wallis) for variables. All statistical tests were performed at a significance level of 5% (P cancer at the time of diagnosis. The mean duration of gap between knowing the problem and consulting a physician (patients delay) was 10.90 months. There was no significant association between stage of cancer and consultation gap. A significant association was found between the stage of breast cancer and income; women with lower income had a higher stage of breast cancer (P breast cancer. It seems necessary to design educating programs for women in both clinical and community settings, about breast cancer and early detection practices.

Delay equations modeling the effects of phase-specific drugs and immunotherapy on proliferating tumor cells.

Science.gov (United States)

Barbarossa, Maria Vittoria; Kuttler, Christina; Zinsl, Jonathan

2012-04-01

In this work we present a mathematical model for tumor growth based on the biology of the cell cycle. For an appropriate description of the effects of phase-specific drugs, it is necessary to look at the cell cycle and its phases. Our model reproduces the dynamics of three different tumor cell populations: quiescent cells, cells during the interphase and mitotic cells. Starting from a partial differential equations (PDEs) setting, a delay differential equations (DDE) model is derived for an easier and more realistic approach. Our equations also include interactions of tumor cells with immune system effectors. We investigate the model both from the analytical and the numerical point of view, give conditions for positivity of solutions and focus on the stability of the cancer-free equilibrium. Different immunotherapeutic strategies and their effects on the tumor growth are considered, as well.

Impact of delay to treatment upon survival in 1067 patients with breast-cancer.

Science.gov (United States)

Rabinovich, M; Vallejo, C; Perez, J; Rodriguez, R; Cuevas, M; Machiavelli, M; Lacava, J; Leone, B; Romero, A; Mickiewicz, E; Chacon, R; Estevez, R

1993-02-01

The medical records of 1067 patients with breast cancer were reviewed to evaluate the influence of delay between first symptom and first treatment upon survival. Three delay intervals were considered: 6 months. At a follow-up of 120 months, survival analyses identified a statistically significant difference (p=0.029) favoring patients with 3 months delay between first symptom and first treatment. Better survival rate for patients with a short delay would obey to a greater number of patients in favorable stages and a higher proportion of women aged 50 or older in this group.

Dynamic contrast-enhanced MR imaging of endometrial cancer. Optimizing the imaging delay for tumour-myometrium contrast

International Nuclear Information System (INIS)

Park, Sung Bin; Moon, Min Hoan; Sung, Chang Kyu; Oh, Sohee; Lee, Young Ho

2014-01-01

To investigate the optimal imaging delay time of dynamic contrast-enhanced magnetic resonance (MR) imaging in women with endometrial cancer. This prospective single-institution study was approved by the institutional review board, and informed consent was obtained from the participants. Thirty-five women (mean age, 54 years; age range, 29-66 years) underwent dynamic contrast-enhanced MR imaging with a temporal resolution of 25-40 seconds. The signal intensity difference ratios between the myometrium and endometrial cancer were analyzed to investigate the optimal imaging delay time using single change-point analysis. The optimal imaging delay time for appropriate tumour-myometrium contrast ranged from 31.7 to 268.1 seconds. The median optimal imaging delay time was 91.3 seconds, with an interquartile range of 46.2 to 119.5 seconds. The median signal intensity difference ratios between the myometrium and endometrial cancer were 0.03, with an interquartile range of -0.01 to 0.06, on the pre-contrast MR imaging and 0.20, with an interquartile range of 0.15 to 0.25, on the post-contrast MR imaging. An imaging delay of approximately 90 seconds after initiating contrast material injection may be optimal for obtaining appropriate tumour-myometrium contrast in women with endometrial cancer. (orig.)

Reasons for diagnostic delay in gynecological malignancies

DEFF Research Database (Denmark)

Vandborg, Mai Partridge; Christensen, René dePont Christensen; Kragstrup, Jakob

2011-01-01

(≤ or > 60 years), performance of gynecological examination by the GP and notification of cancer suspicion on first referral from GP’s on the diagnostic delay (short delay ≤90 days and long delay >90 days). Results Across cancer type a median total delay of 101 days was observed. The 10% of women......Aim The primary aim of this study was to identify and describe different delay types in women with gynecologic cancer, and to analyze the relationship between diagnostic delay and a number of characteristics for patients, cancers and the health care system. Setting A cohort study of women newly......) and The Danish Gynecological Cancer Database (DGCD). 161 women were included; ovarian cancer: 63, endometrial cancer: 50, cervical cancer: 34 and vulvar cancer: 14. Outcome measures were different delay types counted in days and the influence of four clinical important variables: Presence of alarm symptoms, age...

Delays and Refusal in Treatment for Breast Cancer Among Native American and Hispanic Women with Breast Cancer

National Research Council Canada - National Science Library

Saavedra, Elba

2000-01-01

..., attitudinal, spiritual and demographic variables associated with delays and refusals in breast cancer treatment The focus of the semi-structured interview is to encourage the women in story-telling...

A new method for analyzing diagnostic delay in gynecological cancer

DEFF Research Database (Denmark)

Vandborg, Mai Partridge; Edwards, Kasper; Kragtrup, Jakob

2012-01-01

AND METHODS: Six women with a diagnostic delay of 6 weeks or more before treatment of gynecological cancer at a specialized regional department (the Department of Gynecology and Obstetrics, Odense University Hospital, Denmark) were included in the study. Maps of existing processes were performed for each...

A New Method for Analyzing Diagnostic Delay in Gynecological Cancer

DEFF Research Database (Denmark)

Vandborg, Mai Partridge; Edwards, Kasper; Kragstrup, Jakob

2012-01-01

AND METHODS: Six women with a diagnostic delay of 6 weeks or more before treatment of gynecological cancer at a specialized regional department (the Department of Gynecology and Obstetrics, Odense University Hospital, Denmark) were included in the study. Maps of existing processes were performed for each...

Increased Arf/p53 activity in stem cells, aging and cancer.

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Carrasco-Garcia, Estefania; Moreno, Manuel; Moreno-Cugnon, Leire; Matheu, Ander

2017-04-01

Arf/p53 pathway protects the cells against DNA damage induced by acute stress. This characteristic is the responsible for its tumor suppressor activity. Moreover, it regulates the chronic type of stress associated with aging. This is the basis of its anti-aging activity. Indeed, increased gene dosage of Arf/p53 displays elongated longevity and delayed aging. At a cellular level, it has been recently shown that increased dosage of Arf/p53 delays age-associated stem cell exhaustion and the subsequent decline in tissue homeostasis and regeneration. However, p53 can also promote aging if constitutively activated. In this context, p53 reduces tissue regeneration, which correlates with premature exhaustion of stem cells. We discuss here the current evidence linking the Arf/p53 pathway to the processes of aging and cancer through stem cell regulation. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

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

Directory of Open Access Journals (Sweden)

Seog-Young Kim

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

Hedgehog Pathway Inhibition Radiosensitizes Non-Small Cell Lung Cancers

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Zeng, Jing; Aziz, Khaled; Chettiar, Sivarajan T. [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Aftab, Blake T. [Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Armour, Michael; Gajula, Rajendra; Gandhi, Nishant; Salih, Tarek; Herman, Joseph M.; Wong, John [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Rudin, Charles M. [Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Tran, Phuoc T. [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Hales, Russell K., E-mail: rhales1@jhmi.edu [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States)

2013-05-01

Purpose: Despite improvements in chemoradiation, local control remains a major clinical problem in locally advanced non-small cell lung cancer. The Hedgehog pathway has been implicated in tumor recurrence by promoting survival of tumorigenic precursors and through effects on tumor-associated stroma. Whether Hedgehog inhibition can affect radiation efficacy in vivo has not been reported. Methods and Materials: We evaluated the effects of a targeted Hedgehog inhibitor (HhAntag) and radiation on clonogenic survival of human non-small cell lung cancer lines in vitro. Using an A549 cell line xenograft model, we examined tumor growth, proliferation, apoptosis, and gene expression changes after concomitant HhAntag and radiation. In a transgenic mouse model of Kras{sup G12D}-induced and Twist1-induced lung adenocarcinoma, we assessed tumor response to radiation and HhAntag by serial micro-computed tomography (CT) scanning. Results: In 4 human lung cancer lines in vitro, HhAntag showed little or no effect on radiosensitivity. By contrast, in both the human tumor xenograft and murine inducible transgenic models, HhAntag enhanced radiation efficacy and delayed tumor growth. By use of the human xenograft model to differentiate tumor and stromal effects, mouse stromal cells, but not human tumor cells, showed significant and consistent downregulation of Hedgehog pathway gene expression. This was associated with increased tumor cell apoptosis. Conclusions: Targeted Hedgehog pathway inhibition can increase in vivo radiation efficacy in lung cancer preclinical models. This effect is associated with pathway suppression in tumor-associated stroma. These data support clinical testing of Hedgehog inhibitors as a component of multimodality therapy for locally advanced non-small cell lung cancer.

Delay in Diagnosis and Treatment of Breast Cancer among Women Attending a Reference Service in Brazil

Science.gov (United States)

Romeiro Lopes, Tiara Cristina; Gravena, Angela Andréia França; Demitto, Marcela de Oliveira; Borghesan, Deise Helena Pelloso; Dell`Agnolo, Cátia Millene; Brischiliari, Sheila Cristina Rocha; Carvalho, Maria Dalva de Barros; Pelloso, Sandra Marisa

2017-11-26

Background: Cancer is a major public health problem. Early diagnosis and treatment are essential for reducing mortality. This study aimed to analyze factors associated with delay in breast cancer diagnosis and treatment among women attending a reference cancer service. Methods: This retrospective, cross-sectional study was performed with data collected from medical records and interviews conducted with women diagnosed with breast cancer and treated from October 2013 to October 2014 at a cancer reference hospital in Paraná, Southern Brazil. Results: A total of 82 participants were enrolled during the study period; their average age was 58.2 ± 11.5 years. The average time taken for final diagnosis of breast cancer was 102.5 ± 165.5 days. Treatment onset was delayed in the majority of cases, and the average time elapsing from diagnostic biopsy to onset of primary treatment was 72.3 ± 54.0 days. The odds of treatment delay were higher among the women with a low educational level. Conclusions: The results underline the need for proposals aimed at early detection, identification of risk factors and timely provision of treatment by health managers that focus on this group. Creative Commons Attribution License

Delay of Treatment Initiation Does Not Adversely Affect Survival Outcome in Breast Cancer.

Science.gov (United States)

Yoo, Tae-Kyung; Han, Wonshik; Moon, Hyeong-Gon; Kim, Jisun; Lee, Jun Woo; Kim, Min Kyoon; Lee, Eunshin; Kim, Jongjin; Noh, Dong-Young

2016-07-01

Previous studies examining the relationship between time to treatment and survival outcome in breast cancer have shown inconsistent results. The aim of this study was to analyze the overall impact of delay of treatment initiation on patient survival and to determine whether certain subgroups require more prompt initiation of treatment. This study is a retrospective analysis of stage I-III patients who were treated in a single tertiary institution between 2005 and 2008. Kaplan-Meier survival analysis and Cox proportional hazards regression model were used to evaluate the impact of interval between diagnosis and treatment initiation in breast cancer and various subgroups. A total of 1,702 patients were included. Factors associated with longer delay of treatment initiation were diagnosis at another hospital, medical comorbidities, and procedures performed before admission for surgery. An interval between diagnosis and treatment initiation as a continuous variable or with a cutoff value of 15, 30, 45, and 60 days had no impact on disease-free survival (DFS). Subgroup analyses for hormone-responsiveness, triple-negative breast cancer, young age, clinical stage, and type of initial treatment showed no significant association between longer delay of treatment initiation and DFS. Our results show that an interval between diagnosis and treatment initiation of 60 days or shorter does not appear to adversely affect DFS in breast cancer.

Enhanced effect of geldanamycin nanocomposite against breast cancer cells growing in vitro and as xenograft with vanquished normal cell toxicity

Energy Technology Data Exchange (ETDEWEB)

Prabhu, Suma [Department of Radiation Biology and Toxicology, School of Life Sciences, Manipal University, Manipal 576 104, Karnataka (India); Ananthanarayanan, Preeta; Aziz, Sajida Kannangar [Department of Biotechnology, School of Life Sciences, Manipal University, Manipal 576 104, Karnataka (India); Rai, Sharada [Department of Pathology, Kasturba Medical College, Mangalore Campus, Manipal University, Mangalore 575 001, Karnataka (India); Mutalik, Srinivas [Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576 104, Karnataka (India); Sadashiva, Satish Rao Bola, E-mail: rao.satish@manipal.edu [Department of Radiation Biology and Toxicology, School of Life Sciences, Manipal University, Manipal 576 104, Karnataka (India)

2017-04-01

Despite enormous advances in remedies developed for breast cancer, an effective therapeutic strategy by targeting malignant cells with the least normal tissue toxicity is yet to be developed. Hsp90 is considered to be an important therapeutic target to inhibit cell proliferation. Geldanamycin (GDM), a potent inhibitor of Hsp90 was withdrawn from clinical trials due to its undesirable hepatotoxicity. We report a superparamagnetic iron oxide (SPION) based polymeric nanocomposite of GDM augmenting anticancer competence with decreased hepatic toxicity. The particle size of nanocomposite was ascertained to be 76 ± 10 nm with acceptable stability. A comparative dose dependent in vitro validation of cytotoxicity showed an enhanced cellular damage and necrosis in breast cancer (MCF-7) cell line at a low dose of 5.49 nM (in GDM nanocomposite) in contrast to 20 nM of pure GDM, while normal breast epithelial cells (MCF-10A) were least affected. Besides, in vivo study (in breast cancer xenografts) substantiated 2.7 fold delay in tumor progression mediated by redundancy in the downstream functions of p-Akt and MAPK-Erk leading to apoptosis with negligible hepatotoxicity. Pure GDM disrupted the function and morphology of liver with lesser therapeutic efficacy than the GDM nanocomposite. These findings deduce that GDM based polymeric magnetite nanocomposite play a vital role in efficacious therapy while vanquishing normal cells and hepatic toxicity and thereby promising it to be reinstated in clinics. - Highlights: • GDM nanocomposite shows selective cell kill of cancerous breast cells. • Nanocomposite delays the growth of tumor in comparison to pure GDM treatment. • GDM promotes apoptosis by down-regulation of p-Akt and MAPK-Erk. • GDM nanocomposite nullifies the hepatotoxicity generally exhibited by pure GDM.

Does Embarrassment Contribute to Delay in Seeking Medical Care for Breast Cancer? A Review

Directory of Open Access Journals (Sweden)

Mohamadreza Neishaboury

2015-08-01

Full Text Available Background: Embarrassment and shame of visiting a doctor for a breast disease are among psychosocial factors that potentially contribute to delay in seeking medical advice. The purpose of this study is to review the published literature to determine if embarrassment regarding breast examination, diagnosis and treatment is associated with patient delay.Methods: We searched PubMed with the following key terms: patient acceptance of health care (MeSH, breast neoplasms/psychology (MeSH, shame (MeSH, embarrassment, delayed diagnosis, to find relevant literature published before August 2015.Results: The studies that explicitly assessed the association between embarrassment and delay for seeking medical advice for breast cancer were very limited. Among these studies, only 2 were quantitative studies, 4 were based on qualitative research and 4 were reviews. Other studies assessed attitudes in population-based surveys or included patients (females and males suffering from different types of cancer.Conclusions: Women should be educated that diseases of the breast need to be cared for as health issues in other parts of the body. They should be informed that embarrassment in this regard is not related to grace and integrity but can be potentially life-threatening. Further research is necessary to quantify the association of embarrassment or shame with delay in seeking diagnosis and treatment of breast cancer. More research can elucidate the ways that the negative impact of shame/embarrassment can be minimized in different ethnic groups.

Diagnosis and treatment delays among elderly breast cancer patients with pre-existing mental illness.

Science.gov (United States)

Iglay, Kristy; Santorelli, Melissa L; Hirshfield, Kim M; Williams, Jill M; Rhoads, George G; Lin, Yong; Demissie, Kitaw

2017-11-01

This study aimed to compare diagnosis and treatment delays in elderly breast cancer patients with and without pre-existing mental illness. A retrospective cohort study was conducted using the Surveillance, Epidemiology and End Results-Medicare data including 16,636 women 68+ years, who were diagnosed with stage I-IIIa breast cancer in the United States from 2005 to 2007. Mental illness was identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes recorded on inpatient and outpatient claims during the 3 years prior to breast cancer diagnosis. Patients were classified as having no mental illness, anxiety, depression, anxiety and depression, or severe mental illness (bipolar disorder, schizophrenia, and other psychotic disorder). Multivariable binomial regression was used to assess the association between mental illness and delays of ≥60 and ≥90 days after adjustment for confounders. Patients with comorbid anxiety and depression had an increased risk for diagnosis delay of ≥90 days from symptom recognition (RR 1.11; 95% CI 1.00, 1.23), and those with severe mental illness had an increased risk for initial treatment delay of ≥60 days from diagnosis (RR 1.36; 95% CI 1.06, 1.74). Patients with any mental illness experienced an increased risk for adjuvant chemotherapy delay of ≥90 days from last operation (RR 1.13; 95% CI 1.01, 1.26) and each category of mental illness, except depression, showed a non-significant trend for this association. Breast cancer patients with mental illness should be closely managed by a cross-functional care team, including a psychiatrist, a primary care physician, and an oncologist, to ensure adequate care is received within an appropriate timeframe.

Role of Ku80-dependent end-joining in delayed genomic instability in mammalian cells surviving ionizing radiation

International Nuclear Information System (INIS)

Suzuki, Keiji; Kodama, Seiji; Watanabe, Masami

2010-01-01

Ionizing radiation induces delayed destabilization of the genome in the progenies of surviving cells. This phenomenon, which is called radiation-induced genomic instability, is manifested by delayed induction of radiation effects, such as cell death, chromosome aberration, and mutation in the progeny of cells surviving radiation exposure. Previously, there was a report showing that delayed cell death was absent in Ku80-deficient Chinese hamster ovary (CHO) cells, however, the mechanism of their defect has not been determined. We found that delayed induction of DNA double strand breaks and chromosomal breaks were intact in Ku80-deficient cells surviving X-irradiation, whereas there was no sign for the production of chromosome bridges between divided daughter cells. Moreover, delayed induction of dicentric chromosomes was significantly compromised in those cells compared to the wild-type CHO cells. Reintroduction of the human Ku86 gene complimented the defective DNA repair and recovered delayed induction of dicentric chromosomes and delayed cell death, indicating that defective Ku80-dependent dicentric induction was the cause of the absence of delayed cell death. Since DNA-PKcs-defective cells showed delayed phenotypes, Ku80-dependent illegitimate rejoining is involved in delayed impairment of the integrity of the genome in radiation-survived cells.

Role of Ku80-dependent end-joining in delayed genomic instability in mammalian cells surviving ionizing radiation

Energy Technology Data Exchange (ETDEWEB)

Suzuki, Keiji, E-mail: kzsuzuki@nagasaki-u.ac.jp [Course of Life Sciences and Radiation Research, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Kodama, Seiji [Research Institute for Advanced Science and Technology, Osaka Prefecture University, 1-2 Gakuen-machi, Sakai 599-8570 (Japan); Watanabe, Masami [Kyoto University Research Reactor Institute, Kumatori-cho Sennan-gun, Osaka 590-0494 (Japan)

2010-01-05

Ionizing radiation induces delayed destabilization of the genome in the progenies of surviving cells. This phenomenon, which is called radiation-induced genomic instability, is manifested by delayed induction of radiation effects, such as cell death, chromosome aberration, and mutation in the progeny of cells surviving radiation exposure. Previously, there was a report showing that delayed cell death was absent in Ku80-deficient Chinese hamster ovary (CHO) cells, however, the mechanism of their defect has not been determined. We found that delayed induction of DNA double strand breaks and chromosomal breaks were intact in Ku80-deficient cells surviving X-irradiation, whereas there was no sign for the production of chromosome bridges between divided daughter cells. Moreover, delayed induction of dicentric chromosomes was significantly compromised in those cells compared to the wild-type CHO cells. Reintroduction of the human Ku86 gene complimented the defective DNA repair and recovered delayed induction of dicentric chromosomes and delayed cell death, indicating that defective Ku80-dependent dicentric induction was the cause of the absence of delayed cell death. Since DNA-PKcs-defective cells showed delayed phenotypes, Ku80-dependent illegitimate rejoining is involved in delayed impairment of the integrity of the genome in radiation-survived cells.

Putative cancer stem cells may be the key target to inhibit cancer cell repopulation between the intervals of chemoradiation in murine mesothelioma.

Science.gov (United States)

Wu, Licun; Blum, Walter; Zhu, Chang-Qi; Yun, Zhihong; Pecze, Laszlo; Kohno, Mikihiro; Chan, Mei-Lin; Zhao, Yidan; Felley-Bosco, Emanuela; Schwaller, Beat; de Perrot, Marc

2018-04-27

Cancer cell repopulation during chemotherapy or radiotherapy is a major factor limiting the efficacy of treatment. Cancer stem cells (CSC) may play critical roles during this process. We aim to demonstrate the role of mesothelioma stem cells (MSC) in treatment failure and eventually to design specific target therapies against MSC to improve the efficacy of treatment in malignant mesothelioma. Murine mesothelioma AB12 and RN5 cells were used to compare tumorigenicity in mice. The expression of CSC-associated genes was evaluated by quantitative real-time PCR in both cell lines treated with chemo-radiation. Stemness properties of MSC-enriched RN5-EOS-Puro2 cells were characterized with flow cytometry and immunostaining. A MSC-specific gene profile was screened by microarray assay and confirmed thereafter. Gene Ontology analysis of the selected genes was performed by GOMiner. Tumor growth delay of murine mesothelioma AB12 cells was achieved after each cycle of cisplatin treatment, however, tumors grew back rapidly due to cancer cell repopulation between courses of chemotherapy. Strikingly, a 10-times lower number of irradiated cells in both cell lines led to a similar tumor incidence and growth rate as with untreated cells. The expression of CSC-associated genes such as CD24, CD133, CD90 and uPAR was dramatically up-regulated, while others did not change significantly after chemoradiation. Highly enriched MSC after selection with puromycin displayed an increasing GFP-positive population and showed typical properties of stemness. Comparatively, the proportion of MSC significantly increased after RN5-EOS parental cells were treated with either chemotherapy, γ-ray radiation, or a combination of the two, while MSC showed more resistance to the above treatments. A group of identified genes are most likely MSC-specific, and major pathways related to regulation of cell growth or apoptosis are involved. Upregulation of the gene transcripts Tnfsf18, Serpinb9b, Ly6a

Silencing of the integrin-linked kinase gene suppresses the proliferation, migration and invasion of pancreatic cancer cells (Panc-1).

Science.gov (United States)

Zhu, Xiang-Yu; Liu, Ning; Liu, Wei; Song, Shao-Wei; Guo, Ke-Jian

2012-04-01

Integrin-linked kinase (ILK) is an ankyrin repeat-containing serine-threonine protein kinase that is involved in the regulation of integrin-mediated processes such as cancer cell proliferation, migration and invasion. In this study, we examined the effect of a lentivirus-mediated knockdown of ILK on the proliferation, migration and invasion of pancreatic cancer (Panc-1) cells. Immunohistochemical staining showed that ILK expression was enhanced in pancreatic cancer tissue. The silencing of ILK in human Panc-1 cells led to cell cycle arrest in the G0/G1 phase and delayed cell proliferation, in addition to down-regulating cell migration and invasion. The latter effects were mediated by up-regulating the expression of E-cadherin, a key protein in cell adhesion. These findings indicate that ILK may be a new diagnostic marker for pancreatic cancer and that silencing ILK could be a potentially useful therapeutic approach for treating pancreatic cancer.

Diagnostic delay, quality of life and patient satisfaction among women diagnosed with endometrial or ovarian cancer

DEFF Research Database (Denmark)

Robinson, Kirstine M; Christensen, Karl Bang; Ottesen, Bent

2012-01-01

This study investigates the association between diagnostic delay (total delay), quality of life (QoL) and patient satisfaction, and the associations between QoL and patient satisfaction scores and survival for women diagnosed with ovarian or endometrial cancer....

Factors contributing to delayed diagnosis of cancer among Aboriginal people in Australia: a qualitative study

Science.gov (United States)

Shahid, Shaouli; Teng, Tiew-Hwa Katherine; Bessarab, Dawn; Aoun, Samar; Baxi, Siddhartha; Thompson, Sandra C

2016-01-01

Background/objectives Delayed presentation of symptomatic cancer is associated with poorer survival. Aboriginal patients with cancer have higher rates of distant metastases at diagnosis compared with non-Aboriginal Australians. This paper examined factors contributing to delayed diagnosis of cancer among Aboriginal Australians from patient and service providers' perspectives. Methods In-depth, open-ended interviews were conducted in two stages (2006–2007 and 2011). Inductive thematic analysis was assisted by use of NVivo looking around delays in presentation, diagnosis and referral for cancer. Participants Aboriginal patients with cancer/family members (n=30) and health service providers (n=62) were recruited from metropolitan Perth and six rural/remote regions of Western Australia. Results Three broad themes of factors were identified: (1) Contextual factors such as intergenerational impact of colonisation and racism and socioeconomic deprivation have negatively impacted on Aboriginal Australians' trust of the healthcare professionals; (2) health service-related factors included low accessibility to health services, long waiting periods, inadequate numbers of Aboriginal professionals and high staff turnover; (3) patient appraisal of symptoms and decision-making, fear of cancer and denial of symptoms were key reasons patients procrastinated in seeking help. Elements of shame, embarrassment, shyness of seeing the doctor, psychological ‘fear of the whole health system’, attachment to the land and ‘fear of leaving home’ for cancer treatment in metropolitan cities were other deterrents for Aboriginal people. Manifestation of masculinity and the belief that ‘health is women's domain’ emerged as a reason why Aboriginal men were reluctant to receive health checks. Conclusions Solutions to improved Aboriginal cancer outcomes include focusing on the primary care sector encouraging general practitioners to be proactive to suspicion of symptoms with appropriate

Small interfering RNA targeted to IGF-IR delays tumor growth and induces proinflammatory cytokines in a mouse breast cancer model.

Directory of Open Access Journals (Sweden)

Tiphanie Durfort

Full Text Available Insulin-like growth factor I (IGF-I and its type I receptor (IGF-IR play significant roles in tumorigenesis and in immune response. Here, we wanted to know whether an RNA interference approach targeted to IGF-IR could be used for specific antitumor immunostimulation in a breast cancer model. For that, we evaluated short interfering RNA (siRNAs for inhibition of in vivo tumor growth and immunological stimulation in immunocompetent mice. We designed 2'-O-methyl-modified siRNAs to inhibit expression of IGF-IR in two murine breast cancer cell lines (EMT6, C4HD. Cell transfection of IGF-IR siRNAs decreased proliferation, diminished phosphorylation of downstream signaling pathway proteins, AKT and ERK, and caused a G0/G1 cell cycle block. The IGF-IR silencing also induced secretion of two proinflammatory cytokines, TNF- α and IFN-γ. When we transfected C4HD cells with siRNAs targeting IGF-IR, mammary tumor growth was strongly delayed in syngenic mice. Histology of developing tumors in mice grafted with IGF-IR siRNA treated C4HD cells revealed a low mitotic index, and infiltration of lymphocytes and polymorphonuclear neutrophils, suggesting activation of an antitumor immune response. When we used C4HD cells treated with siRNA as an immunogen, we observed an increase in delayed-type hypersensitivity and the presence of cytotoxic splenocytes against wild-type C4HD cells, indicative of evolving immune response. Our findings show that silencing IGF-IR using synthetic siRNA bearing 2'-O-methyl nucleotides may offer a new clinical approach for treatment of mammary tumors expressing IGF-IR. Interestingly, our work also suggests that crosstalk between IGF-I axis and antitumor immune response can mobilize proinflammatory cytokines.

Lung cancer - small cell

Science.gov (United States)

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

Are survivors who report cancer-related financial problems more likely to forgo or delay medical care?

Science.gov (United States)

Kent, Erin E; Forsythe, Laura P; Yabroff, K Robin; Weaver, Kathryn E; de Moor, Janet S; Rodriguez, Juan L; Rowland, Julia H

2013-10-15

Financial problems caused by cancer and its treatment can substantially affect survivors and their families and create barriers to seeking health care. The authors identified cancer survivors diagnosed as adults (n=1556) from the nationally representative 2010 National Health Interview Survey. Using multivariable logistic regression analyses, the authors report sociodemographic, clinical, and treatment-related factors associated with perceived cancer-related financial problems and the association between financial problems and forgoing or delaying health care because of cost. Adjusted percentages using the predictive marginals method are presented. Cancer-related financial problems were reported by 31.8% (95% confidence interval, 29.3%-34.5%) of survivors. Factors found to be significantly associated with cancer-related financial problems in survivors included younger age at diagnosis, minority race/ethnicity, history of chemotherapy or radiation treatment, recurrence or multiple cancers, and shorter time from diagnosis. After adjustment for covariates, respondents who reported financial problems were more likely to report delaying (18.3% vs 7.4%) or forgoing overall medical care (13.8% vs 5.0%), prescription medications (14.2% vs 7.6%), dental care (19.8% vs 8.3%), eyeglasses (13.9% vs 5.8%), and mental health care (3.9% vs 1.6%) than their counterparts without financial problems (all Pfinancial problems are not only disproportionately represented in survivors who are younger, members of a minority group, and have a higher treatment burden, but may also contribute to survivors forgoing or delaying medical care after cancer. Copyright © 2013 American Cancer Society.

Qualitative study of men's perceptions of why treatment delays occur in the UK for those with testicular cancer.

Science.gov (United States)

Chapple, Alison; Ziebland, Sue; McPherson, Ann

2004-01-01

Many studies (but not all) have shown that for men with testicular cancer a longer treatment delay is associated with additional treatments, greater morbidity, and shorter survival. This paper explores patients' perspectives on why treatment delays occur. Qualitative study using narrative interviews Interviews in patient's homes throughout the United Kingdom (UK). Interviews with a maximum variation sample of 45 men with testicular cancer, recruited through general practitioners (GPs), urologists, support groups, and charities. Those who sought help relatively quickly responded to symptoms, had heard about testicular cancer in the media, had seen leaflets in GPs' surgeries, or knew others with this disease. Men delayed because they did not recognise signs and symptoms; feared appearing weak, a hypochondriac, or lacking in masculinity; recalled past illness or painful examinations; were embarrassed; feared the consequences of treatment; or lacked time to consult their doctors. Beliefs about symptoms and pessimistic associations with cancer also led to delay. Treatment delays also resulted from misdiagnosis or waiting lists. Whether or not men should be taught to examine themselves routinely to check for testicular cancer is much debated. This study suggests that it is important that men are aware of the normal shape and feel of their testicles, and may benefit from information about signs and symptoms of testicular cancer and the excellent cure rate. Information, provided in surgeries where men feel welcome, might encourage men to seek help promptly when a problem arises. Our study also suggests that GPs may need to accept a low threshold for ultrasound investigation of testicular symptoms and that the ultrasound service needs to be improved. These measures may further reduce mortality and morbidity.

Isolation and Characterization of Cancer Stem Cells of the Non-Small-Cell Lung Cancer (A549) Cell Line.

Science.gov (United States)

Halim, Noor Hanis Abu; Zakaria, Norashikin; Satar, Nazilah Abdul; Yahaya, Badrul Hisham

2016-01-01

Cancer is a major health problem worldwide. The failure of current treatments to completely eradicate cancer cells often leads to cancer recurrence and dissemination. Studies have suggested that tumor growth and spread are driven by a minority of cancer cells that exhibit characteristics similar to those of normal stem cells, thus these cells are called cancer stem cells (CSCs). CSCs are believed to play an important role in initiating and promoting cancer. CSCs are resistant to currently available cancer therapies, and understanding the mechanisms that control the growth of CSCs might have great implications for cancer therapy. Cancer cells are consist of heterogeneous population of cells, thus methods of identification, isolation, and characterisation of CSCs are fundamental to obtain a pure CSC populations. Therefore, this chapter describes in detail a method for isolating and characterizing a pure population of CSCs from heterogeneous population of cancer cells and CSCs based on specific cell surface markers.

Association of Previous Clinical Breast Examination With Reduced Delays and Earlier-Stage Breast Cancer Diagnosis Among Women in Peru.

Science.gov (United States)

Romanoff, Anya; Constant, Tara Hayes; Johnson, Kay M; Guadiamos, Manuel Cedano; Vega, Ana María Burga; Zunt, Joseph; Anderson, Benjamin O

2017-11-01

Mammographic screening is impractical in most of the world where breast cancers are first identified based on clinical signs and symptoms. Clinical breast examination may improve early diagnosis directly by finding breast cancers at earlier stages or indirectly by heightening women's awareness of breast health concerns. To investigate factors that influence time to presentation and stage at diagnosis among patients with breast cancer to determine whether history of previous clinical breast examination is associated with earlier presentation and/or earlier cancer stage at diagnosis. In this cross-sectional analysis of individual patient interviews using a validated Breast Cancer Delay Questionnaire, 113 (71.1%) of 159 women with breast cancer treated at a federally funded tertiary care referral cancer center in Trujillo, Peru, from February 1 through May 31, 2015, were studied. Method of breast cancer detection and factors that influence time to and stage at diagnosis. Of 113 women with diagnosed cancer (mean [SD] age, 54 [10.8] years; age range, 32-82 years), 105 (92.9%) had self-detected disease. Of the 93 women for whom stage was documented, 45 (48.4%) were diagnosed with early-stage disease (American Joint Committee on Cancer [AJCC] stage 0, I, or II), and 48 (51.6%) were diagnosed with late-stage disease (AJCC stage III or IV). Mean (SD) total delay from symptom onset to initiation of treatment was 407 (665) days because of patient (mean [SD], 198 [449] days) and health care system (mean [SD], 241 [556] days) delay. Fifty-two women (46.0%) had a history of clinical breast examination, and 23 (20.4%) had undergone previous mammography. Women who underwent a previous clinical breast examination were more likely to have shorter delays from symptom development to presentation compared with women who had never undergone a previous clinical breast examination (odds ratio, 2.92; 95% CI, 1.30-6.60; P = .01). Women diagnosed with shorter patient delay were more

Study of Relationship Between Illness Perception and Delay in Seeking Help for Breast Cancer Patients Based on Leventhal's Self-Regulation Model.

Science.gov (United States)

Attari, Seyedeh Maryam; Ozgoli, Giti; Solhi, Mahnaz; Alavi Majd, Hamid

2016-01-01

One of the major causes of morbidity and mortality in breast cancer patients is delay in seeking help. Leventhal's self-regulation model provides an appropriate framework to assess delay in seeking help. The aim of this study was to investigate the relationship between "illness perception" and "help seeking delay" in breast cancer patients based on Leventhal's self-regulation model. In this correlational descriptive study with convenience sampling conducted in 2013, participants were 120 women with breast cancer who were diagnosed in the last year and referred to chemotherapy and radiotherapy centers in Rasht, Iran. Data collection scales included demographic data, Revised Illness Perception Questionnaire (IPQ-R)and a researcher made questionnaire to measure the delay in seeking help. Pre-hospital delay (help seeking delay) was evaluated in 3 phases (assessment, disease, behavior). The data were analyzed using SPSS-19. The mean (SD) age calculated for the patients was 47.3±10.2. Some 43% of the patients had a high school or higher education level and 82% were married. The "pre-hospital delay" was reported ≥3 months. Logistic regression analysis showed that none of the illness perception components were correlated with appraisal and behavioral delay phases. In the illness delay phase, "time line" (p-value =0.04) and "risk factors"(p-value=0.03) had significant effects on reducing and "psychological attributions" had significant effects on increasing the delay (p-value =0.01). "Illness coherence" was correlated with decreased pre-hospital patient delay (p-valueperceptions of breast cancer influences delay in seeking help. In addition to verifying the validity of Leventhal's self-regulation model in explaining delay in seeking help, the results signify the importance of the "illness delay phase" (decision to seek help) and educational interventions-counseling for women in the community.

Silencing of the integrin-linked kinase gene suppresses the proliferation, migration and invasion of pancreatic cancer cells (Panc-1

Directory of Open Access Journals (Sweden)

Xiang-Yu Zhu

2012-01-01

Full Text Available Integrin-linked kinase (ILK is an ankyrin repeat-containing serine-threonine protein kinase that is involved in the regulation of integrin-mediated processes such as cancer cell proliferation, migration and invasion. In this study, we examined the effect of a lentivirus-mediated knockdown of ILK on the proliferation, migration and invasion of pancreatic cancer (Panc-1 cells. Immunohistochemical staining showed that ILK expression was enhanced in pancreatic cancer tissue. The silencing of ILK in human Panc-1 cells led to cell cycle arrest in the G0/G1 phase and delayed cell proliferation, in addition to down-regulating cell migration and invasion. The latter effects were mediated by up-regulating the expression of E-cadherin, a key protein in cell adhesion. These findings indicate that ILK may be a new diagnostic marker for pancreatic cancer and that silencing ILK could be a potentially useful therapeutic approach for treating pancreatic cancer.

A new prospect in cancer therapy: targeting cancer stem cells to eradicate cancer.

Science.gov (United States)

Chen, Li-Sha; Wang, An-Xin; Dong, Bing; Pu, Ke-Feng; Yuan, Li-Hua; Zhu, Yi-Min

2012-12-01

According to the cancer stem cell theory, cancers can be initiated by cancer stem cells. This makes cancer stem cells prime targets for therapeutic intervention. Eradicating cancer stem cells by efficient targeting agents may have the potential to cure cancer. In this review, we summarize recent breakthroughs that have improved our understanding of cancer stem cells, and we discuss the therapeutic strategy of targeting cancer stem cells, a promising future direction for cancer stem cell research.

Delayed changes in gene expression in human fibroblasts after alpha irradiation

International Nuclear Information System (INIS)

Salo, A.; Peraelae, M.; Mustonen, R.; Kadhim, M.; Marsden, S.; Sabatier, L.; Martins, L.

2003-01-01

It has been commonly accepted that the biological consequences following radiation exposure are attributable to DNA damage and expressed within one or two cell generations. Recent evidence, however, has now been emerged to challenge this classical paradigm. Changes in non-irradiated bystander cells may lead to transmissible genomic instability. This phenomenon has been termed 'non-targeted' and in addition to genomic instability, includes also radiation-induced bystander effects. Various types of genomic damage can be observed in affected cells for many generations after irradiation. After alphaparticle irradiation, delayed non-clonal chromosomal aberrations were seen in surviving cells of cultured haematopoietic stem cells from CBA/H mice. These aberrations were mostly of non-identical chromatid type, showing that they had arisen for many generations after the irradiation. Although radiation-induced genomic instability has been observed in several in vitro and in vivo experiments, the mechanisms involved in the induction and transmission of genomic instability remain unknown. The purpose of this work was to provide new information about the delayed or persistent effects of radiation on expression of genes associated with chromosomal instability phenotype. It has been assumed that this phenotype is linked to sustained alterations in gene expression rather than to specific gene mutations. The delayed gene expression changes in cells after irradiation have not been extensively studied. Human syndromes expressing chromosomal instability have been demonstrated to have a role in the evolution of malignancy. Thus, the role of radiation-induced genomic instability in radiation oncogenesis is of importance. The work is part of the joint EU-funded project called 'Genomic instability and radiation-induced cancer' (RADINSTAB). The aim of the RADINSTAB project was to investigate health effects of genomic damage, predisposition to cancer and correlation of genomic instability

Delayed lung scintigraphy with N-isopropyl-I-123-p-iodoamphetamine in lung cancer and inflammatory disease

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Suematsu, Toru; Narabayashi, Isamu; Takada, Yoshiki and others

1989-01-01

Lung studies with N-Isopropyl-I-123-p-Iodoamphetamine (IMP) were performed on patients with lung cancer or inflammatory disease. In the present study, we evaluated the usefulness of the delayed scintigraphy. The subjects consisted of 27 patients with lung cancer (34 lesions), 3 with radiation pneumonitis, 2 with interstitial pneumonitis, 2 with old tuberculous lesion (tuberculomas), 1 with diffuse panbronchiolitis, 1 with pneumonia and 1 with lung abscess. The delayed scintigraphy was performed 24 hr after intravenous injection of 3 mCi IMP, in sitting position. In 10 patients, SPECT images were obtained following the delayed scintigraphy. Delayed scintigraphic appearances of lung cancer were classified into 5 types, high IMP uptake in the area congruent with the lesion of atelectasis and/or obstructive pneumonia (Type I), high IMP uptake in the area surrounded the tumor (Type II), a defect in the area consistent with the tumor and no high IMP uptake in the area surrounded the tumor (Type III), high IMP uptake in the area almost congruent with the tumor (Type IV) and no significant change (Type V). Excluding 10 lesions with Type IV or V, no IMP uptake was seen in the areas congruent with the tumors. Type II was the most frequently observed pattern. Normal scintigrams (Type V) were observed in 8 lesions, whose sizes were fairly small. There was no definite trend caused by difference in histological types of cancers. In 8 patients with viable inflammatory disease of the lung, the delayed scintigrams showed high IMP uptake in the areas congruent with the abnormalities on chest roentgenograms. On the other hand, no uptake was seen in the old tuberculous lesions. (J.P.N.).

Delayed lung scintigraphy with N-isopropyl-I-123-p-iodoamphetamine in lung cancer and inflammatory disease

International Nuclear Information System (INIS)

Suematsu, Toru; Narabayashi, Isamu; Takada, Yoshiki

1989-01-01

Lung studies with N-Isopropyl-I-123-p-Iodoamphetamine (IMP) were performed on patients with lung cancer or inflammatory disease. In the present study, we evaluated the usefulness of the delayed scintigraphy. The subjects consisted of 27 patients with lung cancer (34 lesions), 3 with radiation pneumonitis, 2 with interstitial pneumonitis, 2 with old tuberculous lesion (tuberculomas), 1 with diffuse panbronchiolitis, 1 with pneumonia and 1 with lung abscess. The delayed scintigraphy was performed 24 hr after intravenous injection of 3 mCi IMP, in sitting position. In 10 patients, SPECT images were obtained following the delayed scintigraphy. Delayed scintigraphic appearances of lung cancer were classified into 5 types, high IMP uptake in the area congruent with the lesion of atelectasis and/or obstructive pneumonia (Type I), high IMP uptake in the area surrounded the tumor (Type II), a defect in the area consistent with the tumor and no high IMP uptake in the area surrounded the tumor (Type III), high IMP uptake in the area almost congruent with the tumor (Type IV) and no significant change (Type V). Excluding 10 lesions with Type IV or V, no IMP uptake was seen in the areas congruent with the tumors. Type II was the most frequently observed pattern. Normal scintigrams (Type V) were observed in 8 lesions, whose sizes were fairly small. There was no definite trend caused by difference in histological types of cancers. In 8 patients with viable inflammatory disease of the lung, the delayed scintigrams showed high IMP uptake in the areas congruent with the abnormalities on chest roentgenograms. On the other hand, no uptake was seen in the old tuberculous lesions. (J.P.N.)

Delayed reproductive death as a dominant phenotype in cell clones surviving X-irradiation

International Nuclear Information System (INIS)

Chang, W.P.; Little, J.B.

1992-01-01

Residual damage manifested as reduced cloning efficiency was observed in many of the cloned progeny of Chinese hamster ovary (CHO) cells and human carcinoma SQ-20B cells surviving X-irradiation. This stable phenotype, which we have termed delayed reproductive death, persisted for >50 generations of cell replication post-irradiation. Clones showing this phenotype were aneuploid, and formed colonies with a high proportion of giant cells. By somatic cell hybridization of CHO clones, the delayed reproductive death phenotype was found to be a dominant trait; the cloning efficiency of hybrid clones was persistently depressed, as compared with that of control hybrid cells. These results suggest that delayed reproductive death represents a specific cellular response that may persist in some of the progeny of mammalian cells for long periods after X-irradiation. (author)

The alkylphospholipid, perifosine, radiosensitizes prostate cancer cells both in vitro and in vivo

International Nuclear Information System (INIS)

Gao, Yuanhong; Ittmann, Michael; Thompson, Timothy C; Butler, E Brian; Xu, Bo; Teh, Bin S; Ishiyama, Hiromichi; Sun, Mianen; Brinkman, Kathryn L; Wang, Xiaozhen; Zhu, Julie; Mai, Weiyuan; Huang, Ying; Floryk, Daniel

2011-01-01

Perifosine is a membrane-targeted alkylphospholipid developed to inhibit the PI3K/Akt pathway and has been suggested as a favorable candidate for combined use with radiotherapy. In this study, we investigated the effect of the combined treatment of perifosine and radiation (CTPR) on prostate cancer cells in vitro and on prostate cancer xenografts in vivo. Human prostate cancer cell line, CWR22RV1, was treated with perifosine, radiation, or CTPR. Clonogenic survival assays, sulforhodamine B cytotoxity assays and cell density assays were used to assess the effectiveness of each therapy in vitro. Measurements of apoptosis, cell cycle analysis by flow cytometry and Western blots were used to evaluate mechanisms of action in vitro. Tumor growth delay assays were used to evaluate radiation induced tumor responses in vivo. In vitro, CTPR had greater inhibitory effects on prostate cancer cell viability and clonogenic survival than either perifosine or radiation treatment alone. A marked increase in prostate cancer cell apoptosis was noted in CTPR. Phosphorylation of AKT-T308 AKT and S473 were decreased when using perifosine treatment or CTPR. Cleaved caspase 3 was significantly increased in the CTPR group. In vivo, CTPR had greater inhibitory effects on the growth of xenografts when compared with perifosine or radiation treatment alone groups. Perifosine enhances prostate cancer radiosensitivity in vitro and in vivo. These data provide strong support for further development of this combination therapy in clinical studies

Gigantol Suppresses Cancer Stem Cell-Like Phenotypes in Lung Cancer Cells

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Narumol Bhummaphan

2015-01-01

Full Text Available As cancer stem cells (CSCs contribute to malignancy, metastasis, and relapse of cancers, potential of compound in inhibition of CSCs has garnered most attention in the cancer research as well as drug development fields recently. Herein, we have demonstrated for the first time that gigantol, a pure compound isolated from Dendrobium draconis, dramatically suppressed stem-like phenotypes of human lung cancer cells. Gigantol at nontoxic concentrations significantly reduced anchorage-independent growth and survival of the cancer cells. Importantly, gigantol significantly reduced the ability of the cancer cells to form tumor spheroids, a critical hallmark of CSCs. Concomitantly, the treatment of the compound was shown to reduce well-known lung CSCs markers, including CD133 and ALDH1A1. Moreover, we revealed that gigantol decreased stemness in the cancer cells by suppressing the activation of protein kinase B (Akt signal which in turn decreased the cellular levels of pluripotency and self-renewal factors Oct4 and Nanog. In conclusion, gigantol possesses CSCs suppressing activity which may facilitate the development of this compound for therapeutic approaches by targeting CSCs.

The molecular basis for cell cycle delays following ionizing radiation. A review

International Nuclear Information System (INIS)

Maity, A.; McKenna, W.G.; Muschel, R.J.

1994-01-01

Exposure of a wide variety of cells to ionizing (X- or γ-) irradiation results in a division delay which may have several components including a G 1 block, a G 2 arrest or an S phase delay. The G 1 arrest is absent in many cells lines, and the S phase delay is typically seen following relatively high doses (>5 Gy). In contrast, the G 2 arrest is seen in virtually all eukaryotic cells and occurs following high and low doses, even under 1 Gy. The mechanism underlying the G 2 arrest may involve suppression of cyclin B1 mRNA and/or protein in some cell lines and tyrosine phosphorylation of p34 cdc2 in others. Similar mechanisms are likely to be operative in the G 2 arrest induced by various chemotherapeutic agents including nitrogen mustard and etoposide. The upstream signal transduction pathways involved in the G 2 arrest following ionizing radiation remain obscure in mammalian cells; however, in the budding yeast the rad9 gene and in the fission yeast the chk1/rad27 gene are involved. There is evidence indicating that shortening of the G 2 arrest results in decreased survival which has led to the hypothesis that during this block, cells repair damaged DNA following exposure to genotoxic agents. In cell lines examined to date, wildtype p53 is required for the G 1 arrest following ionizing radiation. The gadd45 gene may also have a role in this arrest. Elimination of the G 1 arrest leads to no change in survival following radiation in some cell lines and increased radioresistance in others. It has been suggested that this induction of radioresistance in certain cell lines is due to loss of the ability to undergo apoptosis. Relatively little is known about the mechanism underlying the S phase delay. This delay is due to a depression in the rate of DNA synthesis and has both a slow and a fast component. In some cells the S phase delay can be abolished by staurosporine, suggesting involvement of a protein kinase. Understanding the molecular mechanisms behind these delays

Sulforaphane, a Dietary Isothiocyanate, Induces G2/M Arrest in Cervical Cancer Cells through CyclinB1 Downregulation and GADD45β/CDC2 Association

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Ya-Min Cheng

2016-09-01

Full Text Available Globally, cervical cancer is the most common malignancy affecting women. The main treatment methods for this type of cancer include conization or hysterectomy procedures. Sulforaphane (SFN is a natural, compound-based drug derived from dietary isothiocyanates which has previously been shown to possess potent anti-tumor and chemopreventive effects against several types of cancer. The present study investigated the effects of SFN on anti-proliferation and G2/M phase cell cycle arrest in cervical cancer cell lines (Cx, CxWJ, and HeLa. We found that cytotoxicity is associated with an accumulation of cells in the G2/M phases of the cell-cycle. Treatment with SFN led to cell cycle arrest as well as the down-regulation of Cyclin B1 expression, but not of CDC2 expression. In addition, the effects of GADD45β gene activation in cell cycle arrest increase proportionally with the dose of SFN; however, mitotic delay and the inhibition of proliferation both depend on the dosage of SFN used to treat cancer cells. These results indicate that SFN may delay the development of cancer by arresting cell growth in the G2/M phase via down-regulation of Cyclin B1 gene expression, dissociation of the cyclin B1/CDC2 complex, and up-regulation of GADD45β proteins.

Cell of Origin and Cancer Stem Cells in Tumor Suppressor Mouse Models of Glioblastoma.

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Alcantara Llaguno, Sheila R; Xie, Xuanhua; Parada, Luis F

2016-01-01

The cellular origins and the mechanisms of progression, maintenance of tumorigenicity, and therapeutic resistance are central questions in the glioblastoma multiforme (GBM) field. Using tumor suppressor mouse models, our group recently reported two independent populations of adult GBM-initiating central nervous system progenitors. We found different functional and molecular subtypes depending on the tumor-initiating cell lineage, indicating that the cell of origin is a driver of GBM subtype diversity. Using an in vivo model, we also showed that GBM cancer stem cells (CSCs) or glioma stem cells (GSCs) contribute to resistance to chemotherapeutic agents and that genetic ablation of GSCs leads to a delay in tumor progression. These studies are consistent with the cell of origin and CSCs as critical regulators of the pathogenesis of GBM. © 2016 Alcantara Llaguno et al; Published by Cold Spring Harbor Laboratory Press.

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

International Nuclear Information System (INIS)

Hamada, Shin; Masamune, Atsushi; Takikawa, Tetsuya; Suzuki, Noriaki; Kikuta, Kazuhiro; Hirota, Morihisa; Hamada, Hirofumi; Kobune, Masayoshi; Satoh, Kennichi; Shimosegawa, Tooru

2012-01-01

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

Are cancer cells really softer than normal cells?

Science.gov (United States)

Alibert, Charlotte; Goud, Bruno; Manneville, Jean-Baptiste

2017-05-01

Solid tumours are often first diagnosed by palpation, suggesting that the tumour is more rigid than its surrounding environment. Paradoxically, individual cancer cells appear to be softer than their healthy counterparts. In this review, we first list the physiological reasons indicating that cancer cells may be more deformable than normal cells. Next, we describe the biophysical tools that have been developed in recent years to characterise and model cancer cell mechanics. By reviewing the experimental studies that compared the mechanics of individual normal and cancer cells, we argue that cancer cells can indeed be considered as softer than normal cells. We then focus on the intracellular elements that could be responsible for the softening of cancer cells. Finally, we ask whether the mechanical differences between normal and cancer cells can be used as diagnostic or prognostic markers of cancer progression. © 2017 Société Française des Microscopies and Société de Biologie Cellulaire de France. Published by John Wiley & Sons Ltd.

Are Survivors Who Report Cancer-Related Financial Problems More Likely to Forgo or Delay Medical Care?

Science.gov (United States)

Kent, Erin E.; Forsythe, Laura P.; Yabroff, K. Robin; Weaver, Kathryn E.; de Moor, Janet S.; Rodriguez, Juan L.; Rowland, Julia H.

2015-01-01

BACKGROUND Financial problems caused by cancer and its treatment can substantially affect survivors and their families and create barriers to seeking health care. METHODS The authors identified cancer survivors diagnosed as adults (n = 1556) from the nationally representative 2010 National Health Interview Survey. Using multivariable logistic regression analyses, the authors report sociodemographic, clinical, and treatment-related factors associated with perceived cancer-related financial problems and the association between financial problems and forgoing or delaying health care because of cost. Adjusted percentages using the predictive marginals method are presented. RESULTS Cancer-related financial problems were reported by 31.8% (95% confidence interval, 29.3%–34.5%) of survivors. Factors found to be significantly associated with cancer-related financial problems in survivors included younger age at diagnosis, minority race/ethnicity, history of chemotherapy or radiation treatment, recurrence or multiple cancers, and shorter time from diagnosis. After adjustment for covariates, respondents who reported financial problems were more likely to report delaying (18.3% vs 7.4%) or forgoing overall medical care (13.8% vs 5.0%), prescription medications (14.2% vs 7.6%), dental care (19.8% vs 8.3%), eyeglasses (13.9% vs 5.8%), and mental health care (3.9% vs 1.6%) than their counterparts without financial problems (all Pfinancial problems are not only disproportionately represented in survivors who are younger, members of a minority group, and have a higher treatment burden, but may also contribute to survivors forgoing or delaying medical care after cancer. PMID:23907958

How Can We Treat Cancer Disease Not Cancer Cells?

Science.gov (United States)

Kim, Kyu-Won; Lee, Su-Jae; Kim, Woo-Young; Seo, Ji Hae; Lee, Ho-Young

2017-01-01

Since molecular biology studies began, researches in biological science have centered on proteins and genes at molecular level of a single cell. Cancer research has also focused on various functions of proteins and genes that distinguish cancer cells from normal cells. Accordingly, most contemporary anticancer drugs have been developed to target abnormal characteristics of cancer cells. Despite the great advances in the development of anticancer drugs, vast majority of patients with advanced cancer have shown grim prognosis and high rate of relapse. To resolve this problem, we must reevaluate our focuses in current cancer research. Cancer should be considered as a systemic disease because cancer cells undergo a complex interaction with various surrounding cells in cancer tissue and spread to whole body through metastasis under the control of the systemic modulation. Human body relies on the cooperative interaction between various tissues and organs, and each organ performs its specialized function through tissue-specific cell networks. Therefore, investigation of the tumor-specific cell networks can provide novel strategy to overcome the limitation of current cancer research. This review presents the limitations of the current cancer research, emphasizing the necessity of studying tissue-specific cell network which could be a new perspective on treating cancer disease, not cancer cells.

ZRBA1, a Mixed EGFR/DNA Targeting Molecule, Potentiates Radiation Response Through Delayed DNA Damage Repair Process in a Triple Negative Breast Cancer Model

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Heravi, Mitra [Department of Human Genetics, McGill University, Montreal (Canada); Department of Radiation Oncology, McGill University, Montreal (Canada); Segal Cancer Center, Jewish General Hospital, Montreal (Canada); Kumala, Slawomir [Department of Radiation Oncology, McGill University, Montreal (Canada); Segal Cancer Center, Jewish General Hospital, Montreal (Canada); Rachid, Zakaria; Jean-Claude, Bertrand J. [Cancer Drug Research Laboratory, McGill University Health Center, Montreal (Canada); Radzioch, Danuta [Department of Human Genetics, McGill University, Montreal (Canada); Muanza, Thierry M., E-mail: tmuanza@yahoo.com [Department of Radiation Oncology, McGill University, Montreal (Canada); Segal Cancer Center, Jewish General Hospital, Montreal (Canada)

2015-06-01

Purpose: ZRBA1 is a combi-molecule designed to induce DNA alkylating lesions and to block epidermal growth factor receptor (EGFR) TK domain. Inasmuch as ZRBA1 downregulates the EGFR TK-mediated antisurvival signaling and induces DNA damage, we postulated that it might be a radiosensitizer. The aim of this study was to further investigate the potentiating effect of ZRBA1 in combination with radiation and to elucidate the possible mechanisms of interaction between these 2 treatment modalities. Methods and Materials: The triple negative human breast MDA-MB-468 cancer cell line and mouse mammary cancer 4T1 cell line were used in this study. Clonogenic assay, Western blot analysis, and DNA damage analysis were performed at multiple time points after treatment. To confirm our in vitro findings, in vivo tumor growth delay assay was performed. Results: Our results show that a combination of ZRBA1 and radiation increases the radiation sensitivity of both cell lines significantly with a dose enhancement factor of 1.56, induces significant numbers of DNA strand breaks, prolongs higher DNA damage up to 24 hours after treatment, and significantly increases tumor growth delay in a syngeneic mouse model. Conclusions: Our data suggest that the higher efficacy of this combination could be partially due to increased DNA damage and delayed DNA repair process and to the inhibition of EGFR. The encouraging results of this combination demonstrated a significant improvement in treatment efficiency and therefore could be applicable in early clinical trial settings.

Changes from 1992 to 2002 in the pretreatment delay for patients with squamous cell carcinoma of larynx or pharynx: a Danish nationwide survey from DAHANCA

DEFF Research Database (Denmark)

Primdahl, Hanne; Nielsen, Anni Linnet; Larsen, Susanne

2006-01-01

In Denmark, a general impression of prolonged pretreatment delay for patients with head and neck cancer led to a nationwide study of time spans from symptom debut over first health care contact to start of treatment. Charts of consecutive new patients with squamous cell carcinoma of the pharynx a...

Squamous cell cancer (image)

Science.gov (United States)

Squamous cell cancer involves cancerous changes to the cells of the middle portion of the epidermal skin layer. It is ... malignant tumor, and is more aggressive than basal cell cancer, but still may be relatively slow-growing. It ...

Galectin-4 Reduces Migration and Metastasis Formation of Pancreatic Cancer Cells.

Directory of Open Access Journals (Sweden)

Ana I Belo

Full Text Available Galectin-4 (Gal-4 is a member of the galectin family of glycan binding proteins that shows a significantly higher expression in cystic tumors of the human pancreas and in pancreatic adenocarcinomas compared to normal pancreas. However, the putative function of Gal-4 in tumor progression of pancreatic cancer is still incompletely understood. In this study the role of Gal-4 in cancer progression was investigated, using a set of defined pancreatic cancer cell lines, Pa-Tu-8988S (PaTu-S and Pa-Tu-8988T (PaTu-T, as a model. These two cell lines are derived from the same liver metastasis of a human primary pancreatic adenocarcinoma, but differ in their growth characteristics and metastatic capacity. We demonstrated that Gal-4 expression is high in PaTu-S, which shows poor migratory properties, whereas much lower Gal-4 levels are observed in the highly metastatic cell line PaTu-T. In PaTu-S, Gal-4 is found in the cytoplasm, but it is also secreted and accumulates at the membrane at sites of contact with neighboring cells. Moreover, we show that Gal-4 inhibits metastasis formation by delaying migration of pancreatic cancer cells in vitro using a scratch assay, and in vivo using zebrafish (Danio rerio as an experimental model. Our data suggest that Gal-4 may act at the cell-surface of PaTu-S as an adhesion molecule to prevent release of the tumor cells, but has in addition a cytosolic function by inhibiting migration via a yet unknown mechanism.

Induction of cancer stem cell properties in colon cancer cells by defined factors.

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Nobu Oshima

Full Text Available Cancer stem cells (CSCs are considered to be responsible for the dismal prognosis of cancer patients. However, little is known about the molecular mechanisms underlying the acquisition and maintenance of CSC properties in cancer cells because of their rarity in clinical samples. We herein induced CSC properties in cancer cells using defined factors. We retrovirally introduced a set of defined factors (OCT3/4, SOX2 and KLF4 into human colon cancer cells, followed by culture with conventional serum-containing medium, not human embryonic stem cell medium. We then evaluated the CSC properties in the cells. The colon cancer cells transduced with the three factors showed significantly enhanced CSC properties in terms of the marker gene expression, sphere formation, chemoresistance and tumorigenicity. We designated the cells with CSC properties induced by the factors, a subset of the transduced cells, as induced CSCs (iCSCs. Moreover, we established a novel technology to isolate and collect the iCSCs based on the differences in the degree of the dye-effluxing activity enhancement. The xenografts derived from our iCSCs were not teratomas. Notably, in contrast to the tumors from the parental cancer cells, the iCSC-based tumors mimicked actual human colon cancer tissues in terms of their immunohistological findings, which showed colonic lineage differentiation. In addition, we confirmed that the phenotypes of our iCSCs were reproducible in serial transplantation experiments. By introducing defined factors, we generated iCSCs with lineage specificity directly from cancer cells, not via an induced pluripotent stem cell state. The novel method enables us to obtain abundant materials of CSCs that not only have enhanced tumorigenicity, but also the ability to differentiate to recapitulate a specific type of cancer tissues. Our method can be of great value to fully understand CSCs and develop new therapies targeting CSCs.

Cell phones and cancer

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

Fast track diagnosis as a means of reducing diagnostic delay in cancer

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Larsen, Mette Bach; Vedsted, Peter; Olesen, Frede

of cancer and expanded services to the general practitioners. Objective: To investigate the diagnostic delay of cancer, patient and provider satisfaction and health economic aspects in two Danish regions with special emphasis on the possible benefits of fast track diagnosis. Methods: The study......Background: Denmark has the highest morbidity and mortality from cancer in Western Europe, and studies suggest that Danish cancer patients are diagnosed at a later stage than patients in the other Nordic countries. To address this issue a Danish hospital has introduced fast track diagnosis...... will be designed as a cross-sectional study with the construction of a clinical database of all incident cancers in two Danish regions within a year (12,000 patients). Data will be collected from general practitioners, patients and national registers. In the first part of the analysis the general variation...

Early versus delayed hormonal treatment in locally advanced or asymptomatic metastatic prostatic cancer patient dilemma.

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Prezioso, Domenico; Iacono, Fabrizio; Romeo, Giuseppe; Ruffo, Antonio; Russo, Nicola; Illiano, Ester

2014-06-01

The objective of this work is to compare the effectiveness of hormonal treatment (luteinizing hormone-releasing hormone agonists and/or antiandrogens) as an early or as a deferred intervention for patients with locally advanced prostate cancer (LAPC) and/or asymptomatic metastasis. Systematic review of trials published in 1950-2007. Sources included MEDLINE and bibliographies of retrieved articles. Eligible trials included adults with a history of LAPC who are not suitable for curative local treatment of prostate cancer. We retrieved 22 articles for detailed review, of which 8 met inclusion criteria. The Veterans Administration Cooperative Urological Research Group suggested that delaying hormonal therapy did not compromise overall survival and that many of the patients died of causes other than prostate cancer. In European Organisation for Research and Treatment of Cancer (EORTC) 30846 trial, the median survival for delayed endocrine treatment was 6.1 year, and for immediate treatment 7.6 year, the HR for survival on delayed versus immediate treatment was 1.23 (95 % CI 0.88-1.71), indicating a 23 % nonsignificant trend in favour of early treatment. In EORTC 30891, the immediate androgen deprivation resulted in a modest but statistically significant increase in overall survival. The protocol SAKK 08/88 showed the lack of any major advantage of immediate compared with deferred hormonal treatment regarding quality of life or overall survival. The early intervention with hormonal treatment for patients with LAPC provides important reductions in all-cause mortality, prostate cancer-specific mortality, overall progression, and distant progression compared with deferring their use until standard care has failed to halt the disease.

Mechanistic Exploration of Cancer Stem Cell Marker Voltage-Dependent Calcium Channel α2δ1 Subunit-mediated Chemotherapy Resistance in Small-Cell Lung Cancer.

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Yu, Jiangyong; Wang, Shuhang; Zhao, Wei; Duan, Jianchun; Wang, Zhijie; Chen, Hanxiao; Tian, Yanhua; Wang, Di; Zhao, Jun; An, Tongtong; Bai, Hua; Wu, Meina; Wang, Jie

2018-05-01

Purpose: Chemoresistance in small-cell lung cancer (SCLC) is reportedly attributed to the existence of resistant cancer stem cells (CSC). Studies involving CSC-specific markers and related mechanisms in SCLC remain limited. This study explored the role of the voltage-dependent calcium channel α2δ1 subunit as a CSC marker in chemoresistance of SCLC, and explored the potential mechanisms of α2δ1-mediated chemoresistance and strategies of overcoming the resistance. Experimental Design: α2δ1-positive cells were identified and isolated from SCLC cell lines and patient-derived xenograft (PDX) models, and CSC-like properties were subsequently verified. Transcriptome sequencing and Western blotting were carried out to identify pathways involved in α2δ1-mediated chemoresistance in SCLC. In addition, possible interventions to overcome α2δ1-mediated chemoresistance were examined. Results: Different proportions of α2δ1 + cells were identified in SCLC cell lines and PDX models. α2δ1 + cells exhibited CSC-like properties (self-renewal, tumorigenic, differentiation potential, and high expression of genes related to CSCs and drug resistance). Chemotherapy induced the enrichment of α2δ1 + cells instead of CD133 + cells in PDXs, and an increased proportion of α2δ1 + cells corresponded to increased chemoresistance. Activation and overexpression of ERK in the α2δ1-positive H1048 cell line was identified at the protein level. mAb 1B50-1 was observed to improve the efficacy of chemotherapy and delay relapse as maintenance therapy in PDX models. Conclusions: SCLC cells expressing α2δ1 demonstrated CSC-like properties, and may contribute to chemoresistance. ERK may play a key role in α2δ1-mediated chemoresistance. mAb 1B50-1 may serve as a potential anti-SCLC drug. Clin Cancer Res; 24(9); 2148-58. ©2018 AACR . ©2018 American Association for Cancer Research.

PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53

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Zandi, Roza; Selivanova, Galina; Christensen, Camilla Laulund

2011-01-01

Small cell lung cancer (SCLC) is a highly malignant disease with poor prognosis, necessitating the need to develop new and efficient treatment modalities. PRIMA-1(Met) (p53-dependent reactivation of massive apoptosis), also known as APR-246, is a small molecule, which restores tumor suppressor...... function to mutant p53 and induces cancer cell death in various cancer types. Since p53 is mutated in more than 90% of SCLC, we investigated the ability of PRIMA-1(Met) to induce apoptosis and inhibit tumor growth in SCLC with different p53 mutations....

Patient Related Factors Associated with Delayed Reporting in Oral Cavity and Oropharyngeal Cancer

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Mohammad Akram

2014-01-01

Conclusions: The results of this study provide guidance towards interventions to reduce patient delay. Interventions should target the rural, older age group and lower socioeconomic population for educating them and to change their psychosocial behavior for oral and oropharyngeal cancer.

Cancer stem cell markers in common cancers - therapeutic implications

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Klonisch, Thomas; Wiechec, Emilia; Hombach-Klonisch, Sabine

2008-01-01

Rapid advance in the cancer stem cell field warrants optimism for the development of more reliable cancer therapies within the next 2-3 decades. Below, we characterize and compare the specific markers that are present on stem cells, cancer cells and cancer stem cells (CSC) in selected tissues...

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

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Mierke, Claudia T.

There exist many reviews on the biological and biochemical interactions of cancer cells and endothelial cells during the transmigration and tissue invasion of cancer cells. For the malignant progression of cancer, the ability to metastasize is a prerequisite. In particular, this means that certain cancer cells possess the property to migrate through the endothelial lining into blood or lymph vessels, and are possibly able to transmigrate through the endothelial lining into the connective tissue and follow up their invasion path in the targeted tissue. On the molecular and biochemical level the transmigration and invasion steps are well-defined, but these signal transduction pathways are not yet clear and less understood in regards to the biophysical aspects of these processes. To functionally characterize the malignant transformation of neoplasms and subsequently reveal the underlying pathway(s) and cellular properties, which help cancer cells to facilitate cancer progression, the biomechanical properties of cancer cells and their microenvironment come into focus in the physics-of-cancer driven view on the metastasis process of cancers. Hallmarks for cancer progression have been proposed, but they still lack the inclusion of specific biomechanical properties of cancer cells and interacting surrounding endothelial cells of blood or lymph vessels. As a cancer cell is embedded in a special environment, the mechanical properties of the extracellular matrix also cannot be neglected. Therefore, in this review it is proposed that a novel hallmark of cancer that is still elusive in classical tumor biological reviews should be included, dealing with the aspect of physics in cancer disease such as the natural selection of an aggressive (highly invasive) subtype of cancer cells displaying a certain adhesion or chemokine receptor on their cell surface. Today, the physical aspects can be analyzed by using state-of-the-art biophysical methods. Thus, this review will present

A Small Molecule Polyamine Oxidase Inhibitor Blocks Androgen-Induced Oxidative Stress and Delays Prostate Cancer Progression in the TRAMP Mouse Model

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Basu, Hirak S.; Thompson, Todd A.; Church, Dawn R.; Clower, Cynthia C.; Mehraein-Ghomi, Farideh; Amlong, Corey A.; Martin, Christopher T.; Woster, Patrick M.; Lindstrom, Mary J.; Wilding, George

2009-01-01

High levels of reactive oxygen species (ROS) present in human prostate epithelia are an important etiological factor in prostate cancer (CaP) occurrence, recurrence and progression. Androgen induces ROS production in the prostate by a yet unknown mechanism. Here, to the best of our knowledge, we report for the first time that androgen induces an overexpression of spermidine/spermine N1-acetyltransferase (SSAT), the rate-limiting enzyme in the polyamine oxidation pathway. As prostatic epithelia produce a large excess of polyamines, the androgen-induced polyamine oxidation that produces H2O2 could be a major reason for the high ROS levels in the prostate epithelia. A small molecule polyamine oxidase inhibitor N,N'-butanedienyl butanediamine (MDL 72,527 or CPC-200) effectively blocks androgen-induced ROS production in human CaP cells as well as significantly delays CaP progression and death in animals developing spontaneous CaP. These data demonstrate that polyamine oxidation is not only a major pathway for ROS production in prostate, but inhibiting this pathway also successfully delays prostate cancer progression. PMID:19773450

Targeting cancer cells using 3-bromopyruvate for selective cancer treatment

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Hussam H Baghdadi

2017-01-01

Full Text Available Cancer treatment deserves more research efforts despite intensive conventional treatment modalities for many types of malignancies. Metastasis and resistance to chemotherapy and radiotherapy receive a lot of global research efforts. The current advances in cancer biology may improve targeting the critical metabolic differences that distinguish cancer cells from normal cells. Cancer cells are highly glycolytic for energy production, exhibit the Warburg effect, establish aggressive acidic microenvironment, maintain cancer stem cells, exhibit resistance to chemotherapy, have low antioxidant systems but different ΔΨm (delta psi, mitochondrial transmembrane potential, express P-glycoprotein for multidrug resistance, upregulate glucose transporters and monocarboxylate transporters and are under high steady-state reactive oxygen species conditions. Normal cells differ in all these aspects. Lactate produced through the Warburg effect helps cancer metastasis. Targeting glycolysis reactions for energy production in cancer cells seems promising in decreasing the proliferation and metastasis of cancer cells. 3-bromopyruvate makes use of cancer biology in treating cancer cells, cancer stem cells and preventing metastasis in human cancer as discussed in this review. Updated advances are analyzed here, which include research analysis of background, experience, readings in the field of cancer biology, oncology and biochemistry.

Barriers and Explanatory Mechanisms of Delays in the Patient and Diagnosis Intervals of Care for Breast Cancer in Mexico.

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Unger-Saldaña, Karla; Ventosa-Santaulària, Daniel; Miranda, Alfonso; Verduzco-Bustos, Guillermo

2018-04-01

Most breast cancer patients in low- and middle-income settings are diagnosed at advanced stages due to lengthy intervals of care. This study aimed to understand the mechanisms through which delays occur in the patient interval and diagnosis interval of care. We conducted a cross-sectional survey including 886 patients referred to four major public cancer hospitals in Mexico City. Based in a conceptual model of help-seeking behavior, a path analysis strategy was used to identify the relationships between explanatory factors of patient delay and diagnosis delay. The patient and the diagnosis intervals were greater than 3 months in 20% and 65% of participants, respectively. We present explanatory models for each interval and the interrelationship between the associated factors. The patient interval was longer among women who were single, interpreted their symptoms as not worrisome, concealed symptoms, and perceived a lack of financial resources and the difficulty of missing a day of work as barriers to seek care. These barriers were more commonly perceived among patients who were younger, had lower socioeconomic status, and lived outside of Mexico City. The diagnosis interval was longer among those who used several different health services prior to the cancer hospital and perceived medical errors in these services. More health services were used among those who perceived errors and long waiting times for appointments, and who first consulted private services. Our findings support the relevance of strengthening early cancer diagnosis strategies, especially the improvement of quality of primary care and expedited referral routes to cancer services. This study's findings suggest that policy in low- and middle-income countries (LMICs) should be directed toward reducing delays in diagnosis, before the implementation of mammography screening programs. The results suggest several factors susceptible to early diagnosis interventions. To reduce patient delays, the usually

Influence of the circadian rhythm in cell division on radiation-induced mitotic delay in vivo

International Nuclear Information System (INIS)

Rubin, N.A.

1980-01-01

All mitotically active normal tissues in mammals investigated to date demonstrate a circadian rhythm in cell division. The murine corneal epithelium is a practical and advantageous tissue model for studying this phenomenon. In animals synchronized to a light-dark (LD) schedule, one sees predictably reproducible occurrences of peaks and troughs in the mitotic index (MI) within each 24-hour (h) period. One of the harmful effects of ionizing radiation on dividing cells is mitotic delay, reported to be a G 2 block in cells approaching mitosis. Affected cells are not killed but are inhibited from entering mitosis and are delayed for a span of time reported to be dose and cell cycle dependent. In the classical description of mitotic delay, MI of irradiated cells begins to drop in relation to the control, which is plotted as a straight line, uniform throughout the experiment. After the damage is repaired, delayed cells can enter mitosis along with other cells in the pool unaffected by the radiation, resulting in a MI higher than control levels. The span of delay and the occurrence of recovery are assumed to be constant for a given dose and tissue under similar experimental conditions. First described in asynchronously-dividing tissue culture cells, this concept is also extrapolated to the in vivo situation

Cancer stem cells and differentiation therapy.

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Jin, Xiong; Jin, Xun; Kim, Hyunggee

2017-10-01

Cancer stem cells can generate tumors from only a small number of cells, whereas differentiated cancer cells cannot. The prominent feature of cancer stem cells is its ability to self-renew and differentiate into multiple types of cancer cells. Cancer stem cells have several distinct tumorigenic abilities, including stem cell signal transduction, tumorigenicity, metastasis, and resistance to anticancer drugs, which are regulated by genetic or epigenetic changes. Like normal adult stem cells involved in various developmental processes and tissue homeostasis, cancer stem cells maintain their self-renewal capacity by activating multiple stem cell signaling pathways and inhibiting differentiation signaling pathways during cancer initiation and progression. Recently, many studies have focused on targeting cancer stem cells to eradicate malignancies by regulating stem cell signaling pathways, and products of some of these strategies are in preclinical and clinical trials. In this review, we describe the crucial features of cancer stem cells related to tumor relapse and drug resistance, as well as the new therapeutic strategy to target cancer stem cells named "differentiation therapy."

Effect of dihydroartemisinin on the cell cycle progress of irradiated human cervical cancer cell line and its mechanism

International Nuclear Information System (INIS)

Chen Xialin; Ji Rong; Cao Jianping; Zhu Wei; Fan Sanjun; Wang Jianfang; Cao Jianping

2010-01-01

Objective: To observe the changes of cell cycle on cancer cells after dihydroartemisinin and X-ray irradiation. Methods: Human HeLa cells of cervical cancer with p53 mutation was used and human SiHa cells of cervical cancer with wild p53 was used as control. Flow cytometry was used to detect the effect of dihydroartemisinin (20 and 100 μmol/L) and irradiation (6 Gy)on cell cycle. Western blot was used to measure the levels of cell cycle protein. Results: G 2 arrest was observed in irradiated HeLa cells, which the proportion of cells in G 2 phase was increased from 14.45% to 73.58% after 6 Gy X-ray irradiation, but it was abrogated by dihydroartemisinin from 73. 58% to 48.31% in HeLa cells, and it had no change on the SiHa cells. The elevated Wee1 protein and the lowered Cyclin B1 protein were observed with the G 2 arrest severity. The expression of radiation-induced Wee1 protein was suppressed and the Cyclin B1 protein was increased after dihydroartemisinin treatment, which was in accordance with the abrogation of radiation-induced G 2 delay. Conclusions: The main effect of irradiation on cell cycle of p53 mutated HeLa cells is G 2 arrest. Dihydroartemisinin could abrogate it, which is associated with the changes of Wee1 protein and Cyclin B1 protein. In Siha cells, the main effect of irradiation on cell cycle is G 1 arrest, and dihydroartemisinin has no effect on it. (authors)

Lung cancer - non-small cell

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Cancer - lung - non-small cell; Non-small cell lung cancer; NSCLC; Adenocarcinoma - lung; Squamous cell carcinoma - lung ... Research shows that smoking marijuana may help cancer cells grow. But there is no direct link between ...

Time delay and noise explaining the behaviour of the cell growth in fermentation process

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Ayuobi, Tawfiqullah; Rosli, Norhayati [Faculty of Industrial Sciences and Technology, Universiti Malaysia Pahang, Lebuhraya Tun Razak, 26300 Gambang, Pahang (Malaysia); Bahar, Arifah [Department of Mathematical Sciences, Faculty of Science, Universiti Teknologi Malaysia, 81310 Johor Bahru, Johor (Malaysia); Salleh, Madihah Md [Department of Biotechnology Industry, Faculty of Biosciences and Bioengineering, Universiti Teknologi Malaysia, 81310 Johor Bahru, Johor (Malaysia)

2015-02-03

This paper proposes to investigate the interplay between time delay and external noise in explaining the behaviour of the microbial growth in batch fermentation process. Time delay and noise are modelled jointly via stochastic delay differential equations (SDDEs). The typical behaviour of cell concentration in batch fermentation process under this model is investigated. Milstein scheme is applied for solving this model numerically. Simulation results illustrate the effects of time delay and external noise in explaining the lag and stationary phases, respectively for the cell growth of fermentation process.

Time delay and noise explaining the behaviour of the cell growth in fermentation process

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Ayuobi, Tawfiqullah; Rosli, Norhayati; Bahar, Arifah; Salleh, Madihah Md

2015-02-01

This paper proposes to investigate the interplay between time delay and external noise in explaining the behaviour of the microbial growth in batch fermentation process. Time delay and noise are modelled jointly via stochastic delay differential equations (SDDEs). The typical behaviour of cell concentration in batch fermentation process under this model is investigated. Milstein scheme is applied for solving this model numerically. Simulation results illustrate the effects of time delay and external noise in explaining the lag and stationary phases, respectively for the cell growth of fermentation process.

Time delay and noise explaining the behaviour of the cell growth in fermentation process

International Nuclear Information System (INIS)

Ayuobi, Tawfiqullah; Rosli, Norhayati; Bahar, Arifah; Salleh, Madihah Md

2015-01-01

This paper proposes to investigate the interplay between time delay and external noise in explaining the behaviour of the microbial growth in batch fermentation process. Time delay and noise are modelled jointly via stochastic delay differential equations (SDDEs). The typical behaviour of cell concentration in batch fermentation process under this model is investigated. Milstein scheme is applied for solving this model numerically. Simulation results illustrate the effects of time delay and external noise in explaining the lag and stationary phases, respectively for the cell growth of fermentation process

Factors affecting presentation and delay in patients with testicular cancer: results of a qualitative study.

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Gascoigne, P; Mason, M D; Roberts, E

1999-01-01

A qualitative study was undertaken with men treated for testicular tumours, to ascertain how they interpreted their symptoms and the factors which influenced a decision to consult a physician. The research was undertaken with six men who had been diagnosed as having testicular tumours. Interviews were also conducted with four wives and one mother. The findings showed that giving men information on testicular cancer may not guarantee early presentation. Symptoms were not generally attributed to cancer and the one patient who practised self-examination had delayed seeking help for 6 months. The extent to which symptoms affected the patient's lifestyle was also a factor in the decision-making process, as was the checking of symptoms with other family members. Wives were often pivotal in persuading men to seek help. The discovery of testicular symptoms produced emotional responses which included embarrassment and fear of both cancer and castration. There was evidence of strong feelings of masculine identity bound up with the appearance of 'normal' genitals. Provider-delay was identified in four cases and was associated with misattribution of symptoms by physicians and the failure to initiate specialist referral. Delay was under-recorded in the hospital notes in all cases where presentation was not immediate.

Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides

International Nuclear Information System (INIS)

Otto, Christoph; Kaemmerer, Ulrike; Illert, Bertram; Muehling, Bettina; Pfetzer, Nadja; Wittig, Rainer; Voelker, Hans Ullrich; Thiede, Arnulf; Coy, Johannes F

2008-01-01

Among the most prominent metabolic alterations in cancer cells are the increase in glucose consumption and the conversion of glucose to lactic acid via the reduction of pyruvate even in the presence of oxygen. This phenomenon, known as aerobic glycolysis or the Warburg effect, may provide a rationale for therapeutic strategies that inhibit tumour growth by administration of a ketogenic diet with average protein but low in carbohydrates and high in fat enriched with omega-3 fatty acids and medium-chain triglycerides (MCT). Twenty-four female NMRI nude mice were injected subcutaneously with tumour cells of the gastric adenocarcinoma cell line 23132/87. The animals were then randomly split into two feeding groups and fed either a ketogenic diet (KD group; n = 12) or a standard diet (SD group; n = 12) ad libitum. Experiments were ended upon attainment of the target tumor volume of 600 mm 3 to 700 mm 3 . The two diets were compared based on tumour growth and survival time (interval between tumour cell injection and attainment of target tumour volume). The ketogenic diet was well accepted by the KD mice. The tumour growth in the KD group was significantly delayed compared to that in the SD group. Tumours in the KD group reached the target tumour volume at 34.2 ± 8.5 days versus only 23.3 ± 3.9 days in the SD group. After day 20, tumours in the KD group grew faster although the differences in mean tumour growth continued significantly. Importantly, they revealed significantly larger necrotic areas than tumours of the SD group and the areas with vital tumour cells appear to have had fewer vessels than tumours of the SD group. Viable tumour cells in the border zone surrounding the necrotic areas of tumours of both groups exhibited a glycolytic phenotype with expression of glucose transporter-1 and transketolase-like 1 enzyme. Application of an unrestricted ketogenic diet enriched with omega-3 fatty acids and MCT delayed tumour growth in a mouse xenograft model. Further

Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides

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Voelker Hans

2008-04-01

Full Text Available Abstract Background Among the most prominent metabolic alterations in cancer cells are the increase in glucose consumption and the conversion of glucose to lactic acid via the reduction of pyruvate even in the presence of oxygen. This phenomenon, known as aerobic glycolysis or the Warburg effect, may provide a rationale for therapeutic strategies that inhibit tumour growth by administration of a ketogenic diet with average protein but low in carbohydrates and high in fat enriched with omega-3 fatty acids and medium-chain triglycerides (MCT. Methods Twenty-four female NMRI nude mice were injected subcutaneously with tumour cells of the gastric adenocarcinoma cell line 23132/87. The animals were then randomly split into two feeding groups and fed either a ketogenic diet (KD group; n = 12 or a standard diet (SD group; n = 12 ad libitum. Experiments were ended upon attainment of the target tumor volume of 600 mm3 to 700 mm3. The two diets were compared based on tumour growth and survival time (interval between tumour cell injection and attainment of target tumour volume. Results The ketogenic diet was well accepted by the KD mice. The tumour growth in the KD group was significantly delayed compared to that in the SD group. Tumours in the KD group reached the target tumour volume at 34.2 ± 8.5 days versus only 23.3 ± 3.9 days in the SD group. After day 20, tumours in the KD group grew faster although the differences in mean tumour growth continued significantly. Importantly, they revealed significantly larger necrotic areas than tumours of the SD group and the areas with vital tumour cells appear to have had fewer vessels than tumours of the SD group. Viable tumour cells in the border zone surrounding the necrotic areas of tumours of both groups exhibited a glycolytic phenotype with expression of glucose transporter-1 and transketolase-like 1 enzyme. Conclusion Application of an unrestricted ketogenic diet enriched with omega-3 fatty acids and MCT

Understanding delayed T-cell priming, lung recruitment, and airway luminal T-cell responses in host defense against pulmonary tuberculosis.

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Shaler, Christopher R; Horvath, Carly; Lai, Rocky; Xing, Zhou

2012-01-01

Mycobacterium tuberculosis (M.tb), the causative bacterium of pulmonary tuberculosis (TB), is a serious global health concern. Central to M.tb effective immune avoidance is its ability to modulate the early innate inflammatory response and prevent the establishment of adaptive T-cell immunity for nearly three weeks. When compared with other intracellular bacterial lung pathogens, such as Legionella pneumophila, or even closely related mycobacterial species such as M. smegmatis, this delay is astonishing. Customarily, the alveolar macrophage (AM) acts as a sentinel, detecting and alerting surrounding cells to the presence of an invader. However, in the case of M.tb, this may be impaired, thus delaying the recruitment of antigen-presenting cells (APCs) to the lung. Upon uptake by APC populations, M.tb is able to subvert and delay the processing of antigen, MHC class II loading, and the priming of effector T cell populations. This delay ultimately results in the deferred recruitment of effector T cells to not only the lung interstitium but also the airway lumen. Therefore, it is of upmost importance to dissect the mechanisms that contribute to the delayed onset of immune responses following M.tb infection. Such knowledge will help design the most effective vaccination strategies against pulmonary TB.

Expression of metastasis suppressor BRMS1 in breast cancer cells results in a marked delay in cellular adhesion to matrix.

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Khotskaya, Yekaterina B; Beck, Benjamin H; Hurst, Douglas R; Han, Zhenbo; Xia, Weiya; Hung, Mien-Chie; Welch, Danny R

2014-12-01

Metastatic dissemination is a multi-step process that depends on cancer cells' ability to respond to microenvironmental cues by adapting adhesion abilities and undergoing cytoskeletal rearrangement. Breast Cancer Metastasis Suppressor 1 (BRMS1) affects several steps of the metastatic cascade: it decreases survival in circulation, increases susceptibility to anoikis, and reduces capacity to colonize secondary organs. In this report, BRMS1 expression is shown to not significantly alter expression levels of integrin monomers, while time-lapse and confocal microscopy revealed that BRMS1-expressing cells exhibited reduced activation of both β1 integrin and focal adhesion kinase, and decreased localization of these molecules to sites of focal adhesions. Short-term plating of BRMS1-expressing cells onto collagen or fibronectin markedly decreased cytoskeletal reorganization and formation of cellular adhesion projections. Under 3D culture conditions, BRMS1-expressing cells remained rounded and failed to reorganize their cytoskeleton and form invasive colonies. Taken together, BRMS1-expressing breast cancer cells are greatly attenuated in their ability to respond to microenvironment changes. © 2013 Wiley Periodicals, Inc. © 2013 Wiley Periodicals, Inc.

The Consequence of Delayed Fixation on Subsequent Preservation of Urine Cells

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Hussain G. Ahmed,

2011-01-01

Full Text Available Objectives: Degenerative changes caused by delays in urine preservation contribute to false-negative and false-positive interpretation of urothelial disease in cytology. The aim of this study is to assess whether the delay of fixation of urine samples makes any significant difference to urine cytology and morphology, and the limit of acceptability of delay for routine use in the hospital laboratory.Methods: Three cell collection fluids were evaluated by analyzing the preservation and degeneration of cells in urine samples. In this study, 50 voided urine specimens were taken at random from females complaining of vaginal discharge. Each specimen was divided into three sterile containers. The first was immediately centrifugated and the deposit was smeared onto a cleaned micro slide and immediately fixed into 95�0ethyl alcohol for 15 minutes. The remaining two were prepared in the same manner, however, the second after two hours of collection and the third after four hours of collection. The degree of degeneration and thus the preservation were assessed by a table of chosen criteria, then ranked and analyzed using Friedman's nonparametric test, atp=0.05.Results: The results showed a significant difference between the preservation and the delay in urine fixation, p<0.0001.Conclusion: Any delay in fixation of urine specimen for cytology affects the preservation of cells, which may result in miss diagnosis. It is recommended that urine samples for cytology should be fixed immediately after collection.

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

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

2016-01-01

Cancer stem cells (CSCs) play vital role in lung cancer progression, resistance, metastasis and relapse. Identifying lung CSCs makers for lung CSCs targeting researches are critical for lung cancer therapy. In this study, utilizing previous identified lung CSCs as model, we compared the expression of CD24, CD133 and CD44 between CSCs and non-stem cancer cells. Increased ratio of CD24- cells were found in CSCs. CD24- cells were then sorted by flow cytometry and their proliferative ability, chemo-resistance property and in vivo tumor formation abilities were detected. A549 CD24- cells formed smaller colonies, slower proliferated in comparison to A549 CD24+ cells. Besides, A549 CD24- exhibited stronger resistance to chemotherapy drug. However, A549 CD24- didn't exert any stronger tumor formation ability in vivo, which is the gold standard of CSCs. These results showed that CD24- A549 cells showed some properties of CSCs but not actually CSCs. This study provides evidence that CD24 cannot be considered as lung CSCs marker.

Mechanisms of therapeutic resistance in cancer (stem cells with emphasis on thyroid cancer cells.

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Sabine eHombach-Klonisch

2014-03-01

Full Text Available Tissue invasion, metastasis and therapeutic resistance to anti-cancer treatments are common and main causes of death in cancer patients. Tumor cells mount complex and still poorly understood molecular defense mechanisms to counteract and evade oxygen deprivation, nutritional restrictions as well as radio- and chemotherapeutic treatment regimens aimed at destabilizing their genomes and important cellular processes. In thyroid cancer, as in other tumors, such defense strategies include the reactivation in cancer cells of early developmental programs normally active exclusively in stem cells, the stimulation of cancer stem-like cells resident within the tumor tissue and the recruitment of bone marrow-derived progenitors into the tumor (Thomas et al., 2008;Klonisch et al., 2009;Derwahl, 2011. Metastasis and therapeutic resistance in cancer (stem cells involves the epithelial-to-mesenchymal transition- (EMT- mediated enhancement in cellular plasticity, which includes coordinated dynamic biochemical and nuclear changes (Ahmed et al., 2010. The purpose of the present review is to provide an overview of the role of DNA repair mechanisms contributing to therapeutic resistance in thyroid cancer and highlight the emerging roles of autophagy and damage associated molecular pattern (DAMP responses in EMT and chemoresistance in tumor cells. Finally, we use the stem cell factor and nucleoprotein High Mobility Group A2 (HMGA2 as an example to demonstrate how factors intended to protect stem cells are wielded by cancer (stem cells to gain increased transformative cell plasticity which enhances metastasis, therapeutic resistance and cell survival. Wherever possible, we have included information on these cellular processes and associated factors as they relate to thyroid cancer cells.

Predictors of delay in starting radiation treatment for patients with early stage breast cancer

International Nuclear Information System (INIS)

Benk, Veronique; Ho, Vivian; Fortin, Paul R.; Zhang, G.; Levinton, Carey; Freeman, C.R.

1998-01-01

Purpose: To describe the factors predicting waiting time for radiation treatment in early breast cancer. Materials and Methods: Between January 1992 and December 1993, 739 patients with Stage I and II breast cancer were treated with conservative treatment at three McGill University Hospitals. Waiting time was defined as the interval between the date of surgery and the date of the first radiation treatment. Delay was defined as a waiting time of more than 7 weeks for women who did not receive chemotherapy (Group NC, n 478), and as a waiting time of more than 24 weeks for those who received chemotherapy (Group C, n = 261). We analyzed predictive factors related to the patient (age, stage, treatment on protocol, income by postal code) and to the referring hospital (university or community hospital). Results: For the entire population, 54% of patients were delayed, 72% in Group NC and 21.4% in Group C. Univariate analysis showed an impact of referring hospital in both groups, and of stage and treatment on protocol in Group C (all p = 0.001). Multivariate analysis showed that delays were significantly less in Group NC for women referred from a community hospital (p = 0.001) and in Group C for women with Stage I disease (p = 0.06), those treated on protocol, and those referred from a university hospital (p = 0.001). Conclusion: More than half of patients with early breast cancer waited more than the recommended intervals for radiation therapy. However, lower income breast cancer patients did not wait longer for treatment than higher income patients, possibly a result of the Canadian Medicare system which provides universal access to health care

Peers without fears? Barriers to effective communication among primary care physicians and oncologists about diagnostic delays in cancer.

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Lipitz-Snyderman, Allison; Kale, Minal; Robbins, Laura; Pfister, David; Fortier, Elizabeth; Pocus, Valerie; Chimonas, Susan; Weingart, Saul N

2017-11-01

Relatively little attention has been devoted to the role of communication between physicians as a mechanism for individual and organisational learning about diagnostic delays. This study's objective was to elicit physicians' perceptions about and experiences with communication among physicians regarding diagnostic delays in cancer. Qualitative analysis based on seven focus groups. Fifty-one physicians affiliated with three New York-based academic medical centres participated, with six to nine subjects per group. We used content analysis to identify commonalities among primary care physicians and specialists (ie, medical and surgical oncologists). Perceptions and experiences with physician-to-physician communication about delays in cancer diagnosis. Our analysis identified five major themes: openness to communication, benefits of communication, fears about giving and receiving feedback, infrastructure barriers to communication and overcoming barriers to communication. Subjects valued communication about cancer diagnostic delays, but they had many concerns and fears about providing and receiving feedback in practice. Subjects expressed reluctance to communicate if there was insufficient information to attribute responsibility, if it would have no direct benefit or if it would jeopardise their existing relationships. They supported sensitive approaches to conveying information, as they feared eliciting or being subject to feelings of incompetence or shame. Subjects also cited organisational barriers. They offered suggestions that might facilitate communication about delays. Addressing the barriers to communication among physicians about diagnostic delays is needed to promote a culture of learning across specialties and institutions. Supporting open and honest discussions about diagnostic delays may help build safer health systems. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use

Tumor-Initiating Label-Retaining Cancer Cells in Human Gastrointestinal Cancers Undergo Asymmetric Cell Division

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Xin, Hong-Wu; Hari, Danielle M.; Mullinax, John E.; Ambe, Chenwi M.; Koizumi, Tomotake; Ray, Satyajit; Anderson, Andrew J.; Wiegand, Gordon W.; Garfield, Susan H.; Thorgeirsson, Snorri S.; Avital, Itzhak

2012-01-01

Label-retaining cells (LRCs) have been proposed to represent adult tissue stem cells. LRCs are hypothesized to result from either slow cycling or asymmetric cell division (ACD). However, the stem cell nature and whether LRC undergo ACD remain controversial. Here, we demonstrate label-retaining cancer cells (LRCCs) in several gastrointestinal (GI) cancers including fresh surgical specimens. Using a novel method for isolation of live LRCC, we demonstrate that a subpopulation of LRCC is actively dividing and exhibits stem cells and pluripotency gene expression profiles. Using real-time confocal microscopic cinematography, we show live LRCC undergoing asymmetric nonrandom chromosomal cosegregation LRC division. Importantly, LRCCs have greater tumor-initiating capacity than non-LRCCs. Based on our data and that cancers develop in tissues that harbor normal-LRC, we propose that LRCC might represent a novel population of GI stem-like cancer cells. LRCC may provide novel mechanistic insights into the biology of cancer and regenerative medicine and present novel targets for cancer treatment. PMID:22331764

Factors influencing delay in the diagnosis of colorectal cancer: a study protocol

International Nuclear Information System (INIS)

Esteva, Magdalena; Ramos, Maria; Cabeza, Elena; Llobera, Joan; Ruiz, Amador; Pita, Salvador; Segura, Josep M; Cortés, Jose M; González-Lujan, Luis

2007-01-01

Colorectal cancer (CRC) is the second most frequent tumor in developed countries. Since survival from CRC depends mostly on disease stage at the time of diagnosis, individuals with symptoms or signs suspicious of CRC should be examined without delay. Many factors, however, intervene between symptom onset and diagnosis. This study was designed to: 1) Describe the diagnostic process of CRC from the onset of first symptoms to diagnosis and treatment. 2) Establish the time interval from initial symptoms to diagnosis and treatment, globally and considering patient's and doctors' delay, with the latter due to family physician and/or hospital services. 3) Identify the factors related to defined types of delay. 4) Assess the concordance between information included in primary health care and hospital clinical records regarding onset of first symptoms. Descriptive study, coordinated, with 5 participant groups of 5 different Spanish regions (Balearic Islands, Galicia, Catalunya, Aragón and Valencia Health Districts), with a total of 8 acute public hospitals and 140 primary care centers. Incident cases of CRC during the study period, as identified from pathology services at the involved hospitals. A sample size of 896 subjects has been estimated, 150 subjects for each participant group. Information will be collected through patient interviews and primary health care and hospital clinical records. Patient variables will include sociodemographic variables, family history of cancer, symptom perception, and confidence in the family physician; tumor variables will include tumor site, histological type, grade and stage; symptom variables will include date of onset, type and number of symptoms; health system variables will include number of patient contacts with family physician, type and content of the referral, hospital services attending the patient, diagnostic modalities and results; and delay intervals, including global delays and delays attributed to the patient

Replication and virus-induced transcriptome of HAdV-5 in normal host cells versus cancer cells--differences of relevance for adenoviral oncolysis.

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Dominik E Dorer

Full Text Available Adenoviruses (Ads, especially HAdV-5, have been genetically equipped with tumor-restricted replication potential to enable applications in oncolytic cancer therapy. Such oncolytic adenoviruses have been well tolerated in cancer patients, but their anti-tumor efficacy needs to be enhanced. In this regard, it should be considered that cancer cells, dependent on their tissue of origin, can differ substantially from the normal host cells to which Ads are adapted by complex virus-host interactions. Consequently, viral replication efficiency, a key determinant of oncolytic activity, might be suboptimal in cancer cells. Therefore, we have analyzed both the replication kinetics of HAdV-5 and the virus-induced transcriptome in human bronchial epithelial cells (HBEC in comparison to cancer cells. This is the first report on genome-wide expression profiling of Ads in their native host cells. We found that E1A expression and onset of viral genome replication are most rapid in HBEC and considerably delayed in melanoma cells. In squamous cell lung carcinoma cells, we observed intermediate HAdV-5 replication kinetics. Infectious particle production, viral spread and lytic activity of HAdV-5 were attenuated in melanoma cells versus HBEC. Expression profiling at the onset of viral genome replication revealed that HAdV-5 induced the strongest changes in the cellular transcriptome in HBEC, followed by lung cancer and melanoma cells. We identified prominent regulation of genes involved in cell cycle and DNA metabolism, replication and packaging in HBEC, which is in accord with the necessity to induce S phase for viral replication. Strikingly, in melanoma cells HAdV-5 triggered opposing regulation of said genes and, in contrast to lung cancer cells, no weak S phase induction was detected when using the E2F promoter as reporter. Our results provide a rationale for improving oncolytic adenoviruses either by adaptation of viral infection to target tumor cells or by

Fisetin Enhances Chemotherapeutic Effect of Cabazitaxel against Human Prostate Cancer Cells.

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Mukhtar, Eiman; Adhami, Vaqar Mustafa; Siddiqui, Imtiaz Ahmad; Verma, Ajit Kumar; Mukhtar, Hasan

2016-12-01

Although treatment of prostate cancer has improved over the past several years, taxanes, such as cabazitaxel, remain the only form of effective chemotherapy that improves survival in patients with metastatic castration-resistant prostate cancer. However, the effectiveness of this class of drugs has been associated with various side effects and drug resistance. We previously reported that fisetin, a hydroxyflavone, is a microtubule-stabilizing agent and inhibits prostate cancer cell proliferation, migration, and invasion and suggested its use as an adjuvant for treatment of prostate and other cancer types. In this study, we investigated the effect of fisetin in combination with cabazitaxel with the objective to achieve maximum therapeutic benefit, reduce dose and toxicity, and minimize or delay the induction of drug resistance and metastasis. Our data show for the first time that a combination of fisetin (20 μmol/L) enhances cabazitaxel (5 nmol/L) and synergistically reduces 22Rν1, PC-3M-luc-6, and C4-2 cell viability and metastatic properties with minimal adverse effects on normal prostate epithelial cells. In addition, the combination of fisetin with cabazitaxel was associated with inhibition of proliferation and enhancement of apoptosis. Furthermore, combination treatment resulted in the inhibition of tumor growth, invasion, and metastasis when assessed in two in vivo xenograft mouse models. These results provide evidence that fisetin may have therapeutic benefit for patients with advanced prostate cancer through enhancing the efficacy of cabazitaxel under both androgen-dependent and androgen-independent conditions. This study underscores the benefit of the combination of fisetin with cabazitaxel for the treatment of advanced and resistant prostate cancer and possibly other cancer types. Mol Cancer Ther; 15(12); 2863-74. ©2016 AACR. ©2016 American Association for Cancer Research.

Local advanced transitional cell cancer and squamous cell cancer of ...

African Journals Online (AJOL)

Case report: A 51-year-old man presented with a locally advanced squamous cell cancer of the periurethral tissues as well as an underlying isolated transitional cell cancer of the urethra. Chemotherapy with Gemcitabin and Cisplatinum together with local radiation to the pelvis and the perineum was given. There was ...

Applying the Stress and ‘Strength’ Hypothesis to Black Women’s Breast Cancer Screening Delays

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Black, Angela Rose; Woods-Giscombé, Cheryl

2013-01-01

Associations between stress and breast cancer highlight stressful life events as barriers to breast cancer screening, increased stress due to a breast cancer scare or diagnosis, or the immunosuppressive properties of stress as a risk factor for breast cancer occurrence. Little is known, however, about how women’s reactions to stressful life events impact their breast health trajectory. In this study, we explore how reactions to stressors serve as a potential barrier to breast cancer screening among Black women. We apply a gender-specific, culturally responsive stress-process framework, the Stress and ‘Strength’ Hypothesis (“strength hypothesis”), to understand links between the ‘Strong Black Woman role’ role, Black women’s stress reactions and their observed screening delays. We conceptualize strength as a culturally prescribed coping style that conditions resilience, self-reliance and psychological hardiness as a survival response to race-related and gender-related stressors. Using qualitative methods, we investigate the potential for this coping mechanism to manifest as extraordinary caregiving, emotional suppression and self-care postponement. These manifestations may result in limited time for scheduling and attending screening appointments, lack of or delay in acknowledgement of breast health symptoms and low prioritization of breast care. Limitations and future directions are discussed. PMID:23129558

Cancer stem cells in head and neck cancer

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Trapasso S

2012-11-01

Full Text Available Eugenia Allegra, Serena TrapassoOtolaryngology – Head and Neck Surgery, University Magna Graecia of Catanzaro, Catanzaro, ItalyAbstract: Cancer stem cells (CSCs, also called "cells that start the tumor," represent in themselves one of the most topical and controversial issues in the field of cancer research. Tumor stem cells are able to self-propagate in vitro (self-renewal, giving rise both to other tumor stem cells and most advanced cells in the line of differentiation (asymmetric division. A final characteristic is tumorigenicity, a fundamental property, which outlines the tumor stem cell as the only cell able to initiate the formation of a tumor when implanted in immune-deficient mice. The hypothesis of a hierarchical organization of tumor cells dates back more than 40 years, but only in 1997, thanks to the work of John Dick and Dominique Bonnet, was there the formal proof of such an organization in acute myeloid leukemia. Following this, many other research groups were able to isolate CSCs, by appropriate selection markers, in various malignancies, such as breast, brain, colon, pancreas, and liver cancers and in melanoma. To date, however, it is not possible to isolate stem cells from all types of neoplasia, particularly in solid tumors. From a therapeutic point of view, the concept of tumor stem cells implies a complete revision of conventional antineoplastic treatment. Conventional cytotoxic agents are designed to target actively proliferating cells. In the majority of cases, this is not sufficient to eliminate the CSCs, which thanks to their reduced proliferative activity and/or the presence of proteins capable of extruding chemotherapeutics from the cell are not targeted. Therefore, the theory of cancer stem cells can pose new paradigms in terms of cancer treatment. Potential approaches, even in the very early experimental stages, relate to the selective inhibition of pathways connected with self-renewal, or more specifically based on

Prediction of X-ray induced mitotic delay and recovery of G2 cells

International Nuclear Information System (INIS)

Easton, D.M.; Schneiderman, M.H.

1987-01-01

A mathematical model is presented that predicts the delay of mitosis caused by X-irradiation of an asynchronous, exponentially growing cell culture. In the model, based on Gompertz kinetics, the driving function to generate the curves is a simple exponential decay expression. For the delayed mitotic progress curves, this function characterizes the distribution of the time required for cells to enter mitosis. (author)

Modeling protective anti-tumor immunity via preventative cancer vaccines using a hybrid agent-based and delay differential equation approach.

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Kim, Peter S; Lee, Peter P

2012-01-01

A next generation approach to cancer envisions developing preventative vaccinations to stimulate a person's immune cells, particularly cytotoxic T lymphocytes (CTLs), to eliminate incipient tumors before clinical detection. The purpose of our study is to quantitatively assess whether such an approach would be feasible, and if so, how many anti-cancer CTLs would have to be primed against tumor antigen to provide significant protection. To understand the relevant dynamics, we develop a two-compartment model of tumor-immune interactions at the tumor site and the draining lymph node. We model interactions at the tumor site using an agent-based model (ABM) and dynamics in the lymph node using a system of delay differential equations (DDEs). We combine the models into a hybrid ABM-DDE system and investigate dynamics over a wide range of parameters, including cell proliferation rates, tumor antigenicity, CTL recruitment times, and initial memory CTL populations. Our results indicate that an anti-cancer memory CTL pool of 3% or less can successfully eradicate a tumor population over a wide range of model parameters, implying that a vaccination approach is feasible. In addition, sensitivity analysis of our model reveals conditions that will result in rapid tumor destruction, oscillation, and polynomial rather than exponential decline in the tumor population due to tumor geometry.

Value of the post-operative CT in predicting delayed flap failures following head and neck cancer surgery

International Nuclear Information System (INIS)

Kim, Bitna; Yoon, Dae Young; Seo, Young Lan; Park, Min Woo; Kwon, Kee Hwan; Rho, Young Soo; Chung, Chul Hoon

2017-01-01

To identify post-operative computed tomography (CT) findings associated with delayed flap failures following head and neck cancer surgery. We retrospectively reviewed 60 patients who underwent flap reconstruction after head and neck cancer surgery and post-operative (3–14 days) contrast-enhanced CT scans for suspected complications. Patients were divided into two groups: delayed flap failure patients (patients required flap revision) (n = 18) and flap success patients (n = 42). Clinical data (age, sex, T-stage, type of flap, and time interval between reconstruction surgery and CT) and post-operative CT findings of flap status (maximum dimension of the flap, intra- or peri-flap fluid collection and intra- or peri-flap air collection, fat infiltration within the flap, fistula to adjacent aerodigestive tract or skin, and enhanced vascular pedicle) were assessed and compared between the two groups. CT findings showed that the following flap anomalies were observed more frequently in the delayed flap failure group than in the flap success group: intra- or peri-flap fluid collection > 4 cm (61.1% vs. 23.8%, p 2 cm (61.1% vs. 2.4%, p < 0.001), and fistula to adjacent aerodigestive tract or skin (44.4% vs. 0%, p < 0.001). The maximum dimension of the flap, fat infiltration within the flap, and enhanced vascular pedicle were not associated with delayed flap failures. A large amount of fluid or air collection and fistula are the CT findings that were associated with delayed flap failures in patients with suspected post-operative complications after head and neck cancer surgery

Does delay in diagnosing colorectal cancer in symptomatic patients affect tumor stage and survival? A population-based observational study

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Visser Otto

2010-06-01

Full Text Available Abstract Background Diagnosing colorectal cancer (CRC at an early stage improves survival. To what extent any delay affects outcome once patients are symptomatic is still unclear. Our objectives were to evaluate the association between diagnostic delay and survival in symptomatic patients with early stage CRC and late stage CRC. Methods Prospective population-based observational study evaluating daily clinical practice in Northern Holland. Diagnostic delay was determined through questionnaire-interviews. Dukes' stage was classified into two groups: early stage (Dukes A or B and late stage (Dukes C or D cancer. Patients were followed up for 3.5 years after diagnosis. Results In total, 272 patients were available for analysis. Early stage CRC was present in 136 patients while 136 patients had late stage CRC. The mean total diagnostic delay (SE was 31 (1.5 weeks in all CRC patients. No significant difference was observed in the mean total diagnostic delay in early versus late stage CRC (p = 0.27. In early stage CRC, no difference in survival was observed between patients with total diagnostic delay shorter and longer than the median (Kaplan-Meier, log-rank p = 0.93. In late stage CRC, patients with a diagnostic delay shorter than the median had a shorter survival than patients with a diagnostic delay longer than the median (log-rank p = 0.01. In the multivariate Cox regression model with survival as dependent variable and median delay, age, open access endoscopy, number and type of symptoms as independent variables, the odd's ratio for survival in patients with long delay (>median versus short delay (≤median was 1.8 (95% confidence interval (CI 1.1 to 3.0; p = 0.01. Tumor-site was not associated with patient survival. When separating late stage CRC in Dukes C and Dukes D tumors, a shorter delay was associated with a shorter survival in Dukes D tumors only and not in Dukes C tumors. Conclusion In symptomatic CRC patients, a longer diagnostic and

Drug Treatment of Cancer Cell Lines: A Way to Select for Cancer Stem Cells?

International Nuclear Information System (INIS)

Chiodi, Ilaria; Belgiovine, Cristina; Donà, Francesca; Scovassi, A. Ivana; Mondello, Chiara

2011-01-01

Tumors are generally composed of different cell types. In recent years, it has been shown that in many types of cancers a subset of cells show peculiar characteristics, such as the ability to induce tumors when engrafted into host animals, self-renew and being immortal, and give rise to a differentiated progeny. These cells have been defined as cancer stem cells (CSCs) or tumor initiating cells. CSCs can be isolated both from tumor specimens and established cancer cell lines on the basis of their ability to exclude fluorescent dyes, express specific cell surface markers or grow in particular culture conditions. A key feature of CSCs is their resistance to chemotherapeutic agents, which could contribute to the remaining of residual cancer cells after therapeutic treatments. It has been shown that CSC-like cells can be isolated after drug treatment of cancer cell lines; in this review, we will describe the strategies so far applied to identify and isolate CSCs. Furthermore, we will discuss the possible use of these selected populations to investigate CSC biology and develop new anticancer drugs

Colorectal cancer stem cells.

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Salama, Paul; Platell, Cameron

2009-10-01

Somatic stem cells reside at the base of the crypts throughout the colonic mucosa. These cells are essential for the normal regeneration of the colonic epithelium. The stem cells reside within a special 'niche' comprised of intestinal sub-epithelial myofibroblasts that tightly control their function. It has been postulated that mutations within these adult colonic stem cells may induce neoplastic changes. Such cells can then dissociate from the epithelium and travel into the mesenchyme and thus form invasive cancers. This theory is based on the observation that within a colon cancer, less than 1% of the neoplastic cells have the ability to regenerate the tumour. It is this group of cells that exhibits characteristics of colonic stem cells. Although anti-neoplastic agents can induce remissions by inhibiting cell division, the stem cells appear to be remarkably resistant to both standard chemotherapy and radiotherapy. These stem cells may therefore persist after treatment and form the nucleus for cancer recurrence. Hence, future treatment modalities should focus specifically on controlling the cancer stem cells. In this review, we discuss the biology of normal and malignant colonic stem cells.

Identification and characterization of cells with cancer stem cell properties in human primary lung cancer cell lines.

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Ping Wang

Full Text Available Lung cancer (LC with its different subtypes is generally known as a therapy resistant cancer with the highest morbidity rate worldwide. Therapy resistance of a tumor is thought to be related to cancer stem cells (CSCs within the tumors. There have been indications that the lung cancer is propagated and maintained by a small population of CSCs. To study this question we established a panel of 15 primary lung cancer cell lines (PLCCLs from 20 fresh primary tumors using a robust serum-free culture system. We subsequently focused on identification of lung CSCs by studying these cell lines derived from 4 representative lung cancer subtypes such as small cell lung cancer (SCLC, large cell carcinoma (LCC, squamous cell carcinoma (SCC and adenocarcinoma (AC. We identified a small population of cells strongly positive for CD44 (CD44(high and a main population which was either weakly positive or negative for CD44 (CD44(low/-. Co-expression of CD90 further narrowed down the putative stem cell population in PLCCLs from SCLC and LCC as spheroid-forming cells were mainly found within the CD44(highCD90(+ sub-population. Moreover, these CD44(highCD90(+ cells revealed mesenchymal morphology, increased expression of mesenchymal markers N-Cadherin and Vimentin, increased mRNA levels of the embryonic stem cell related genes Nanog and Oct4 and increased resistance to irradiation compared to other sub-populations studied, suggesting the CD44(highCD90(+ population a good candidate for the lung CSCs. Both CD44(highCD90(+ and CD44(highCD90(- cells in the PLCCL derived from SCC formed spheroids, whereas the CD44(low/- cells were lacking this potential. These results indicate that CD44(highCD90(+ sub-population may represent CSCs in SCLC and LCC, whereas in SCC lung cancer subtype, CSC potentials were found within the CD44(high sub-population.

Identification and Characterization of Cells with Cancer Stem Cell Properties in Human Primary Lung Cancer Cell Lines

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Suo, Zhenhe; Munthe, Else; Solberg, Steinar; Ma, Liwei; Wang, Mengyu; Westerdaal, Nomdo Anton Christiaan; Kvalheim, Gunnar; Gaudernack, Gustav

2013-01-01

Lung cancer (LC) with its different subtypes is generally known as a therapy resistant cancer with the highest morbidity rate worldwide. Therapy resistance of a tumor is thought to be related to cancer stem cells (CSCs) within the tumors. There have been indications that the lung cancer is propagated and maintained by a small population of CSCs. To study this question we established a panel of 15 primary lung cancer cell lines (PLCCLs) from 20 fresh primary tumors using a robust serum-free culture system. We subsequently focused on identification of lung CSCs by studying these cell lines derived from 4 representative lung cancer subtypes such as small cell lung cancer (SCLC), large cell carcinoma (LCC), squamous cell carcinoma (SCC) and adenocarcinoma (AC). We identified a small population of cells strongly positive for CD44 (CD44high) and a main population which was either weakly positive or negative for CD44 (CD44low/−). Co-expression of CD90 further narrowed down the putative stem cell population in PLCCLs from SCLC and LCC as spheroid-forming cells were mainly found within the CD44highCD90+ sub-population. Moreover, these CD44highCD90+ cells revealed mesenchymal morphology, increased expression of mesenchymal markers N-Cadherin and Vimentin, increased mRNA levels of the embryonic stem cell related genes Nanog and Oct4 and increased resistance to irradiation compared to other sub-populations studied, suggesting the CD44highCD90+ population a good candidate for the lung CSCs. Both CD44highCD90+ and CD44highCD90− cells in the PLCCL derived from SCC formed spheroids, whereas the CD44low/− cells were lacking this potential. These results indicate that CD44highCD90+ sub-population may represent CSCs in SCLC and LCC, whereas in SCC lung cancer subtype, CSC potentials were found within the CD44high sub-population. PMID:23469181

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

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Zilal Kattan

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

Stem cells and cancer: A review

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Najeeb Ullah

2016-05-01

Full Text Available Stem cells are the small units of multicellular creature. Regeneration and self-renewal are the ability of the stem cells. Each tissue is having particular stem cells, specific to it. These normal stem cells are converted into cancer stem cells through mutations in it. Although the expression of oncogenes is enhanced a lot, the tumor-supressing gene is lessened. Cancer stem cells are isolated and visualized through different techniques like immunocytochemical staining, spectral karyotyping, immunohistochemistry, induction method and dissection measures, then are performed histological procedures which include fascination, immunohistochemistry, dispensation, in situ hybridization and also quantitative examination of tissue flow cytometric analysis. For the analysis of quantization, statistical tests are also performed as two-sample t-test, Chi-square test, SD and arithmetic mean. Tumor cells generate glioma spheres. These are used in cancer study. Axin 1 is the gene suppressing cancer. Its removal causes the generation of liver cancer. Curcumin is the most effective for suppressing cancer as it increases the normal stem cell function and decreases the cancer stem cell function. Brahma-related gene 1 is crucial for the safeguarding of the stem cell residents in tissue-specific comportment. Different types of cancers originate through genetic mutation, tissue disorganization and cell proliferation. Tumor configuration is produced by the alteration in original cell culture having stem cells and progenitor cell populations. The developmental facets about cancer cells and cancer stem cells as well as their personal natal functions sustain an intricate steadiness to settle on their personal donations to the efficacy or harmfulness of the biological organization.

Multifaceted Interpretation of Colon Cancer Stem Cells.

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Hatano, Yuichiro; Fukuda, Shinya; Hisamatsu, Kenji; Hirata, Akihiro; Hara, Akira; Tomita, Hiroyuki

2017-07-05

Colon cancer is one of the leading causes of cancer-related deaths worldwide, despite recent advances in clinical oncology. Accumulating evidence sheds light on the existence of cancer stem cells and their role in conferring therapeutic resistance. Cancer stem cells are a minor fraction of cancer cells, which enable tumor heterogeneity and initiate tumor formation. In addition, these cells are resistant to various cytotoxic factors. Therefore, elimination of cancer stem cells is difficult but essential to cure the malignant foci completely. Herein, we review the recent evidence for intestinal stem cells and colon cancer stem cells, methods to detect the tumor-initiating cells, and clinical significance of cancer stem cell markers. We also describe the emerging problems of cancer stem cell theory, including bidirectional conversion and intertumoral heterogeneity of stem cell phenotype.

Prostate Cancer Cells Express More Androgen Receptor (AR) Following Androgen Deprivation, Improving Recognition by AR-Specific T Cells.

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Olson, Brian M; Gamat, Melissa; Seliski, Joseph; Sawicki, Thomas; Jeffery, Justin; Ellis, Leigh; Drake, Charles G; Weichert, Jamey; McNeel, Douglas G

2017-12-01

Androgen deprivation is the primary therapy for recurrent prostate cancer, and agents targeting the androgen receptor (AR) pathway continue to be developed. Because androgen-deprivation therapy (ADT) has immmunostimulatory effects as well as direct antitumor effects, AR-targeted therapies have been combined with other anticancer therapies, including immunotherapies. Here, we sought to study whether an antigen-specific mechanism of resistance to ADT (overexpression of the AR) may result in enhanced AR-specific T-cell immune recognition, and whether this might be strategically combined with an antitumor vaccine targeting the AR. Androgen deprivation increased AR expression in human and murine prostate tumor cells in vitro and in vivo The increased expression persisted over time. Increased AR expression was associated with recognition and cytolytic activity by AR-specific T cells. Furthermore, ADT combined with vaccination, specifically a DNA vaccine encoding the ligand-binding domain of the AR, led to improved antitumor responses as measured by tumor volumes and delays in the emergence of castrate-resistant prostate tumors in two murine prostate cancer models (Myc-CaP and prostate-specific PTEN-deficient mice). Together, these data suggest that ADT combined with AR-directed immunotherapy targets a major mechanism of resistance, overexpression of the AR. This combination may be more effective than ADT combined with other immunotherapeutic approaches. Cancer Immunol Res; 5(12); 1074-85. ©2017 AACR . ©2017 American Association for Cancer Research.

Epigenetics in cancer stem cells.

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Toh, Tan Boon; Lim, Jhin Jieh; Chow, Edward Kai-Hua

2017-02-01

Compelling evidence have demonstrated that bulk tumors can arise from a unique subset of cells commonly termed "cancer stem cells" that has been proposed to be a strong driving force of tumorigenesis and a key mechanism of therapeutic resistance. Recent advances in epigenomics have illuminated key mechanisms by which epigenetic regulation contribute to cancer progression. In this review, we present a discussion of how deregulation of various epigenetic pathways can contribute to cancer initiation and tumorigenesis, particularly with respect to maintenance and survival of cancer stem cells. This information, together with several promising clinical and preclinical trials of epigenetic modulating drugs, offer new possibilities for targeting cancer stem cells as well as improving cancer therapy overall.

Squamous cell skin cancer

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... that reflect light more, such as water, sand, concrete, and areas that are painted white. The higher ... - skin - squamous cell; Skin cancer - squamous cell; Nonmelanoma skin cancer - squamous ...

Mitotic delay of irradiated cells and its connection with quantity of radiation injuries

International Nuclear Information System (INIS)

Lobachevskij, P.N.; Fominykh, E.V.

1989-01-01

The study is dedicated to development of mathematical approach to interpret radiation-induced mitosic delay. An assumption is made that mitotic delay is conditioned by discrete injuries distributed in cells according to stochasticity of interaction of radiation and target substance. It is supposed to consider the problem on injuries nature causing mitotic delay and to use the developed method for accounting the effect of radiation-induced mitotic delay on registered chromosomal aberration yield. 10 refs.; 2 figs.; 3 tabs

Carbonate fuel cell and components thereof for in-situ delayed addition of carbonate electrolyte

Science.gov (United States)

Johnsen, Richard [Waterbury, CT; Yuh, Chao-Yi [New Milford, CT; Farooque, Mohammad [Danbury, CT

2011-05-10

An apparatus and method in which a delayed carbonate electrolyte is stored in the storage areas of a non-electrolyte matrix fuel cell component and is of a preselected content so as to obtain a delayed time release of the electrolyte in the storage areas in the operating temperature range of the fuel cell.

Pancreatic stellate cells promote epithelial-mesenchymal transition in pancreatic cancer cells

International Nuclear Information System (INIS)

Kikuta, Kazuhiro; Masamune, Atsushi; Watanabe, Takashi; Ariga, Hiroyuki; Itoh, Hiromichi; Hamada, Shin; Satoh, Kennichi; Egawa, Shinichi; Unno, Michiaki; Shimosegawa, Tooru

2010-01-01

Research highlights: → Recent studies have shown that pancreatic stellate cells (PSCs) promote the progression of pancreatic cancer. → Pancreatic cancer cells co-cultured with PSCs showed loose cell contacts and scattered, fibroblast-like appearance. → PSCs decreased the expression of epithelial markers but increased that of mesenchymal markers, along with increased migration. → This study suggests epithelial-mesenchymal transition as a novel mechanism by which PSCs contribute to the aggressive behavior of pancreatic cancer cells. -- Abstract: The interaction between pancreatic cancer cells and pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, is receiving increasing attention. There is accumulating evidence that PSCs promote the progression of pancreatic cancer by increasing cancer cell proliferation and invasion as well as by protecting them from radiation- and gemcitabine-induced apoptosis. Because epithelial-mesenchymal transition (EMT) plays a critical role in the progression of pancreatic cancer, we hypothesized that PSCs promote EMT in pancreatic cancer cells. Panc-1 and SUIT-2 pancreatic cancer cells were indirectly co-cultured with human PSCs isolated from patients undergoing operation for pancreatic cancer. The expression of epithelial and mesenchymal markers was examined by real-time PCR and immunofluorescent staining. The migration of pancreatic cancer cells was examined by scratch and two-chamber assays. Pancreatic cancer cells co-cultured with PSCs showed loose cell contacts and a scattered, fibroblast-like appearance. The expression of E-cadherin, cytokeratin 19, and membrane-associated β-catenin was decreased, whereas vimentin and Snail (Snai-1) expression was increased more in cancer cells co-cultured with PSCs than in mono-cultured cells. The migration of pancreatic cancer cells was increased by co-culture with PSCs. The PSC-induced decrease of E-cadherin expression was not altered by treatment with anti

Value of the post-operative CT in predicting delayed flap failures following head and neck cancer surgery

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Kim, Bitna; Yoon, Dae Young; Seo, Young Lan; Park, Min Woo; Kwon, Kee Hwan; Rho, Young Soo; Chung, Chul Hoon [Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul (Korea, Republic of)

2017-06-15

To identify post-operative computed tomography (CT) findings associated with delayed flap failures following head and neck cancer surgery. We retrospectively reviewed 60 patients who underwent flap reconstruction after head and neck cancer surgery and post-operative (3–14 days) contrast-enhanced CT scans for suspected complications. Patients were divided into two groups: delayed flap failure patients (patients required flap revision) (n = 18) and flap success patients (n = 42). Clinical data (age, sex, T-stage, type of flap, and time interval between reconstruction surgery and CT) and post-operative CT findings of flap status (maximum dimension of the flap, intra- or peri-flap fluid collection and intra- or peri-flap air collection, fat infiltration within the flap, fistula to adjacent aerodigestive tract or skin, and enhanced vascular pedicle) were assessed and compared between the two groups. CT findings showed that the following flap anomalies were observed more frequently in the delayed flap failure group than in the flap success group: intra- or peri-flap fluid collection > 4 cm (61.1% vs. 23.8%, p < 0.05), intra- or peri-flap air collection > 2 cm (61.1% vs. 2.4%, p < 0.001), and fistula to adjacent aerodigestive tract or skin (44.4% vs. 0%, p < 0.001). The maximum dimension of the flap, fat infiltration within the flap, and enhanced vascular pedicle were not associated with delayed flap failures. A large amount of fluid or air collection and fistula are the CT findings that were associated with delayed flap failures in patients with suspected post-operative complications after head and neck cancer surgery.

Stages of Renal Cell Cancer

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... Tumors Treatment Genetics of Kidney Cancer Research Renal Cell Cancer Treatment (PDQ®)–Patient Version General Information About Renal Cell Cancer Go to Health Professional Version Key Points Renal ...

Cancer stem cells and personalized cancer nanomedicine.

Science.gov (United States)

Gener, Petra; Rafael, Diana Fernandes de Sousa; Fernández, Yolanda; Ortega, Joan Sayós; Arango, Diego; Abasolo, Ibane; Videira, Mafalda; Schwartz, Simo

2016-02-01

Despite the progress in cancer treatment over the past years advanced cancer is still an incurable disease. Special attention is pointed toward cancer stem cell (CSC)-targeted therapies, because this minor cell population is responsible for the treatment resistance, metastatic growth and tumor recurrence. The recently described CSC dynamic phenotype and interconversion model of cancer growth hamper even more the possible success of current cancer treatments in advanced cancer stages. Accordingly, CSCs can be generated through dedifferentiation processes from non-CSCs, in particular, when CSC populations are depleted after treatment. In this context, the use of targeted CSC nanomedicines should be considered as a promising tool to increase CSC sensitivity and efficacy of specific anti-CSC therapies.

A Novel Scheme for Optimal Control of a Nonlinear Delay Differential Equations Model to Determine Effective and Optimal Administrating Chemotherapy Agents in Breast Cancer.

Science.gov (United States)

Ramezanpour, H R; Setayeshi, S; Akbari, M E

2011-01-01

Determining the optimal and effective scheme for administrating the chemotherapy agents in breast cancer is the main goal of this scientific research. The most important issue here is the amount of drug or radiation administrated in chemotherapy and radiotherapy for increasing patient's survival. This is because in these cases, the therapy not only kills the tumor cells, but also kills some of the healthy tissues and causes serious damages. In this paper we investigate optimal drug scheduling effect for breast cancer model which consist of nonlinear ordinary differential time-delay equations. In this paper, a mathematical model of breast cancer tumors is discussed and then optimal control theory is applied to find out the optimal drug adjustment as an input control of system. Finally we use Sensitivity Approach (SA) to solve the optimal control problem. The goal of this paper is to determine optimal and effective scheme for administering the chemotherapy agent, so that the tumor is eradicated, while the immune systems remains above a suitable level. Simulation results confirm the effectiveness of our proposed procedure. In this paper a new scheme is proposed to design a therapy protocol for chemotherapy in Breast Cancer. In contrast to traditional pulse drug delivery, a continuous process is offered and optimized, according to the optimal control theory for time-delay systems.

Surfactant protein D delays Fas- and TRAIL-mediated extrinsic pathway of apoptosis in T cells.

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Djiadeu, Pascal; Kotra, Lakshmi P; Sweezey, Neil; Palaniyar, Nades

2017-05-01

Only a few extracellular soluble proteins are known to modulate apoptosis. We considered that surfactant-associated protein D (SP-D), an innate immune collectin present on many mucosal surfaces, could regulate apoptosis. Although SP-D is known to be important for immune cell homeostasis, whether SP-D affects apoptosis is unknown. In this study we aimed to determine the effects of SP-D on Jurkat T cells and human T cells dying by apoptosis. Here we show that SP-D binds to Jurkat T cells and delays the progression of Fas (CD95)-Fas ligand and TRAIL-TRAIL receptor induced, but not TNF-TNF receptor-mediated apoptosis. SP-D exerts its effects by reducing the activation of initiator caspase-8 and executioner caspase-3. SP-D also delays the surface exposure of phosphatidylserine. The effect of SP-D was ablated by the presence of caspase-8 inhibitor, but not by intrinsic pathway inhibitors. The binding ability of SP-D to dying cells decreases during the early stages of apoptosis, suggesting the release of apoptotic cell surface targets during apoptosis. SP-D also delays FasL-induced death of primary human T cells. SP-D delaying the progression of the extrinsic pathway of apoptosis could have important implications in regulating immune cell homeostasis at mucosal surfaces.

Metabolic cooperation between cancer and non-cancerous stromal cells is pivotal in cancer progression.

Science.gov (United States)

Lopes-Coelho, Filipa; Gouveia-Fernandes, Sofia; Serpa, Jacinta

2018-02-01

The way cancer cells adapt to microenvironment is crucial for the success of carcinogenesis, and metabolic fitness is essential for a cancer cell to survive and proliferate in a certain organ/tissue. The metabolic remodeling in a tumor niche is endured not only by cancer cells but also by non-cancerous cells that share the same microenvironment. For this reason, tumor cells and stromal cells constitute a complex network of signal and organic compound transfer that supports cellular viability and proliferation. The intensive dual-address cooperation of all components of a tumor sustains disease progression and metastasis. Herein, we will detail the role of cancer-associated fibroblasts, cancer-associated adipocytes, and inflammatory cells, mainly monocytes/macrophages (tumor-associated macrophages), in the remodeling and metabolic adaptation of tumors.

TRX-E-002-1 Induces c-Jun-Dependent Apoptosis in Ovarian Cancer Stem Cells and Prevents Recurrence In Vivo.

Science.gov (United States)

Alvero, Ayesha B; Heaton, Andrew; Lima, Eydis; Pitruzzello, Mary; Sumi, Natalia; Yang-Hartwich, Yang; Cardenas, Carlos; Steinmacher, Sahra; Silasi, Dan-Arin; Brown, David; Mor, Gil

2016-06-01

Chemoresistance is a major hurdle in the management of patients with epithelial ovarian cancer and is responsible for its high mortality. Studies have shown that chemoresistance is due to the presence of a subgroup of cancer cells with stemness properties and a high capacity for tumor repair. We have developed a library of super-benzopyran analogues to generate potent compounds that can induce cell death in chemoresistant cancer stem cells. TRX-E-002-1 is identified as the most potent analogue and can induce cell death in all chemoresistant CD44(+)/MyD88(+) ovarian cancer stem cells tested (IC50 = 50 nmol/L). TRX-E-002-1 is also potent against spheroid cultures formed from cancer stem cells, chemosensitive CD44(-)/MyD88(-) ovarian cancer cells, and heterogeneous cultures of ovarian cancer cells. Cell death was associated with the phosphorylation and increased levels of c-Jun and induction of caspases. In vivo, TRX-E-002-1 given as daily intraperitoneal monotherapy at 100 mg/kg significantly decreased intraperitoneal tumor burden compared with vehicle control. When given in combination with cisplatin, animals receiving the combination of cisplatin and TRX-E-002-1 showed decreased tumor burden compared with each monotherapy. Finally, TRX-E-002-1 given as maintenance treatment after paclitaxel significantly delayed disease recurrence. Our results suggest that TRX-E-002-1 may fill the current need for better therapeutic options in the control and management of recurrent ovarian cancer and may help improve patient survival. Mol Cancer Ther; 15(6); 1279-90. ©2016 AACR. ©2016 American Association for Cancer Research.

The Haiti Breast Cancer Initiative: Initial Findings and Analysis of Barriers-to-Care Delaying Patient Presentation

Directory of Open Access Journals (Sweden)

Ketan Sharma

2013-01-01

Full Text Available Background. In Haiti, breast cancer patients present at such advanced stages that even modern therapies offer modest survival benefit. Identifying the personal, sociocultural, and economic barriers-to-care delaying patient presentation is crucial to controlling disease. Methods. Patients presenting to the Hôpital Bon Sauveur in Cange were prospectively accrued. Delay was defined as 12 weeks or longer from initial sign/symptom discovery to presentation, as durations greater than this cutoff correlate with reduced survival. A matched case-control analysis with multivariate logistic regression was used to identify factors predicting delay. Results. Of N=123 patients accrued, 90 (73% reported symptom-presentation duration and formed the basis of this study: 52 patients presented within 12 weeks of symptoms, while 38 patients waited longer than 12 weeks. On logistic regression, lower education status (OR = 5.6, P=0.03, failure to initially recognize mass as important (OR = 13.0, P<0.01, and fear of treatment cost (OR = 8.3, P=0.03 were shown to independently predict delayed patient presentation. Conclusion. To reduce stage at presentation, future interventions must educate patients on the recognition of initial breast cancer signs and symptoms and address cost concerns by providing care free of charge and/or advertising that existing care is already free.

Characterization of the N-methoxyindole-3-carbinol (NI3C)–Induced Cell Cycle Arrest in Human Colon Cancer Cell Lines

DEFF Research Database (Denmark)

Neave, Antje S.; Sarup, Sussi; Seidelin, Michel

2005-01-01

Recent results have shown that indole-3-carbinol (I3C) inhibits the cellular growth of human cancer cell lines. In some cruciferous vegetables, another indole, N-methoxyindole-3-carbinol (NI3C), is found beside I3C. Knowledge about the biological effects of NI3C is limited. The aim of the present...... study was to show the effect of NI3C on cell growth of two human colon cancer cell lines, DLD-1 and HCT-116. For the first time it is shown that NI3C inhibits cellular growth of DLD-1 and HCT-116 and that NI3C is a more potent inhibitor of cell proliferation than I3C. In addition to the inhibition...... of cellular proliferation, NI3C caused an accumulation of HCT-116 cells in the G2/M phase, in contrast to I3C, which led to an accumulation of the colon cells in G0/G1 phase. Furthermore, NI3C delays the G1-S phase transition of synchronized HCT-116 cells. The indole-mediated cell-cycle arrest may be related...

Random start ovarian stimulation for fertility preservation appears unlikely to delay initiation of neoadjuvant chemotherapy for breast cancer.

Science.gov (United States)

Letourneau, Joseph M; Sinha, Nikita; Wald, Kaitlyn; Harris, Eve; Quinn, Molly; Imbar, Tal; Mok-Lin, Evelyn; Chien, A Jo; Rosen, Mitchell

2017-10-01

Is random start ovarian stimulation associated with delays in initiation of neoadjuvant chemotherapy for breast cancer? Among women who complete fertility preservation (FP) consultation, random start ovarian stimulation is unlikely to delay time to initiation of neoadjuvant chemotherapy start. Neoadjuvant chemotherapy is now a widely accepted treatment modality for operable breast cancer and random start ovarian stimulation is an increasingly-utilized modality for FP. While conventional ovarian stimulation does not appear to delay starting adjuvant chemotherapy, the relationship between random start ovarian stimulation and neoadjuvant chemotherapy start is not well-understood. Cross-sectional study of all women seen between from January 2011 to April 2017 for FP consultation prior to starting neoadjuvant chemotherapy for breast cancer. A chart-review was performed. Study inclusion criteria were female sex; age 18-45; non-metastatic breast cancer diagnosis; underwent FP consultation; underwent neoadjuvant chemotherapy. Referrals for FP evaluation came from a regional referral base of oncology clinics. Various time-points related to cancer diagnosis, FP or chemotherapy were obtained from medical record review. We compared time-points between those who underwent ovarian stimulation for FP versus those who did not using T-tests and linear modeling. A total of 89 women who had FP consultation prior to neoadjuvant chemotherapy were identified. Sixty-seven percent underwent ovarian stimulation prior to cancer treatment and 33% did not. Women who underwent ovarian stimulation were similar in parity and clinical cancer stage to those who did not. Overall, the average time from cancer diagnosis to chemotherapy start was similar between the group that did undergo ovarian stimulation and those who did not (38.1 ± 11.3 versus 39.4 ± 18.5 days, P = 0.672). Those that underwent ovarian stimulation were referred 9.4 ± 6.8 days after diagnosis versus 17.9 ± 15.3 days for those

Adipocyte activation of cancer stem cell signaling in breast cancer

Institute of Scientific and Technical Information of China (English)

Benjamin; Wolfson; Gabriel; Eades; Qun; Zhou

2015-01-01

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

Gastric stem cells and gastric cancer stem cells

OpenAIRE

Han, Myoung-Eun; Oh, Sae-Ock

2013-01-01

The gastric epithelium is continuously regenerated by gastric stem cells, which give rise to various kinds of daughter cells, including parietal cells, chief cells, surface mucous cells, mucous neck cells, and enteroendocrine cells. The self-renewal and differentiation of gastric stem cells need delicate regulation to maintain the normal physiology of the stomach. Recently, it was hypothesized that cancer stem cells drive the cancer growth and metastasis. In contrast to conventional clonal ev...

Multimodal Nanomedicine Strategies for Targeting Cancer Cells as well as Cancer Stem Cell Signalling Mechanisms.

Science.gov (United States)

Kanwar, Jagat R; Samarasinghe, Rasika M; Kamalapuram, Sishir K; Kanwar, Rupinder K

2017-01-01

Increasing evidence suggests that stem cells, a small population of cells with unique selfrenewable and tumour regenerative capacity, are aiding tumour re-growth and multidrug resistance. Conventional therapies are highly ineffective at eliminating these cells leading to relapse of disease and formation of chemoresistance tumours. Cancer and stem cells targeted therapies that utilizes nanotherapeutics to delivery anti-cancer drugs to specific sites are continuously investigated. This review focuses on recent research using nanomedicine and targeting entities to eliminate cancer cells and cancer stem cells. Current nanotherapeutics in clinical trials along with more recent publications on targeted therapies are addressed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Road for understanding cancer stem cells

DEFF Research Database (Denmark)

Serakinci, Nedime; Erzik, Can

2007-01-01

There is increasing evidence suggesting that stem cells are susceptive to carcinogenesis and, consequently, can be the origin of many cancers. Recently, the neoplastic potential of stem cells has been supported by many groups showing the existence of subpopulations with stem cell characteristics...... in tumor biopsies such as brain and breast. Evidence supporting the cancer stem cell hypothesis has gained impact due to progress in stem cell biology and development of new models to validate the self-renewal potential of stem cells. Recent evidence on the possible identification of cancer stem cells may...... offer an opportunity to use these cells as future therapeutic targets. Therefore, model systems in this field have become very important and useful. This review will focus on the state of knowledge on cancer stem cell research, including cell line models for cancer stem cells. The latter will, as models...

Cancer Stem Cells in Pancreatic Cancer

Energy Technology Data Exchange (ETDEWEB)

Bao, Qi; Zhao, Yue; Renner, Andrea; Niess, Hanno; Seeliger, Hendrik; Jauch, Karl-Walter; Bruns, Christiane J., E-mail: christiane.bruns@med.uni-muenchen.de [Department of Surgery, Ludwig Maximilian University of Munich, Klinikum Grosshadern, Marchioninistr. 15, D-81377, Munich (Germany)

2010-08-19

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

TAS-116, a novel Hsp90 inhibitor, selectively enhances radio-sensitivity of human cancer cells to X-rays and carbon ion radiation

Science.gov (United States)

Lee, Younghyun; Sunada, Shigeaki; Hirakawa, Hirokazu; Fujimori, Akira; Nickoloff, Jac A.; Okayasu, Ryuichi

2016-01-01

Hsp90 inhibitors have been investigated as cancer therapeutics in mono-therapy and to augment radiotherapy, however serious adverse effects of early generation Hsp90 inhibitors limited their development. TAS-116 is a novel Hsp90 inhibitor with lower adverse effects than other Hsp90 inhibitors, and here we investigated the radio-sensitizing effects of TAS-116 in low LET X-ray, and high LET carbon ion irradiated human cancer cells and mouse tumor xenografts. TAS-116 decreased cell survival of both X-ray and carbon ion-irradiated human cancer cell lines (HeLa and H1299 cells), and similar to other Hsp90 inhibitors, it did not affect radiosensitivity of non-cancerous human fibroblasts. TAS-116 increased the number of radiation-induced γ-H2AX foci, and delayed the repair of DNA double-strand breaks (DSBs). TAS-116 reduced the expression of proteins that mediate repair of DSBs by homologous recombination (RAD51) and non-homologous end joining (Ku, DNA-PKcs), and suppressed formation of RAD51 foci and phosphorylation/activation of DNA-PKcs. TAS-116 also decreased expression of the cdc25 cell cycle progression marker, markedly increasing G2/M arrest. Combined treatment of mouse tumor xenografts with carbon ions and TAS-116 showed promising delay in tumor growth compared to either individual treatment. These results demonstrate that TAS-116 radio-sensitizes human cancer cells to both X rays and carbon ions by inhibiting the two major DSB repair pathways, and these effects were accompanied by marked cell cycle arrest. The promising results of combination TAS-116 + carbon ion radiation therapy of tumor xenografts justify further exploration of TAS-116 as an adjunct to radiotherapy using low or high LET radiation. PMID:28062703

Cancer stem cells in colorectal cancer: a review.

Science.gov (United States)

Munro, Matthew J; Wickremesekera, Susrutha K; Peng, Lifeng; Tan, Swee T; Itinteang, Tinte

2018-02-01

Colorectal cancer (CRC) is the second most common cancer in women and the third most common in men. Adenocarcinoma accounts for 90% of CRC cases. There has been accumulating evidence in support of the cancer stem cell (CSC) concept of cancer which proposes that CSCs are central in the initiation of cancer. CSCs have been the focus of study in a range of cancers, including CRC. This has led to the identification and understanding of genes involved in the induction and maintenance of pluripotency of stem cells, and markers for CSCs, including those investigated specifically in CRC. Knowledge of the expression pattern of CSCs in CRC has been increasing in recent years, revealing a heterogeneous population of cells within CRC ranging from pluripotent to differentiated cells, with overlapping and sometimes unique combinations of markers. This review summarises current literature on the understanding of CSCs in CRC, including evidence of the presence of CSC subpopulations, and the stem cell markers currently used to identify and localise these CSC subpopulations. Future research into this field may lead to improved methods for early detection of CRC, novel therapy and monitoring of treatment for CRC and other cancer types. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Extragonadal Germ Cell Cancer (EGC)

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The Testicular Cancer Resource Center Extragonadal Germ Cell Cancer (EGC) 95% of all testicular tumors are germ cell tumors. That is, the tumors originate in the sperm forming cells in the testicles ( ...

Differential Sensitivities of Fast- and Slow-Cycling Cancer Cells to Inosine Monophosphate Dehydrogenase 2 Inhibition by Mycophenolic Acid

Science.gov (United States)

Chen, Kan; Cao, Wanlu; Li, Juan; Sprengers, Dave; Hernanda, Pratika Y; Kong, Xiangdong; van der Laan, Luc JW; Man, Kwan; Kwekkeboom, Jaap; Metselaar, Herold J; Peppelenbosch, Maikel P; Pan, Qiuwei

2015-01-01

As uncontrolled cell proliferation requires nucleotide biosynthesis, inhibiting enzymes that mediate nucleotide biosynthesis constitutes a rational approach to the management of oncological diseases. In practice, however, results of this strategy are mixed and thus elucidation of the mechanisms by which cancer cells evade the effect of nucleotide biosynthesis restriction is urgently needed. Here we explored the notion that intrinsic differences in cancer cell cycle velocity are important in the resistance toward inhibition of inosine monophosphate dehydrogenase (IMPDH) by mycophenolic acid (MPA). In short-term experiments, MPA treatment of fast-growing cancer cells effectively elicited G0/G1 arrest and provoked apoptosis, thus inhibiting cell proliferation and colony formation. Forced expression of a mutated IMPDH2, lacking a binding site for MPA but retaining enzymatic activity, resulted in complete resistance of cancer cells to MPA. In nude mice subcutaneously engrafted with HeLa cells, MPA moderately delayed tumor formation by inhibiting cell proliferation and inducing apoptosis. Importantly, we developed a lentiviral vector–based Tet-on label-retaining system that enables to identify, isolate and functionally characterize slow-cycling or so-called label-retaining cells (LRCs) in vitro and in vivo. We surprisingly found the presence of LRCs in fast-growing tumors. LRCs were superior in colony formation, tumor initiation and resistance to MPA as compared with fast-cycling cells. Thus, the slow-cycling compartment of cancer seems predominantly responsible for resistance to MPA. PMID:26467706

DNA damage in oral cancer cells induced by nitrogen atmospheric pressure plasma jets

Science.gov (United States)

Han, Xu; Klas, Matej; Liu, Yueying; Stack, M. Sharon; Ptasinska, Sylwia

2013-09-01

The nitrogen atmospheric pressure plasma jet (APPJ) has been shown to effectively induce DNA double strand breaks in SCC-25 oral cancer cells. The APPJ source constructed in our laboratory consists of two external electrodes wrapping around a quartz tube and nitrogen as a feed gas and operates based on dielectric barrier gas discharge. Generally, it is more challenging to ignite plasma in N2 atmosphere than in noble gases. However, this design provides additional advantages such as lower costs compared to the noble gases for future clinical operation. Different parameters of the APPJ configuration were tested in order to determine radiation dosage. To explore the effects of delayed damage and cell self-repairing, various incubation times of cells after plasma treatment were also performed. Reactive species generated in plasma jet and in liquid environment are essential to be identified and quantified, with the aim of unfolding the mystery of detailed mechanisms for plasma-induced cell apoptosis. Moreover, from the comparison of plasma treatment effect on normal oral cells OKF6T, an insight to the selectivity for cancer treatment by APPJ can be explored. All of these studies are critical to better understand the damage responses of normal and abnormal cellular systems to plasma radiation, which are useful for the development of advanced plasma therapy for cancer treatment at a later stage.

Effect of cryoablation sequential chemotherapy on patients with advanced non-small cell lung cancer

Directory of Open Access Journals (Sweden)

Shu-Hui Yao

2016-03-01

Full Text Available Objective: To evaluate the effect of cryoablation sequential chemotherapy on patients with advanced non-small cell lung cancer. Methods: A total of 39 cases with advanced non-small cell lung cancer who received cryoablation sequential chemotherapy and 39 cases with advanced non-small cell lung cancer who received chemotherapy alone were selected and enrolled in sequential group and control group, disease progression and survival of two groups were followed up, and contents of tumor markers and angiogenesis molecules in serum as well as contents of T-lymphocyte subsets in peripheral blood were detected. Results: Progressionfree survival and median overall survival (mOS of sequential group were longer than those of control group, and cumulative cases of tumor progression at various points in time were significantly less than those of control group (P<0.05; 1 month after treatment, serum tumor markers CEA, CYFRA21-1 and NSE contents, serum angiogenesis molecules PCDGF, VEGF and HDGF contents as well as CD3+CD4-CD8+CD28-T cell content in peripheral blood of sequential group were significantly lower than those of control group (P<0.05, and contents of CD3+CD4+CD8-T cell and CD3+CD4-CD8+CD28+T cell in peripheral blood were higher than those of control group (P<0.05. Conclusions: Cryoablation sequential chemotherapy can improve the prognosis of patients with advanced non-small cell lung cancer, delay disease progression, prolong survival time, inhibit angiogenesis and improve immune function.

BCL-2 family protein, BAD is down-regulated in breast cancer and inhibits cell invasion

Energy Technology Data Exchange (ETDEWEB)

Cekanova, Maria, E-mail: mcekanov@utk.edu [Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN (United States); Fernando, Romaine I. [Department of Obstetrics and Gynecology, Graduate School of Medicine, Medical Center, The University of Tennessee, Knoxville, TN (United States); Siriwardhana, Nalin [Department of Animal Science, The University of Tennessee, Knoxville, TN (United States); Sukhthankar, Mugdha [Department of Biomedical and Diagnostics Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN (United States); Parra, Columba de la [Department of Biochemistry, School of Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, PR (United States); Woraratphoka, Jirayus [Department of Obstetrics and Gynecology, Graduate School of Medicine, Medical Center, The University of Tennessee, Knoxville, TN (United States); Malone, Christine [Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC (United States); Ström, Anders [Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX (United States); Baek, Seung J. [Department of Biomedical and Diagnostics Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN (United States); Wade, Paul A. [Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC (United States); Saxton, Arnold M. [Department of Animal Science, The University of Tennessee, Knoxville, TN (United States); Donnell, Robert M. [Department of Biomedical and Diagnostics Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN (United States); Pestell, Richard G. [Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA (United States); and others

2015-02-01

We have previously demonstrated that the anti-apoptotic protein BAD is expressed in normal human breast tissue and shown that BAD inhibits expression of cyclin D1 to delay cell-cycle progression in breast cancer cells. Herein, expression of proteins in breast tissues was studied by immunohistochemistry and results were analyzed statistically to obtain semi-quantitative data. Biochemical and functional changes in BAD-overexpressing MCF7 breast cancer cells were evaluated using PCR, reporter assays, western blotting, ELISA and extracellular matrix invasion assays. Compared to normal tissues, Grade II breast cancers expressed low total/phosphorylated forms of BAD in both cytoplasmic and nuclear compartments. BAD overexpression decreased the expression of β-catenin, Sp1, and phosphorylation of STATs. BAD inhibited Ras/MEK/ERK and JNK signaling pathways, without affecting the p38 signaling pathway. Expression of the metastasis-related proteins, MMP10, VEGF, SNAIL, CXCR4, E-cadherin and TlMP2 was regulated by BAD with concomitant inhibition of extracellular matrix invasion. Inhibition of BAD by siRNA increased invasion and Akt/p-Akt levels. Clinical data and the results herein suggest that in addition to the effect on apoptosis, BAD conveys anti-metastatic effects and is a valuable prognostic marker in breast cancer. - Highlights: • BAD and p-BAD expressions are decreased in breast cancer compared with normal breast tissue. • BAD impedes breast cancer invasion and migration. • BAD inhibits the EMT and transcription factors that promote cancer cell migration. • Invasion and migration functions of BAD are distinct from the BAD's role in apoptosis.

BCL-2 family protein, BAD is down-regulated in breast cancer and inhibits cell invasion

International Nuclear Information System (INIS)

Cekanova, Maria; Fernando, Romaine I.; Siriwardhana, Nalin; Sukhthankar, Mugdha; Parra, Columba de la; Woraratphoka, Jirayus; Malone, Christine; Ström, Anders; Baek, Seung J.; Wade, Paul A.; Saxton, Arnold M.; Donnell, Robert M.; Pestell, Richard G.

2015-01-01

We have previously demonstrated that the anti-apoptotic protein BAD is expressed in normal human breast tissue and shown that BAD inhibits expression of cyclin D1 to delay cell-cycle progression in breast cancer cells. Herein, expression of proteins in breast tissues was studied by immunohistochemistry and results were analyzed statistically to obtain semi-quantitative data. Biochemical and functional changes in BAD-overexpressing MCF7 breast cancer cells were evaluated using PCR, reporter assays, western blotting, ELISA and extracellular matrix invasion assays. Compared to normal tissues, Grade II breast cancers expressed low total/phosphorylated forms of BAD in both cytoplasmic and nuclear compartments. BAD overexpression decreased the expression of β-catenin, Sp1, and phosphorylation of STATs. BAD inhibited Ras/MEK/ERK and JNK signaling pathways, without affecting the p38 signaling pathway. Expression of the metastasis-related proteins, MMP10, VEGF, SNAIL, CXCR4, E-cadherin and TlMP2 was regulated by BAD with concomitant inhibition of extracellular matrix invasion. Inhibition of BAD by siRNA increased invasion and Akt/p-Akt levels. Clinical data and the results herein suggest that in addition to the effect on apoptosis, BAD conveys anti-metastatic effects and is a valuable prognostic marker in breast cancer. - Highlights: • BAD and p-BAD expressions are decreased in breast cancer compared with normal breast tissue. • BAD impedes breast cancer invasion and migration. • BAD inhibits the EMT and transcription factors that promote cancer cell migration. • Invasion and migration functions of BAD are distinct from the BAD's role in apoptosis

Pentoxifylline regulates the cellular adhesion and its allied receptors to extracellular matrix components in breast cancer cells.

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Goel, Peeyush N; Gude, Rajiv P

2014-02-01

Pentoxifylline (PTX) is a methylxanthine derivative that improves blood flow by decreasing its viscosity. Being an inhibitor of platelet aggregation, it can thus reduce the adhesiveness of cancer cells prolonging their circulation time. This delay in forming secondary tumours makes them more prone to immunological surveillance. Recently, we have evaluated its anti-metastatic efficacy against breast cancer, using MDA-MB-231 model system. In view of this, we had ascertained the effect of PTX on adhesion of MDA-MB-231 cells to extracellular matrix components (ECM) and its allied receptors such as the integrins. PTX affected adhesion of breast cancer cells to matrigel, collagen type IV, fibronectin and laminin in a dose dependent manner. Further, PTX showed a differential effect on integrin expression profile. The experimental metastasis model using NOD-SCID mice showed lesser tumour island formation when treated with PTX compared to the control. These findings further substantiate the anti-adhesive potential of PTX in breast cancer and warrant further insights into the functional regulation. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Automatic cell cloning assay for determining the clonogenic capacity of cancer and cancer stem-like cells.

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Fedr, Radek; Pernicová, Zuzana; Slabáková, Eva; Straková, Nicol; Bouchal, Jan; Grepl, Michal; Kozubík, Alois; Souček, Karel

2013-05-01

The clonogenic assay is a well-established in vitro method for testing the survival and proliferative capability of cells. It can be used to determine the cytotoxic effects of various treatments including chemotherapeutics and ionizing radiation. However, this approach can also characterize cells with different phenotypes and biological properties, such as stem cells or cancer stem cells. In this study, we implemented a faster and more precise method for assessing the cloning efficiency of cancer stem-like cells that were characterized and separated using a high-speed cell sorter. Cell plating onto a microplate using an automatic cell deposition unit was performed in a single-cell or dilution rank mode by the fluorescence-activated cell sorting method. We tested the new automatic cell-cloning assay (ACCA) on selected cancer cell lines and compared it with the manual approach. The obtained results were also compared with the results of the limiting dilution assay for different cell lines. We applied the ACCA to analyze the cloning capacity of different subpopulations of prostate and colon cancer cells based on the expression of the characteristic markers of stem (CD44 and CD133) and cancer stem cells (TROP-2, CD49f, and CD44). Our results revealed that the novel ACCA is a straightforward approach for determining the clonogenic capacity of cancer stem-like cells identified in both cell lines and patient samples. Copyright © 2013 International Society for Advancement of Cytometry.

Cancer Stem Cells in Pancreatic Cancer

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

2010-01-01

Pancreatic cancer is an aggressive malignant solid tumor well-known by early metastasis, local invasion, resistance to standard chemo- and radiotherapy and poor prognosis. Increasing evidence indicates that pancreatic cancer is initiated and propagated by cancer stem cells (CSCs). Here we review the current research results regarding CSCs in pancreatic cancer and discuss the different markers identifying pancreatic CSCs. This review will focus on metastasis, microRNA regulation and anti-CSC therapy in pancreatic cancer. PMID:24281178

Cancer Stem Cells in Pancreatic Cancer

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Karl-Walter Jauch

2010-08-01

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

Inhibition of androgen receptor by decoy molecules delays progression to castration-recurrent prostate cancer.

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Jae-Kyung Myung

Full Text Available Androgen receptor (AR is a member of the steroid receptor family and a therapeutic target for all stages of prostate cancer. AR is activated by ligand binding within its C-terminus ligand-binding domain (LBD. Here we show that overexpression of the AR NTD to generate decoy molecules inhibited both the growth and progression of prostate cancer in castrated hosts. Specifically, it was shown that lentivirus delivery of decoys delayed hormonal progression in castrated hosts as indicated by increased doubling time of tumor volume, prolonged time to achieve pre-castrate levels of serum prostate-specific antigen (PSA and PSA nadir. These clinical parameters are indicative of delayed hormonal progression and improved therapeutic response and prognosis. Decoys reduced the expression of androgen-regulated genes that correlated with reduced in situ interaction of the AR with androgen response elements. Decoys did not reduce levels of AR protein or prevent nuclear localization of the AR. Nor did decoys interact directly with the AR. Thus decoys did not inhibit AR transactivation by a dominant negative mechanism. This work provides evidence that the AR NTD plays an important role in the hormonal progression of prostate cancer and supports the development of AR antagonists that target the AR NTD.

Stages of Small Cell Lung Cancer

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... Lung Cancer Prevention Lung Cancer Screening Research Small Cell Lung Cancer Treatment (PDQ®)–Patient Version General Information About Small Cell Lung Cancer Go to Health Professional Version Key Points Small ...

Hypoxic stellate cells of pancreatic cancer stroma regulate extracellular matrix fiber organization and cancer cell motility.

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Sada, Masafumi; Ohuchida, Kenoki; Horioka, Kohei; Okumura, Takashi; Moriyama, Taiki; Miyasaka, Yoshihiro; Ohtsuka, Takao; Mizumoto, Kazuhiro; Oda, Yoshinao; Nakamura, Masafumi

2016-03-28

Desmoplasia and hypoxia in pancreatic cancer mutually affect each other and create a tumor-supportive microenvironment. Here, we show that microenvironment remodeling by hypoxic pancreatic stellate cells (PSCs) promotes cancer cell motility through alteration of extracellular matrix (ECM) fiber architecture. Three-dimensional (3-D) matrices derived from PSCs under hypoxia exhibited highly organized parallel-patterned matrix fibers compared with 3-D matrices derived from PSCs under normoxia, and promoted cancer cell motility by inducing directional migration of cancer cells due to the parallel fiber architecture. Microarray analysis revealed that procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in PSCs was the gene that potentially regulates ECM fiber architecture under hypoxia. Stromal PLOD2 expression in surgical specimens of pancreatic cancer was confirmed by immunohistochemistry. RNA interference-mediated knockdown of PLOD2 in PSCs blocked parallel fiber architecture of 3-D matrices, leading to decreased directional migration of cancer cells within the matrices. In conclusion, these findings indicate that hypoxia-induced PLOD2 expression in PSCs creates a permissive microenvironment for migration of cancer cells through architectural regulation of stromal ECM in pancreatic cancer. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Inactivated Sendai virus particle upregulates cancer cell expression of intercellular adhesion molecule-1 and enhances natural killer cell sensitivity on cancer cells.

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Li, Simin; Nishikawa, Tomoyuki; Kaneda, Yasufumi

2017-12-01

We have already reported that the inactivated Sendai virus (hemagglutinating virus of Japan; HVJ) envelope (HVJ-E) has multiple anticancer effects, including induction of cancer-selective cell death and activation of anticancer immunity. The HVJ-E stimulates dendritic cells to produce cytokines and chemokines such as β-interferon, interleukin-6, chemokine (C-C motif) ligand 5, and chemokine (C-X-C motif) ligand 10, which activate both CD8 + T cells and natural killer (NK) cells and recruit them to the tumor microenvironment. However, the effect of HVJ-E on modulating the sensitivity of cancer cells to immune cell attack has yet to be investigated. In this study, we found that HVJ-E induced the production of intercellular adhesion molecule-1 (ICAM-1, CD54), a ligand of lymphocyte function-associated antigen 1, in several cancer cell lines through the activation of nuclear factor-κB downstream of retinoic acid-inducible gene I and the mitochondrial antiviral signaling pathway. The upregulation of ICAM-1 on the surface of cancer cells increased the sensitivity of cancer cells to NK cells. Knocking out expression of ICAM-1 in MDA-MB-231 cells using the CRISPR/Cas9 method significantly reduced the killing effect of NK cells on ICAM-1-depleted MDA-MB-231 cells. In addition, HVJ-E suppressed tumor growth in MDA-MB-231 tumor-bearing SCID mice, and the HVJ-E antitumor effect was impaired when NK cells were depleted by treatment with the anti-asialo GM1 antibody. Our findings suggest that HVJ-E enhances NK cell sensitivity against cancer cells by increasing ICAM-1 expression on the cancer cell surface. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Targetless T cells in cancer immunotherapy

DEFF Research Database (Denmark)

thor Straten, Eivind Per; Garrido, Federico

2016-01-01

Attention has recently focused on new cancer immunotherapy protocols aiming to activate T cell mediated anti-tumor responses. To this end, administration of antibodies that target inhibitory molecules regulating T-cell cytotoxicity has achieved impressive clinical responses, as has adoptive cell...... infiltrate tumor tissues and destroy HLA class I positive tumor cells expressing the specific antigen. In fact, current progress in the field of cancer immune therapy is based on the capacity of T cells to kill cancer cells that present tumor antigen in the context on an HLA class I molecule. However......, it is also well established that cancer cells are often characterized by loss or down regulation of HLA class I molecules, documented in a variety of human tumors. Consequently, immune therapy building on CD8 T cells will be futile in patients harboring HLA class-I negative or deficient cancer cells...

Microscopic time-resolved imaging of singlet oxygen by delayed fluorescence in living cells.

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Scholz, Marek; Dědic, Roman; Hála, Jan

2017-11-08

Singlet oxygen is a highly reactive species which is involved in a number of processes, including photodynamic therapy of cancer. Its very weak near-infrared emission makes imaging of singlet oxygen in biological systems a long-term challenge. We address this challenge by introducing Singlet Oxygen Feedback Delayed Fluorescence (SOFDF) as a novel modality for semi-direct microscopic time-resolved wide-field imaging of singlet oxygen in biological systems. SOFDF has been investigated in individual fibroblast cells incubated with a well-known photosensitizer aluminium phthalocyanine tetrasulfonate. The SOFDF emission from the cells is several orders of magnitude stronger and much more readily detectable than the very weak near-infrared phosphorescence of singlet oxygen. Moreover, the analysis of SOFDF kinetics enables us to estimate the lifetimes of the involved excited states. Real-time SOFDF images with micrometer spatial resolution and submicrosecond temporal-resolution have been recorded. Interestingly, a steep decrease in the SOFDF intensity after the photodynamically induced release of a photosensitizer from lysosomes has been demonstrated. This effect could be potentially employed as a valuable diagnostic tool for monitoring and dosimetry in photodynamic therapy.

Hybrid clone cells derived from human breast epithelial cells and human breast cancer cells exhibit properties of cancer stem/initiating cells.

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Gauck, Daria; Keil, Silvia; Niggemann, Bernd; Zänker, Kurt S; Dittmar, Thomas

2017-08-02

The biological phenomenon of cell fusion has been associated with cancer progression since it was determined that normal cell × tumor cell fusion-derived hybrid cells could exhibit novel properties, such as enhanced metastatogenic capacity or increased drug resistance, and even as a mechanism that could give rise to cancer stem/initiating cells (CS/ICs). CS/ICs have been proposed as cancer cells that exhibit stem cell properties, including the ability to (re)initiate tumor growth. Five M13HS hybrid clone cells, which originated from spontaneous cell fusion events between M13SV1-EGFP-Neo human breast epithelial cells and HS578T-Hyg human breast cancer cells, and their parental cells were analyzed for expression of stemness and EMT-related marker proteins by Western blot analysis and confocal laser scanning microscopy. The frequency of ALDH1-positive cells was determined by flow cytometry using AldeRed fluorescent dye. Concurrently, the cells' colony forming capabilities as well as the cells' abilities to form mammospheres were investigated. The migratory activity of the cells was analyzed using a 3D collagen matrix migration assay. M13HS hybrid clone cells co-expressed SOX9, SLUG, CK8 and CK14, which were differently expressed in parental cells. A variation in the ALDH1-positive putative stem cell population was observed among the five hybrids ranging from 1.44% (M13HS-7) to 13.68% (M13HS-2). In comparison to the parental cells, all five hybrid clone cells possessed increased but also unique colony formation and mammosphere formation capabilities. M13HS-4 hybrid clone cells exhibited the highest colony formation capacity and second highest mammosphere formation capacity of all hybrids, whereby the mean diameter of the mammospheres was comparable to the parental cells. In contrast, the largest mammospheres originated from the M13HS-2 hybrid clone cells, whereas these cells' mammosphere formation capacity was comparable to the parental breast cancer cells. All M13HS

Differential Cytotoxic Potential of Silver Nanoparticles in Human Ovarian Cancer Cells and Ovarian Cancer Stem Cells

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Yun-Jung Choi

2016-12-01

Full Text Available The cancer stem cell (CSC hypothesis postulates that cancer cells are composed of hierarchically-organized subpopulations of cells with distinct phenotypes and tumorigenic capacities. As a result, CSCs have been suggested as a source of disease recurrence. Recently, silver nanoparticles (AgNPs have been used as antimicrobial, disinfectant, and antitumor agents. However, there is no study reporting the effects of AgNPs on ovarian cancer stem cells (OvCSCs. In this study, we investigated the cytotoxic effects of AgNPs and their mechanism of causing cell death in A2780 (human ovarian cancer cells and OvCSCs derived from A2780. In order to examine these effects, OvCSCs were isolated and characterized using positive CSC markers including aldehyde dehydrogenase (ALDH and CD133 by fluorescence-activated cell sorting (FACS. The anticancer properties of the AgNPs were evaluated by assessing cell viability, leakage of lactate dehydrogenase (LDH, reactive oxygen species (ROS, and mitochondrial membrane potential (mt-MP. The inhibitory effect of AgNPs on the growth of ovarian cancer cells and OvCSCs was evaluated using a clonogenic assay. Following 1–2 weeks of incubation with the AgNPs, the numbers of A2780 (bulk cells and ALDH+/CD133+ colonies were significantly reduced. The expression of apoptotic and anti-apoptotic genes was measured by real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR. Our observations showed that treatment with AgNPs resulted in severe cytotoxicity in both ovarian cancer cells and OvCSCs. In particular, AgNPs showed significant cytotoxic potential in ALDH+/CD133+ subpopulations of cells compared with other subpopulation of cells and also human ovarian cancer cells (bulk cells. These findings suggest that AgNPs can be utilized in the development of novel nanotherapeutic molecules for the treatment of ovarian cancers by specific targeting of the ALDH+/CD133+ subpopulation of cells.

Targeting Cell Polarity Machinery to Exhaust Breast Cancer Stem Cells

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2017-10-01

AWARD NUMBER: W81XWH-15-1-0644 TITLE: Targeting Cell Polarity Machinery to Exhaust Breast Cancer Stem Cells PRINCIPAL INVESTIGATOR: Chun-Ju...Targeting Cell Polarity Machinery to Exhaust Breast Cancer Stem Cells 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-15-1-0644 5c. PROGRAM ELEMENT...Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Cancer stem cells (CSCs), a cell population with acquired perpetuating self-renewal properties which

Growth delay of human bladder cancer cells by Prostate Stem Cell Antigen downregulation is associated with activation of immune signaling pathways

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Nicosia Alfredo

2010-04-01

Full Text Available Abstract Background Prostate stem cell antigen (PSCA is a glycosylphosphatidylinositol (GPI anchored protein expressed not only in prostate but also in pancreas and bladder cancer as shown by immunohistochemistry and mRNA analysis. It has been targeted by monoclonal antibodies in preclinical animal models and more recently in a clinical trial in prostate cancer patients. The biological role played in tumor growth is presently unknown. In this report we have characterized the contribution of PSCA expression to tumor growth. Methods A bladder cell line was engineered to express a doxycycline (dox regulated shRNA against PSCA. To shed light on the PSCA biological role in tumor growth, microarray analysis was carried out as a function of PSCA expression. Expression of gene set of interest was further analyzed by qPCR Results Down regulation of the PSCA expression was associated with reduced cell proliferation in vitro and in vivo. Mice bearing subcutaneous tumors showed a reduced tumor growth upon treatment with dox, which effectively induced shRNA against PSCA as revealed by GFP expression. Pathway analysis of deregulated genes suggests a statistical significant association between PSCA downregulation and activation of genes downstream of the IFNα/β receptor. Conclusions These experiments established for the first time a correlation between the level of PSCA expression and tumor growth and suggest a role of PSCA in counteracting the natural immune response.

Growth delay of human bladder cancer cells by Prostate Stem Cell Antigen downregulation is associated with activation of immune signaling pathways

International Nuclear Information System (INIS)

Marra, Emanuele; Ciliberto, Gennaro; Palombo, Fabio; Uva, Paolo; Viti, Valentina; Simonelli, Valeria; Dogliotti, Eugenia; De Rinaldis, Emanuele; Lahm, Armin; La Monica, Nicola; Nicosia, Alfredo

2010-01-01

Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI) anchored protein expressed not only in prostate but also in pancreas and bladder cancer as shown by immunohistochemistry and mRNA analysis. It has been targeted by monoclonal antibodies in preclinical animal models and more recently in a clinical trial in prostate cancer patients. The biological role played in tumor growth is presently unknown. In this report we have characterized the contribution of PSCA expression to tumor growth. A bladder cell line was engineered to express a doxycycline (dox) regulated shRNA against PSCA. To shed light on the PSCA biological role in tumor growth, microarray analysis was carried out as a function of PSCA expression. Expression of gene set of interest was further analyzed by qPCR Down regulation of the PSCA expression was associated with reduced cell proliferation in vitro and in vivo. Mice bearing subcutaneous tumors showed a reduced tumor growth upon treatment with dox, which effectively induced shRNA against PSCA as revealed by GFP expression. Pathway analysis of deregulated genes suggests a statistical significant association between PSCA downregulation and activation of genes downstream of the IFNα/β receptor. These experiments established for the first time a correlation between the level of PSCA expression and tumor growth and suggest a role of PSCA in counteracting the natural immune response

Assessment of Confounding in Studies of Delay and Survival

DEFF Research Database (Denmark)

Tørring, Marie Louise; Vedsted, Peter; Frydenberg, Morten

BACKGROUND: Whether longer time to diagnosis (diagnostic delay) in patients with cancer symptoms is directly and independently associated with poor prognosis cannot be determined in randomised controlled trials. Analysis of observational data is therefore necessary. Many previous studies of the i......BACKGROUND: Whether longer time to diagnosis (diagnostic delay) in patients with cancer symptoms is directly and independently associated with poor prognosis cannot be determined in randomised controlled trials. Analysis of observational data is therefore necessary. Many previous studies......) Clarify which factors are considered confounders or intermediate variables in the literature. 2) Assess how and to what extent these factors bias survival estimates. CONSIDERATIONS: As illustrated in Figure 1, symptoms of cancer may alert patients, GP's, and hospital doctors differently and influence both...... delay and survival time in different ways. We therefore assume that the impact of confounding factors depends on the type of delay studied (e.g., patient delay, GP delay, referral delay, or treatment delay). MATERIALS & METHODS: The project includes systematic review and methodological developments...

Cancer cell uptake behavior of Au nanoring and its localized surface plasmon resonance induced cell inactivation

International Nuclear Information System (INIS)

Chu, Che-Kuan; Tu, Yi-Chou; Chang, Yu-Wei; Chu, Chih-Ken; Chen, Shih-Yang; Chi, Ting-Ta; Kiang, Yean-Woei; Yang, Chih-Chung

2015-01-01

Au nanorings (NRIs), which have the localized surface plasmon resonance (LSPR) wavelength around 1058 nm, either with or without linked antibodies, are applied to SAS oral cancer cells for cell inactivation through the LSPR-induced photothermal effect when they are illuminated by a laser of 1065 nm in wavelength. Different incubation times of cells with Au NRIs are considered for observing the variations of cell uptake efficiency of Au NRI and the threshold laser intensity for cell inactivation. In each case of incubation time, the cell sample is washed for evaluating the total Au NRI number per cell adsorbed and internalized by the cells based on inductively coupled plasma mass spectrometry measurement. Also, the Au NRIs remaining on cell membrane are etched with KI/I 2 solution to evaluate the internalized Au NRI number per cell. The threshold laser intensities for cell inactivation before washout, after washout, and after KI/I 2 etching are calibrated from the circular area sizes of inactivated cells around the illuminated laser spot center with various laser power levels. By using Au NRIs with antibodies, the internalized Au NRI number per cell increases monotonically with incubation time up to 24 h. However, the number of Au NRI remaining on cell membrane reaches a maximum at 12 h in incubation time. The cell uptake behavior of an Au NRI without antibodies is similar to that with antibodies except that the uptake NRI number is significantly smaller and the incubation time for the maximum NRI number remaining on cell membrane is delayed to 20 h. By comparing the threshold laser intensities before and after KI/I 2 etching, it is found that the Au NRIs remaining on cell membrane cause more effective cancer cell inactivation, when compared with the internalized Au NRIs. (paper)

Advanced research on separating prostate cancer stem cells

International Nuclear Information System (INIS)

Hao Yumei; He Xin; Song Naling

2013-01-01

Prostate cancer is a common malignant tumor in male urinary system,and may easily develop into the hormone refractory prostate cancer which can hardly be cured. Recent studies had found that the prostate cancer stem cells may be the source of the prostate cancer's occurrence,development, metastasis and recurrence. The therapy targeting the prostate cancer stem cells may be the effective way to cure prostate cancer. But these cells is too low to be detected. The difficulty lies in the low separation efficiency of prostate cancer stem cell, so the effectively separating prostate cancer stem cells occupied the main position for the more in-depth research of prostate cancer stem cells. This paper reviews the research progress and existing problems on the several main separating methods of prostate cancer stem cells, includes the fluorescence activated cells sorting and magnetic activated cells sorting based on prostate cancer stem cell surface markers, the side-population sorting and serum-free medium sphere forming sorting based on prostate cancer stem cell's biology. (authors)

Social isolation and cancer management - advanced rectal cancer with patient delay following the 2011 triple disaster in Fukushima, Japan: a case report.

Science.gov (United States)

Ozaki, Akihiko; Leppold, Claire; Sawano, Toyoaki; Tsubokura, Masaharu; Tsukada, Manabu; Tanimoto, Tetsuya; Kami, Masahiro; Ohira, Hiromichi

2017-05-16

Little is known about the effects of social isolation in the elderly on their process of gaining health information and seeking health care. In March 2011, Fukushima, Japan experienced an earthquake, tsunami, and nuclear disaster, also known as Japan's triple disaster. In June 2016, an 80-year-old Japanese man, who lived alone after divorce at the age of 42, presented to our hospital with bloody stools and dizziness. Although his bloody stools initially occurred in May 2015, a year earlier, he did not pursue the possibility of malignancy. He was diagnosed as having stage IIIA rectal cancer. Detailed history taking revealed that he experienced social isolation after the disaster, due to the evacuation of his friends, losing his regular opportunities for socialization. He additionally reported that the current diagnosis of rectal cancer made him feel he had lost his health in addition to his social relationships. Although radical surgery was attempted, it failed to resect the lesion completely, and thereafter his disease gradually progressed. As support from family or friends was not available, he was not able to receive palliative radiation therapy or home-based care in his end-of-life period. He died at a long-term care facility in February 2017. This case suggests that intense social isolation after the Fukushima disaster was a likely contributor to the patient delay, poor treatment course, and poor outcome of an elderly patient with rectal cancer. Direct communication with family and friends may play an indispensable role in increasing health awareness and promoting health-seeking behaviors, and in the midst of social isolation, elderly patients with cancer may lose these opportunities and experience increased risk of patient delay. Although health care providers may be able to alleviate isolation-induced delay by promoting cancer knowledge and awareness widely among local residents, policy-led interventions at the community level may be essential to reducing

Restoration of Mitochondrial NAD+ Levels Delays Stem Cell Senescence and Facilitates Reprogramming of Aged Somatic Cells.

Science.gov (United States)

Son, Myung Jin; Kwon, Youjeong; Son, Taekwon; Cho, Yee Sook

2016-12-01

The fundamental tenet that aging is irreversible has been challenged by the development of reprogramming technology that can restore molecular and cellular age by reversing the progression of aging. The use of cells from aged individuals as sources for reprogramming or transplantation creates a major barrier in stem cell therapy with respect to cell quality and quantity. Here, we investigated the molecular features underlying senescence and rejuvenation during aged cell reprogramming and identified novel factors that can overcome age-associated barriers. Enzymes, such as nicotinamide nucleotide transhydrogenase (NNT) and nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3), that control mitochondrial NAD + levels appear to be susceptible to aging. In aged cells, mitochondrial NAD + levels decrease, accompanied by reduced SIRT3 activity; these changes severely impede cell fate transition. However, in cells collected from aged p16 knockout mice, which exhibit delayed cellular senescence, no changes in NNT or NMNAT3 expression were found. Importantly, restoring mitochondrial NAD + levels by overexpressing NNT and NMNAT3 enhanced reprogramming efficiency of aged somatic cells and extended the lifespan of human mesenchymal stem cells by delaying replicative senescence. These results demonstrate that maintenance of mitochondrial NAD + levels is critical for reversing the mechanisms of aging and ensuring that cells collected from aged individuals are of high quality. Stem Cells 2016;34:2840-2851. © 2016 AlphaMed Press.

Dendritic cell vaccination in combination with docetaxel for patients with metastatic castration-resistant prostate cancer

DEFF Research Database (Denmark)

Kongsted, Per; Borch, Troels Holz; Ellebaek, Eva

2017-01-01

Background aims  We investigated whether the addition of an autologous dendritic cell–based cancer vaccine (DCvac) induces an immune response in patients with metastatic castration-resistant prostate cancer treated with docetaxel.  Methods  Forty-three patients were randomized 1:1 to receive up...... twice through treatment cycles 1–4 and once through treatment cycles 5–10. Immune cell composition and antigen-specific responses were analyzed using flow cytometry, ELISpot and delayed type hypersensitivity (DTH) tests. Toxicity was graded according to Common Terminology Criteria for Adverse Events...... to local reactions. Decline in myeloid-derived suppressor cells at the third treatment cycle was found to be an independent predictor of DSS.  Conclusions  The addition of DCvac was safe. Immune responses were detected in approximately half of the patients investigated....

The cancer-germline antigen SSX2 causes cell cycle arrest and DNA damage in cancer cells

DEFF Research Database (Denmark)

Greve, Katrine Buch Vidén; Lindgreen, Jonas; Terp, Mikkel Green

2011-01-01

The SSX family of cancer and germline antigens is mainly expressed in the germ cells of healthy individuals as well as wide range of cancers and is therefore potential targets for immunotherapy. However, little is known about the role of SSX proteins in tumorigenesis and normal cell function. Here......, we show that SSX2 is involved in regulation of cancer cell growth. We found that ectopic expression of SSX2 in melanoma and colon cancer cells strongly reduced cell growth and induced apoptosis in vitro. Importantly, in a xenograft mouse model, the growth of tumors derived from SSX2 overexpressing...... melanoma cells was severely reduced compared to those derived from the isogenic parental cell line. Cell cycle analysis showed that SSX2 caused an accumulation of cells arrested in G1. Consistent with this, we observed a marked decrease in cells expressing the proliferation marker Ki67 and concomitantly...

Tumour cell lysate-loaded dendritic cell vaccine induces biochemical and memory immune response in castration-resistant prostate cancer patients.

Science.gov (United States)

Reyes, D; Salazar, L; Espinoza, E; Pereda, C; Castellón, E; Valdevenito, R; Huidobro, C; Inés Becker, M; Lladser, A; López, M N; Salazar-Onfray, F

2013-09-17

Recently, we produced a tumour antigen-presenting cells (TAPCells) vaccine using a melanoma cell lysate, called TRIMEL, as an antigen source and an activation factor. Tumour antigen-presenting cells induced immunological responses and increased melanoma patient survival. Herein, we investigated the effect of TAPCells loaded with prostate cancer cell lysates (PCCL) as an antigen source, and TRIMEL as a dendritic cell (DC) activation factor; which were co-injected with the Concholepas concholepas haemocyanin (CCH) as an adjuvant on castration-resistant prostate cancer (CRPC) patients. The lysate mix capacity, for inducing T-cell activation, was analysed by flow cytometry and Elispot. Delayed-type hypersensitivity (DTH) reaction against PCCL, frequency of CD8(+) memory T cells (Tm) in blood and prostate-specific antigen (PSA) levels in serum were measured in treated patients. The lysate mix induced functional mature DCs that were capable of activating PCCL-specific T cells. No relevant adverse reactions were observed. Six out of 14 patients showed a significant decrease in levels of PSA. DTH(+) patients showed a prolonged PSA doubling-time after treatment. Expansion of functional central and effector CD8(+) Tm were detected. Treatment of CRPC patients with lysate-loaded TAPCells and CCH as an adjuvant is safe: generating biochemical and memory immune responses. However, the limited number of cases requires confirmation in a phase II clinical trial.

Ursodeoxycholic acid inhibits the proliferation of colon cancer cells by regulating oxidative stress and cancer stem-like cell growth

Science.gov (United States)

Kim, EuiJoo

2017-01-01

Introduction The regulation of reactive oxygen species (ROS) exists as a therapeutic target for cancer treatments. Previous studies have shown that ursodeoxycholic acid (UDCA) suppresses the proliferation of colon cancer cells. The aim of this study was to evaluate the effect of UDCA upon the proliferation of colon cancer cells as a direct result of the regulation of ROS. Method Colon cancer cell lines (HT29 and HCT116) were treated with UDCA. The total number of cells and the number of dead cells were determined using cell counters. A fluorescein isothiocyanate-bromodeoxyuridine flow kit was used to analyze cell cycle variations. Upon exposure to UDCA, the protein levels of p27, p21, CDK2, CDK4 and CDK6 were determined using western blotting, and qRT-PCR was used to determine levels of mRNA. We preformed dichlorofluorescindiacetate (DCF-DA) staining to detect alteration of intracellular ROS using fluorescence activated cell sorting (FACS). Colon cancer stem-like cell lines were generated by tumorsphere culture and treated with UDCA for seven days. The total number of tumorspheres was determined using microscopy. Results We found that UDCA reduced the total number of colon cancer cells, but did not increase the number of dead cells. UDCA inhibited the G1/S and G2/M transition phases in colon cancer cells. UDCA induced expression of cell cycle inhibitors such as p27 and p21. However, it was determined that UDCA suppressed levels of CDK2, CDK4, and CDK6. UDCA regulated intracellular ROS generation in colon cancer cells, and induced activation of Erk1/2. Finally, UDCA inhibited formation of colon cancer stem-like cells. Conclusion Our results indicate that UDCA suppresses proliferation through regulation of oxidative stress in colon cancer cells, as well as colon cancer stem-like cells. PMID:28708871

Aberrant Apoptotic Response of Colorectal Cancer Cells to Novel Nucleoside Analogues.

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Leonie Harmse

Full Text Available Despite the increased understanding of colorectal cancer and the introduction of targeted drug therapy, the metastatic phase of the disease remains refractory to treatment. Since the deregulation of normal apoptosis contributes to the pathogenesis of colorectal cancer, novel nucleoside analogues were synthesized here and evaluated for their ability to induce apoptosis and cause cell death in two colorectal adeno-carcinoma cell lines, Caco-2 and HT-29. Three novel nucleoside analogues assessed here showed cytotoxic activity, as measured by the MTT assay against both cell lines: the IC50 values ranged between 3 and 37 μM, with Caco-2 cells being more sensitive than HT-29 cells. Compared to camptothecin, the positive control, the nucleoside analogues were significantly less toxic to normal unstimulated leukocytes (p>0.05. Moreover, the nucleosides were able to induce apoptosis as measured by an increase in caspase 8 and caspase 3 activity above that of the control. This was additionally supported by data derived from Annexin V-FITC assays. Despite marginal changes to the mitochondrial membrane potential, all three nucleosides caused a significant increase in cytosolic cytochrome c (p>0.05, with a corresponding decrease in mitochondrial cytochrome c. Morphological analysis of both cell lines showed the rapid appearance of vacuoles following exposure to two of the nucleosides, while a third caused cellular detachment, delayed cytoplasmic vacuolisation and nuclear abnormalities. Preliminary investigations, using the autophagic indicator monodansylcadaverine and chloroquine as positive control, showed that two of the nucleosides induced the formation of autophagic vacuoles. In summary, the novel nucleoside analogues showed selective cytotoxicity towards both cancer cell lines and are effective initiators of an unusual apoptotic response, demonstrating their potential to serve as structural scaffolds for more potent analogues.

Aberrant Apoptotic Response of Colorectal Cancer Cells to Novel Nucleoside Analogues.

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Harmse, Leonie; Dahan-Farkas, Nurit; Panayides, Jenny-Lee; van Otterlo, Willem; Penny, Clement

2015-01-01

Despite the increased understanding of colorectal cancer and the introduction of targeted drug therapy, the metastatic phase of the disease remains refractory to treatment. Since the deregulation of normal apoptosis contributes to the pathogenesis of colorectal cancer, novel nucleoside analogues were synthesized here and evaluated for their ability to induce apoptosis and cause cell death in two colorectal adeno-carcinoma cell lines, Caco-2 and HT-29. Three novel nucleoside analogues assessed here showed cytotoxic activity, as measured by the MTT assay against both cell lines: the IC50 values ranged between 3 and 37 μM, with Caco-2 cells being more sensitive than HT-29 cells. Compared to camptothecin, the positive control, the nucleoside analogues were significantly less toxic to normal unstimulated leukocytes (p>0.05). Moreover, the nucleosides were able to induce apoptosis as measured by an increase in caspase 8 and caspase 3 activity above that of the control. This was additionally supported by data derived from Annexin V-FITC assays. Despite marginal changes to the mitochondrial membrane potential, all three nucleosides caused a significant increase in cytosolic cytochrome c (p>0.05), with a corresponding decrease in mitochondrial cytochrome c. Morphological analysis of both cell lines showed the rapid appearance of vacuoles following exposure to two of the nucleosides, while a third caused cellular detachment, delayed cytoplasmic vacuolisation and nuclear abnormalities. Preliminary investigations, using the autophagic indicator monodansylcadaverine and chloroquine as positive control, showed that two of the nucleosides induced the formation of autophagic vacuoles. In summary, the novel nucleoside analogues showed selective cytotoxicity towards both cancer cell lines and are effective initiators of an unusual apoptotic response, demonstrating their potential to serve as structural scaffolds for more potent analogues.

Mesenchymal Stem Cells Induce Epithelial to Mesenchymal Transition in Colon Cancer Cells through Direct Cell-to-Cell Contact

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Hidehiko Takigawa

2017-05-01

Full Text Available We previously reported that in an orthotopic nude mouse model of human colon cancer, bone marrow–derived mesenchymal stem cells (MSCs migrated to the tumor stroma and promoted tumor growth and metastasis. Here, we evaluated the proliferation and migration ability of cancer cells cocultured with MSCs to elucidate the mechanism of interaction between cancer cells and MSCs. Proliferation and migration of cancer cells increased following direct coculture with MSCs but not following indirect coculture. Thus, we hypothesized that direct contact between cancer cells and MSCs was important. We performed a microarray analysis of gene expression in KM12SM colon cancer cells directly cocultured with MSCs. Expression of epithelial-mesenchymal transition (EMT–related genes such as fibronectin (FN, SPARC, and galectin 1 was increased by direct coculture with MSCs. We also confirmed the upregulation of these genes with real-time polymerase chain reaction. Gene expression was not elevated in cancer cells indirectly cocultured with MSCs. Among the EMT-related genes upregulated by direct coculture with MSCs, we examined the immune localization of FN, a well-known EMT marker. In coculture assay in chamber slides, expression of FN was seen only at the edges of cancer clusters where cancer cells directly contacted MSCs. FN expression in cancer cells increased at the tumor periphery and invasive edge in orthotopic nude mouse tumors and human colon cancer tissues. These results suggest that MSCs induce EMT in colon cancer cells via direct cell-to-cell contact and may play an important role in colon cancer metastasis.

General Information about Renal Cell Cancer

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... Tumors Treatment Genetics of Kidney Cancer Research Renal Cell Cancer Treatment (PDQ®)–Patient Version General Information About Renal Cell Cancer Go to Health Professional Version Key Points Renal ...

Treatment Option Overview (Renal Cell Cancer)

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... Tumors Treatment Genetics of Kidney Cancer Research Renal Cell Cancer Treatment (PDQ®)–Patient Version General Information About Renal Cell Cancer Go to Health Professional Version Key Points Renal ...

Ionizing radiation induces stemness in cancer cells.

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Laura Ghisolfi

Full Text Available The cancer stem cell (CSC model posits the presence of a small number of CSCs in the heterogeneous cancer cell population that are ultimately responsible for tumor initiation, as well as cancer recurrence and metastasis. CSCs have been isolated from a variety of human cancers and are able to generate a hierarchical and heterogeneous cancer cell population. CSCs are also resistant to conventional chemo- and radio-therapies. Here we report that ionizing radiation can induce stem cell-like properties in heterogeneous cancer cells. Exposure of non-stem cancer cells to ionizing radiation enhanced spherogenesis, and this was accompanied by upregulation of the pluripotency genes Sox2 and Oct3/4. Knockdown of Sox2 or Oct3/4 inhibited radiation-induced spherogenesis and increased cellular sensitivity to radiation. These data demonstrate that ionizing radiation can activate stemness pathways in heterogeneous cancer cells, resulting in the enrichment of a CSC subpopulation with higher resistance to radiotherapy.

Help seeking behavior of women with self-discovered breast cancer symptoms: a meta-ethnographic synthesis of patient delay.

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Zohreh Khakbazan

Full Text Available BACKGROUND AND OBJECTIVE: Patient delay makes a critical contribution to late diagnosis and poor survival in cases of breast cancer. Identifying the factors that influence patient delay could provide information for adopting strategies that shorten this delay. The aim of this meta-ethnography was to synthesize existing qualitative evidence in order to gain a new understanding of help seeking behavior in women with self-discovered breast cancer symptoms and to determine the factors that influence patient delay. METHODS: The design was a meta-ethnography approach. A systematic search of the articles was performed in different databases including Elsevier, PubMed, ProQuest and SCOPUS. Qualitative studies with a focus on help seeking behaviors in women with self-discovered breast cancer symptoms and patient delay, published in the English language between 1990 and 2013 were included. The quality appraisal of the articles was carried out using the Critical Appraisal Skills Programme qualitative research checklist and 13 articles met the inclusion criteria. The synthesis was conducted according to Noblit and Hare's meta-ethnographic approach (1988, through reciprocal translational analysis and lines-of-argument. FINDINGS: The synthesis led to identification of eight repeated key concepts including: symptom detection, initial symptom interpretation, symptom monitoring, social interaction, emotional reaction, priority of medical help, appraisal of health services and personal-environmental factors. Symptom interpretation is identified as the important step of the help seeking process and which changed across the process through active monitoring of their symptoms, social interactions and emotional reactions. The perceived seriousness of the situation, priority to receive medical attention, perceived inaccessibility and unacceptability of the health care system influenced women's decision-making about utilizing health services. CONCLUSION: Help seeking

Susceptibility of cancer cells to β-lapachone is enhanced by ionizing radiation

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Park, Heon Joo; Ahn, Ki-Jung; Ahn, Seung-Do; Choi, Eunkyung; Lee, Sang Wook; Williams, Brent; Kim, Eun Jung; Griffin, Robert; Bey, Erik A.; Bornmann, William G.; Gao, Jinming; Park, Heon Jin; Boothman, David A.; Song, Chang W.

2005-01-01

Purpose: To reveal the interaction between β-lapachone (β-lap) and ionizing radiation (IR) in causing clonogenic death in cancer cells and to elucidate the potential usefulness of β-lap treatment in combination with radiotherapy of cancer. Methods and materials: FSaII tumor cells of C3H mice were used. The cytotoxicity of β-lap alone or in combination with IR in vitro was determined using clonogenic survival assay method. The IR-induced changes in the expression and the enzymatic activity of NAD(P)H:quinone oxidoreductase (NQO1), a mediator of β-lap cytotoxicity, were elucidated and the relationship between the NQO1 level and the sensitivity of cells to β-lap was investigated. The combined effect of IR and β-lap to suppress tumor growth was studied using FSaII tumors grown subcutaneously in the thigh of C3H mice. Results: β-Lap caused clonogenic death of FSaII tumor cells in vitro in a dose- and time-dependent manner. When cells were treated first with β-lap and then exposed to IR in vitro, the resultant cell death was only additive. On the contrary, exposing cells to IR at 2.5 Gy first and then treating the cells with β-lap killed the cells in a synergistic manner. Importantly, the 2.5 Gy cells were sensitive to β-lap as long as 10 h after irradiation, which was long after the sublethal radiation damage was repaired. Irradiation of FSaII cells in vitro with 2.5 Gy significantly increased the expression and enzymatic activity of NQO1. The growth delay of FSaII tumors caused by an intraperitoneal injection of β-lap in combination with 20 Gy irradiation of tumor was significantly greater than that caused by β-lap or 20 Gy irradiation alone. Conclusion: The sensitivity of cells to β-lap is dependent on NQO1 activity. IR caused a long-lasting increase in NQO1 activity in cancer cells, thereby sensitizing cells to β-lap and treatment of experimental mouse tumors with IR and β-lap suppressed tumor growth in a synergistic manner. The combination of �

Extinction models for cancer stem cell therapy

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Sehl, Mary; Zhou, Hua; Sinsheimer, Janet S.; Lange, Kenneth L.

2012-01-01

Cells with stem cell-like properties are now viewed as initiating and sustaining many cancers. This suggests that cancer can be cured by driving these cancer stem cells to extinction. The problem with this strategy is that ordinary stem cells are apt to be killed in the process. This paper sets bounds on the killing differential (difference between death rates of cancer stem cells and normal stem cells) that must exist for the survival of an adequate number of normal stem cells. Our main tools are birth–death Markov chains in continuous time. In this framework, we investigate the extinction times of cancer stem cells and normal stem cells. Application of extreme value theory from mathematical statistics yields an accurate asymptotic distribution and corresponding moments for both extinction times. We compare these distributions for the two cell populations as a function of the killing rates. Perhaps a more telling comparison involves the number of normal stem cells NH at the extinction time of the cancer stem cells. Conditioning on the asymptotic time to extinction of the cancer stem cells allows us to calculate the asymptotic mean and variance of NH. The full distribution of NH can be retrieved by the finite Fourier transform and, in some parameter regimes, by an eigenfunction expansion. Finally, we discuss the impact of quiescence (the resting state) on stem cell dynamics. Quiescence can act as a sanctuary for cancer stem cells and imperils the proposed therapy. We approach the complication of quiescence via multitype branching process models and stochastic simulation. Improvements to the τ-leaping method of stochastic simulation make it a versatile tool in this context. We conclude that the proposed therapy must target quiescent cancer stem cells as well as actively dividing cancer stem cells. The current cancer models demonstrate the virtue of attacking the same quantitative questions from a variety of modeling, mathematical, and computational perspectives

BCL-2 family protein, BAD is down-regulated in breast cancer and inhibits cell invasion.

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Cekanova, Maria; Fernando, Romaine I; Siriwardhana, Nalin; Sukhthankar, Mugdha; De la Parra, Columba; Woraratphoka, Jirayus; Malone, Christine; Ström, Anders; Baek, Seung J; Wade, Paul A; Saxton, Arnold M; Donnell, Robert M; Pestell, Richard G; Dharmawardhane, Suranganie; Wimalasena, Jay

2015-02-01

We have previously demonstrated that the anti-apoptotic protein BAD is expressed in normal human breast tissue and shown that BAD inhibits expression of cyclin D1 to delay cell-cycle progression in breast cancer cells. Herein, expression of proteins in breast tissues was studied by immunohistochemistry and results were analyzed statistically to obtain semi-quantitative data. Biochemical and functional changes in BAD-overexpressing MCF7 breast cancer cells were evaluated using PCR, reporter assays, western blotting, ELISA and extracellular matrix invasion assays. Compared to normal tissues, Grade II breast cancers expressed low total/phosphorylated forms of BAD in both cytoplasmic and nuclear compartments. BAD overexpression decreased the expression of β-catenin, Sp1, and phosphorylation of STATs. BAD inhibited Ras/MEK/ERK and JNK signaling pathways, without affecting the p38 signaling pathway. Expression of the metastasis-related proteins, MMP10, VEGF, SNAIL, CXCR4, E-cadherin and TlMP2 was regulated by BAD with concomitant inhibition of extracellular matrix invasion. Inhibition of BAD by siRNA increased invasion and Akt/p-Akt levels. Clinical data and the results herein suggest that in addition to the effect on apoptosis, BAD conveys anti-metastatic effects and is a valuable prognostic marker in breast cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

Adipose tissue-derived stem cells promote pancreatic cancer cell proliferation and invasion

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Ji, S.Q.; Cao, J.; Zhang, Q.Y.; Li, Y.Y.; Yan, Y.Q.; Yu, F.X.

2013-01-01

To explore the effects of adipose tissue-derived stem cells (ADSCs) on the proliferation and invasion of pancreatic cancer cells in vitro and the possible mechanism involved, ADSCs were cocultured with pancreatic cancer cells, and a cell counting kit (CCK-8) was used to detect the proliferation of pancreatic cancer cells. ELISA was used to determine the concentration of stromal cell-derived factor-1 (SDF-1) in the supernatants. RT-PCR was performed to detect the expression of the chemokine receptor CXCR4 in pancreatic cancer cells and ADSCs. An in vitro invasion assay was used to measure invasion of pancreatic cancer cells. SDF-1 was detected in the supernatants of ADSCs, but not in pancreatic cancer cells. Higher CXCR4 mRNA levels were detected in the pancreatic cancer cell lines compared with ADSCs (109.3±10.7 and 97.6±7.6 vs 18.3±1.7, respectively; P<0.01). In addition, conditioned medium from ADSCs promoted the proliferation and invasion of pancreatic cancer cells, and AMD3100, a CXCR4 antagonist, significantly downregulated these growth-promoting effects. We conclude that ADSCs can promote the proliferation and invasion of pancreatic cancer cells, which may involve the SDF-1/CXCR4 axis

Adipose tissue-derived stem cells promote pancreatic cancer cell proliferation and invasion

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Ji, S.Q.; Cao, J. [Department of Liver Surgery I, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai (China); Zhang, Q.Y.; Li, Y.Y. [Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Wenzhou Medical College, Wenzhou (China); Yan, Y.Q. [Department of Liver Surgery I, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai (China); Yu, F.X. [Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Wenzhou Medical College, Wenzhou (China)

2013-09-27

To explore the effects of adipose tissue-derived stem cells (ADSCs) on the proliferation and invasion of pancreatic cancer cells in vitro and the possible mechanism involved, ADSCs were cocultured with pancreatic cancer cells, and a cell counting kit (CCK-8) was used to detect the proliferation of pancreatic cancer cells. ELISA was used to determine the concentration of stromal cell-derived factor-1 (SDF-1) in the supernatants. RT-PCR was performed to detect the expression of the chemokine receptor CXCR4 in pancreatic cancer cells and ADSCs. An in vitro invasion assay was used to measure invasion of pancreatic cancer cells. SDF-1 was detected in the supernatants of ADSCs, but not in pancreatic cancer cells. Higher CXCR4 mRNA levels were detected in the pancreatic cancer cell lines compared with ADSCs (109.3±10.7 and 97.6±7.6 vs 18.3±1.7, respectively; P<0.01). In addition, conditioned medium from ADSCs promoted the proliferation and invasion of pancreatic cancer cells, and AMD3100, a CXCR4 antagonist, significantly downregulated these growth-promoting effects. We conclude that ADSCs can promote the proliferation and invasion of pancreatic cancer cells, which may involve the SDF-1/CXCR4 axis.

Palmitate-induced ER stress increases trastuzumab sensitivity in HER2/neu-positive breast cancer cells

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Baumann, Jan; Wong, Jason; Sun, Yan; Conklin, Douglas S.

2016-01-01

HER2/neu-positive breast cancer cells have recently been shown to use a unique Warburg-like metabolism for survival and aggressive behavior. These cells exhibit increased fatty acid synthesis and storage compared to normal breast cells or other tumor cells. Disruption of this synthetic process results in apoptosis. Since the addition of physiological doses of exogenous palmitate induces cell death in HER2/neu-positive breast cancer cells, the pathway is likely operating at its limits in these cells. We have studied the response of HER2/neu-positive breast cancer cells to physiological concentrations of exogenous palmitate to identify lipotoxicity-associated consequences of this physiology. Since epidemiological data show that a diet rich in saturated fatty acids is negatively associated with the development of HER2/neu-positive cancer, this cellular physiology may be relevant to the etiology and treatment of the disease. We sought to identify signaling pathways that are regulated by physiological concentrations of exogenous palmitate specifically in HER2/neu-positive breast cancer cells and gain insights into the molecular mechanism and its relevance to disease prevention and treatment. Transcriptional profiling was performed to assess programs that are regulated in HER2-normal MCF7 and HER2/neu-positive SKBR3 breast cancer cells in response to exogenous palmitate. Computational analyses were used to define and predict functional relationships and identify networks that are differentially regulated in the two cell lines. These predictions were tested using reporter assays, fluorescence-based high content microscopy, flow cytometry and immunoblotting. Physiological effects were confirmed in HER2/neu-positive BT474 and HCC1569 breast cancer cell lines. Exogenous palmitate induces functionally distinct transcriptional programs in HER2/neu-positive breast cancer cells. In the lipogenic HER2/neu-positive SKBR3 cell line, palmitate induces a G2 phase cell cycle delay and

Wnt/β-catenin signaling regulates cancer stem cells in lung cancer A549 cells

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Teng, Ying; Wang, Xiuwen; Wang, Yawei; Ma, Daoxin

2010-01-01

Wnt/β-catenin signaling plays an important role not only in cancer, but also in cancer stem cells. In this study, we found that β-catenin and OCT-4 was highly expressed in cisplatin (DDP) selected A549 cells. Stimulating A549 cells with lithium chloride (LiCl) resulted in accumulation of β-catenin and up-regulation of a typical Wnt target gene cyclin D1. This stimulation also significantly enhanced proliferation, clone formation, migration and drug resistance abilities in A549 cells. Moreover, the up-regulation of OCT-4, a stem cell marker, was observed through real-time PCR and Western blotting. In a reverse approach, we inhibited Wnt signaling by knocking down the expression of β-catenin using RNA interference technology. This inhibition resulted in down-regulation of the Wnt target gene cyclin D1 as well as the proliferation, clone formation, migration and drug resistance abilities. Meanwhile, the expression of OCT-4 was reduced after the inhibition of Wnt/β-catenin signaling. Taken together, our study provides strong evidence that canonical Wnt signaling plays an important role in lung cancer stem cell properties, and it also regulates OCT-4, a lung cancer stem cell marker.

Targeting Stromal-Cancer Cell Crosstalk Networks in Ovarian Cancer Treatment

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Tsz-Lun Yeung

2016-01-01

Full Text Available Ovarian cancer is a histologically, clinically, and molecularly diverse disease with a five-year survival rate of less than 30%. It has been estimated that approximately 21,980 new cases of epithelial ovarian cancer will be diagnosed and 14,270 deaths will occur in the United States in 2015, making it the most lethal gynecologic malignancy. Ovarian tumor tissue is composed of cancer cells and a collection of different stromal cells. There is increasing evidence that demonstrates that stromal involvement is important in ovarian cancer pathogenesis. Therefore, stroma-specific signaling pathways, stroma-derived factors, and genetic changes in the tumor stroma present unique opportunities for improving the diagnosis and treatment of ovarian cancer. Cancer-associated fibroblasts (CAFs are one of the major components of the tumor stroma that have demonstrated supportive roles in tumor progression. In this review, we highlight various types of signaling crosstalk between ovarian cancer cells and stromal cells, particularly with CAFs. In addition to evaluating the importance of signaling crosstalk in ovarian cancer progression, we discuss approaches that can be used to target tumor-promoting signaling crosstalk and how these approaches can be translated into potential ovarian cancer treatment.

Tumorigenic hybrids between mesenchymal stem cells and gastric cancer cells enhanced cancer proliferation, migration and stemness

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Xue, Jianguo; Zhu, Yuan; Sun, Zixuan; Ji, Runbi; Zhang, Xu; Xu, Wenrong; Yuan, Xiao; Zhang, Bin; Yan, Yongmin; Yin, Lei; Xu, Huijuan; Zhang, Leilei; Zhu, Wei; Qian, Hui

2015-01-01

Emerging evidence indicates that inappropriate cell-cell fusion might contribute to cancer progression. Similarly, mesenchymal stem cells (MSCs) can also fuse with other cells spontaneously and capable of adopting the phenotype of other cells. The aim of our study was to investigate the role of MSCs participated cell fusion in the tumorigenesis of gastric cancer. We fused human umbilical cord mesenchymal stem cells (hucMSCs) with gastric cancer cells in vitro by polyethylene glycol (PEG), the hybrid cells were sorted by flow cytometer. The growth and migration of hybrids were assessed by cell counting, cell colony formation and transwell assays. The proteins and genes related to epithelial-mesenchymal transition and stemness were tested by western blot, immunocytochemistry and real-time RT-PCR. The expression of CD44 and CD133 was examined by immunocytochemistry and flow cytometry. The xenograft assay was used to evaluation the tumorigenesis of the hybrids. The obtained hybrids exhibited epithelial- mesenchymal transition (EMT) change with down-regulation of E-cadherin and up-regulation of Vimentin, N-cadherin, α-smooth muscle actin (α-SMA), and fibroblast activation protein (FAP). The hybrids also increased expression of stemness factors Oct4, Nanog, Sox2 and Lin28. The expression of CD44 and CD133 on hybrid cells was stronger than parental gastric cancer cells. Moreover, the migration and proliferation of heterotypic hybrids were enhanced. In addition, the heterotypic hybrids promoted the growth abilities of gastric xenograft tumor in vivo. Taken together, our results suggest that cell fusion between hucMSCs and gastric cancer cells could contribute to tumorigenic hybrids with EMT and stem cell-like properties, which may provide a flexible tool for investigating the roles of MSCs in gastric cancer. The online version of this article (doi:10.1186/s12885-015-1780-1) contains supplementary material, which is available to authorized users

Financial Toxicity among Patients with Bladder Cancer: Reasons for Delay in Care and Effect on Quality of Life.

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Casilla-Lennon, Marianne M; Choi, Seul Ki; Deal, Allison M; Bensen, Jeannette T; Narang, Gopal; Filippou, Pauline; McCormick, Benjamin; Pruthi, Raj; Wallen, Eric; Tan, Hung-Jui; Woods, Michael; Nielsen, Matthew; Smith, Angela

2018-05-01

Costly surveillance and treatment of bladder cancer can lead to financial toxicity, a treatment related financial burden. Our objective was to define the prevalence of financial toxicity among patients with bladder cancer and identify delays in care and its effect on health related quality of life. We identified patients with bladder cancer in the University of North Carolina Health Registry/Cancer Survivorship Cohort. Financial toxicity was defined as agreement with having "to pay more for medical care than you can afford." Health related quality of life was measured using general and cancer specific validated questionnaires. Statistical analyses were performed using the Fisher exact test and the Student t-test. A total of 138 patients with bladder cancer were evaluated. Median age was 66.9 years, 75% of the patients were male and 89% were white. Of the participants 33 (24%) endorsed financial toxicity. Participants who were younger (p = 0.02), black (p = 0.01), reported less than a college degree (p = 0.01) and had noninvasive disease (p = 0.04) were more likely to report financial toxicity. On multivariable analysis only age was a significant predictor of financial toxicity. Patients who endorsed financial toxicity were more likely to report delaying care (39% vs 23%, p = 0.07) due to the inability to take time off work or afford general expenses. On general health related quality of life questionnaires patients with financial toxicity reported worse physical and mental health (p = 0.03 and life (p = 0.01), physical well-being (p = 0.01) and functional well-being (p = 0.05). Financial toxicity is a major concern among patients with bladder cancer. Younger patients were more likely to experience financial toxicity. Those who endorsed financial toxicity experienced delays in care and poorer health related quality of life, suggesting that treatment costs should have an important role in medical decision making. Copyright © 2018 American Urological Association

Histone Deacetylase Inhibitor Induced Radiation Sensitization Effects on Human Cancer Cells after Photon and Hadron Radiation Exposure

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Ariungerel Gerelchuluun

2018-02-01

Full Text Available Suberoylanilide hydroxamic acid (SAHA is a histone deacetylase inhibitor, which has been widely utilized throughout the cancer research field. SAHA-induced radiosensitization in normal human fibroblasts AG1522 and lung carcinoma cells A549 were evaluated with a combination of γ-rays, proton, and carbon ion exposure. Growth delay was observed in both cell lines during SAHA treatment; 2 μM SAHA treatment decreased clonogenicity and induced cell cycle block in G1 phase but 0.2 μM SAHA treatment did not show either of them. Low LET (Linear Energy Transfer irradiated A549 cells showed radiosensitization effects on cell killing in cycling and G1 phase with 0.2 or 2 μM SAHA pretreatment. In contrast, minimal sensitization was observed in normal human cells after low and high LET radiation exposure. The potentially lethal damage repair was not affected by SAHA treatment. SAHA treatment reduced the rate of γ-H2AX foci disappearance and suppressed RAD51 and RPA (Replication Protein A focus formation. Suppression of DNA double strand break repair by SAHA did not result in the differences of SAHA-induced radiosensitization between human cancer cells and normal cells. In conclusion, our results suggest SAHA treatment will sensitize cancer cells to low and high LET radiation with minimum effects to normal cells.

The Implications of Cancer Stem Cells for Cancer Therapy

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Wenjing Jiang

2012-12-01

Full Text Available Surgery, radiotherapy and chemotherapy are universally recognized as the most effective anti-cancer therapies. Despite significant advances directed towards elucidating molecular mechanisms and developing clinical trials, cancer still remains a major public health issue. Recent studies have showed that cancer stem cells (CSCs, a small subpopulation of tumor cells, can generate bulk populations of nontumorigenic cancer cell progeny through the self-renewal and differentiation processes. As CSCs are proposed to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors, development of CSC-targeted therapeutic strategies holds new hope for improving survival and quality of life in patients with cancer. Therapeutic innovations will emerge from a better understanding of the biology and environment of CSCs, which, however, are largely unexplored. This review summarizes the characteristics, evidences and development of CSCs, as well as implications and challenges for cancer treatment.

Delayed animal aging through the recovery of stem cell senescence by platelet rich plasma.

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Liu, Hen-Yu; Huang, Chiung-Fang; Lin, Tzu-Chieh; Tsai, Ching-Yu; Tina Chen, Szu-Yu; Liu, Alice; Chen, Wei-Hong; Wei, Hong-Jian; Wang, Ming-Fu; Williams, David F; Deng, Win-Ping

2014-12-01

Aging is related to loss of functional stem cell accompanying loss of tissue and organ regeneration potentials. Previously, we demonstrated that the life span of ovariectomy-senescence accelerated mice (OVX-SAMP8) was significantly prolonged and similar to that of the congenic senescence-resistant strain of mice after platelet rich plasma (PRP)/embryonic fibroblast transplantation. The aim of this study is to investigate the potential of PRP for recovering cellular potential from senescence and then delaying animal aging. We first examined whether stem cells would be senescent in aged mice compared to young mice. Primary adipose derived stem cells (ADSCs) and bone marrow derived stem cells (BMSCs) were harvested from young and aged mice, and found that cell senescence was strongly correlated to animal aging. Subsequently, we demonstrated that PRP could recover cell potential from senescence, such as promote cell growth (cell proliferation and colony formation), increase osteogenesis, decrease adipogenesis, restore cell senescence related markers and resist the oxidative stress in stem cells from aged mice. The results also showed that PRP treatment in aged mice could delay mice aging as indicated by survival, body weight and aging phenotypes (behavior and gross morphology) in term of recovering the cellular potential of their stem cells compared to the results on aged control mice. In conclusion these findings showed that PRP has potential to delay aging through the recovery of stem cell senescence and could be used as an alternative medicine for tissue regeneration and future rejuvenation. Copyright © 2014 Elsevier Ltd. All rights reserved.

A POX on Renal Cancer Cells | Center for Cancer Research

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Proline oxidase, or POX, is an enzyme responsible for metabolizing the amino acid proline. POX contributes to the regulation of cell death that occurs when cellular systems malfunction, a process called apoptosis. Previous studies have determined that levels of POX are reduced in several types of human cancer. Likewise, many cancer cells become resistant to apoptosis, suggesting a link between POX and cancer cell survival.

Triiodothyronine regulates cell growth and survival in renal cell cancer.

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Czarnecka, Anna M; Matak, Damian; Szymanski, Lukasz; Czarnecka, Karolina H; Lewicki, Slawomir; Zdanowski, Robert; Brzezianska-Lasota, Ewa; Szczylik, Cezary

2016-10-01

Triiodothyronine plays an important role in the regulation of kidney cell growth, differentiation and metabolism. Patients with renal cell cancer who develop hypothyreosis during tyrosine kinase inhibitor (TKI) treatment have statistically longer survival. In this study, we developed cell based model of triiodothyronine (T3) analysis in RCC and we show the different effects of T3 on renal cell cancer (RCC) cell growth response and expression of the thyroid hormone receptor in human renal cell cancer cell lines from primary and metastatic tumors along with human kidney cancer stem cells. Wild-type thyroid hormone receptor is ubiquitously expressed in human renal cancer cell lines, but normalized against healthy renal proximal tube cell expression its level is upregulated in Caki-2, RCC6, SKRC-42, SKRC-45 cell lines. On the contrary the mRNA level in the 769-P, ACHN, HKCSC, and HEK293 cells is significantly decreased. The TRβ protein was abundant in the cytoplasm of the 786-O, Caki-2, RCC6, and SKRC-45 cells and in the nucleus of SKRC-42, ACHN, 769-P and cancer stem cells. T3 has promoting effect on the cell proliferation of HKCSC, Caki-2, ASE, ACHN, SK-RC-42, SMKT-R2, Caki-1, 786-0, and SK-RC-45 cells. Tyrosine kinase inhibitor, sunitinib, directly inhibits proliferation of RCC cells, while thyroid hormone receptor antagonist 1-850 (CAS 251310‑57-3) has less significant inhibitory impact. T3 stimulation does not abrogate inhibitory effect of sunitinib. Renal cancer tumor cells hypostimulated with T3 may be more responsive to tyrosine kinase inhibition. Moreover, some tumors may be considered as T3-independent and present aggressive phenotype with thyroid hormone receptor activated independently from the ligand. On the contrary proliferation induced by deregulated VHL and or c-Met pathways may transgress normal T3 mediated regulation of the cell cycle.

Gastric cancer stem cells: A novel therapeutic target

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Singh, Shree Ram

2013-01-01

Gastric cancer remains one of the leading causes of global cancer mortality. Multipotent gastric stem cells have been identified in both mouse and human stomachs, and they play an essential role in the self-renewal and homeostasis of gastric mucosa. There are several environmental and genetic factors known to promote gastric cancer. In recent years, numerous in vitro and in vivo studies suggest that gastric cancer may originate from normal stem cells or bone marrow–derived mesenchymal cells, and that gastric tumors contain cancer stem cells. Cancer stem cells are believed to share a common microenvironment with normal niche, which play an important role in gastric cancer and tumor growth. This mini-review presents a brief overview of the recent developments in gastric cancer stem cell research. The knowledge gained by studying cancer stem cells in gastric mucosa will support the development of novel therapeutic strategies for gastric cancer. PMID:23583679

Staphylococcus aureus Lpl Lipoproteins Delay G2/M Phase Transition in HeLa Cells.

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Nguyen, Minh-Thu; Deplanche, Martine; Nega, Mulugeta; Le Loir, Yves; Peisl, Loulou; Götz, Friedrich; Berkova, Nadia

2016-01-01

The cell cycle is an ordered set of events, leading to cell growth and division into two daughter cells. The eukaryotic cell cycle consists of interphase (G 1 , S, and G 2 phases), followed by the mitotic phase and G 0 phase. Many bacterial pathogens secrete cyclomodulins that interfere with the host cell cycle. In Staphylococcus aureus four cyclomodulins have been described so far that all represent toxins and are secreted into the culture supernatant. Here we show that the membrane-anchored lipoprotein-like proteins (Lpl), encoded on a genomic island called νSaα, interact with the cell cycle of HeLa cells. By comparing wild type and lpl deletion mutant it turned out that the lpl cluster is causative for the G2/M phase transition delay and also contributes to increased invasion frequency. The lipoprotein Lpl1, a representative of the lpl cluster, also caused G2/M phase transition delay. Interestingly, the lipid modification, which is essential for TLR2 signaling and activation of the immune system, is not necessary for cyclomodulin activity. Unlike the other staphylococcal cyclomodulins Lpl1 shows no cytotoxicity even at high concentrations. As all Lpl proteins are highly conserved there might be a common function that is accentuated by their multiplicity in a tandem gene cluster. The cell surface localized Lpls' suggests a correlation between G2/M phase transition delay and host cell invasion.

Cancer cells enter dormancy after cannibalizing mesenchymal stem/stromal cells (MSCs).

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Bartosh, Thomas J; Ullah, Mujib; Zeitouni, Suzanne; Beaver, Joshua; Prockop, Darwin J

2016-10-18

Patients with breast cancer often develop malignant regrowth of residual drug-resistant dormant tumor cells years after primary treatment, a process defined as cancer relapse. Deciphering the causal basis of tumor dormancy therefore has obvious therapeutic significance. Because cancer cell behavior is strongly influenced by stromal cells, particularly the mesenchymal stem/stromal cells (MSCs) that are actively recruited into tumor-associated stroma, we assessed the impact of MSCs on breast cancer cell (BCC) dormancy. Using 3D cocultures to mimic the cellular interactions of an emerging tumor niche, we observed that MSCs sequentially surrounded the BCCs, promoted formation of cancer spheroids, and then were internalized/degraded through a process resembling the well-documented yet ill-defined clinical phenomenon of cancer cell cannibalism. This suspected feeding behavior was less appreciable in the presence of a rho kinase inhibitor and in 2D monolayer cocultures. Notably, cannibalism of MSCs enhanced survival of BCCs deprived of nutrients but suppressed their tumorigenicity, together suggesting the cancer cells entered dormancy. Transcriptome profiles revealed that the resulting BCCs acquired a unique molecular signature enriched in prosurvival factors and tumor suppressors, as well as inflammatory mediators that demarcate the secretome of senescent cells, also referred to as the senescence-associated secretory phenotype. Overall, our results provide intriguing evidence that cancer cells under duress enter dormancy after cannibalizing MSCs. Importantly, our practical 3D coculture model could provide a valuable tool to understand the antitumor activity of MSCs and cell cannibalism further, and therefore open new therapeutic avenues for the prevention of cancer recurrence.

Targeting lipid metabolism of cancer cells: A promising therapeutic strategy for cancer.

Science.gov (United States)

Liu, Qiuping; Luo, Qing; Halim, Alexander; Song, Guanbin

2017-08-10

One of the most important metabolic hallmarks of cancer cells is deregulation of lipid metabolism. In addition, enhancing de novo fatty acid (FA) synthesis, increasing lipid uptake and lipolysis have also been considered as means of FA acquisition in cancer cells. FAs are involved in various aspects of tumourigenesis and tumour progression. Therefore, targeting lipid metabolism is a promising therapeutic strategy for human cancer. Recent studies have shown that reprogramming lipid metabolism plays important roles in providing energy, macromolecules for membrane synthesis, and lipid signals during cancer progression. Moreover, accumulation of lipid droplets in cancer cells acts as a pivotal adaptive response to harmful conditions. Here, we provide a brief review of the crucial roles of FA metabolism in cancer development, and place emphasis on FA origin, utilization and storage in cancer cells. Understanding the regulation of lipid metabolism in cancer cells has important implications for exploring a new therapeutic strategy for management and treatment of cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

Delay in diagnosis of cancer as a patient safety issue - a root cause analysis based on a representative case report

Directory of Open Access Journals (Sweden)

Mansour Paul

2011-07-01

Full Text Available Abstract Background It is well known in the literature that imaging has almost no value for diagnosis of superficial bladder cancer. However, wide gap exists between knowledge on diagnosis of bladder cancer and actual clinical practice. Case presentation Delay in diagnosis of bladder cancer in a male person with tetraplegia occurred because of reliance on negative flexible cystoscopy and single biopsy, negative ultrasound examination of urinary bladder, and computerised tomography of pelvis. Difficulties in scheduling cystoscopy also contributed to a delay of nearly ten months between the onset of haematuria and establishing a histological diagnosis of vesical malignancy in this patient. The time interval between transurethral resection and cystectomy was 42 days. This delay was mainly due to scheduling of surgery. Conclusion We learn from this case that doctors should be aware of the limitations of negative flexible cystoscopy and single biopsy, cytology of urine, ultrasound examination of urinary bladder, and computed tomography of pelvis for diagnosis of bladder cancer in spinal cord injury patients. Random bladder biopsies must be considered under general anaesthesia when there is high suspicion of bladder cancer. Spinal cord injury patients with lesions above T-6 may develop autonomic dysreflexia; therefore, one should be extremely well prepared to prevent or manage autonomic dysreflexia when performing cystoscopy and bladder biopsy. Spinal cord injury patients, who pass blood in urine, should be accorded top priority in scheduling of investigations and surgical procedures.

Osteoblast-Prostate Cancer Cell Interaction in Prostate Cancer Bone Metastases

National Research Council Canada - National Science Library

Navone, Nora

2001-01-01

.... This suggests that prostate cancer cells interact with cells from the osteoblastic lineage. To understand the molecular bases of prostatic bone metastases, we established two prostate cancer cell lines, MDA PCa 2a and MDA PCa 2b (1...

High-dimensional single-cell cancer biology.

Science.gov (United States)

Irish, Jonathan M; Doxie, Deon B

2014-01-01

Cancer cells are distinguished from each other and from healthy cells by features that drive clonal evolution and therapy resistance. New advances in high-dimensional flow cytometry make it possible to systematically measure mechanisms of tumor initiation, progression, and therapy resistance on millions of cells from human tumors. Here we describe flow cytometry techniques that enable a "single-cell " view of cancer. High-dimensional techniques like mass cytometry enable multiplexed single-cell analysis of cell identity, clinical biomarkers, signaling network phospho-proteins, transcription factors, and functional readouts of proliferation, cell cycle status, and apoptosis. This capability pairs well with a signaling profiles approach that dissects mechanism by systematically perturbing and measuring many nodes in a signaling network. Single-cell approaches enable study of cellular heterogeneity of primary tissues and turn cell subsets into experimental controls or opportunities for new discovery. Rare populations of stem cells or therapy-resistant cancer cells can be identified and compared to other types of cells within the same sample. In the long term, these techniques will enable tracking of minimal residual disease (MRD) and disease progression. By better understanding biological systems that control development and cell-cell interactions in healthy and diseased contexts, we can learn to program cells to become therapeutic agents or target malignant signaling events to specifically kill cancer cells. Single-cell approaches that provide deep insight into cell signaling and fate decisions will be critical to optimizing the next generation of cancer treatments combining targeted approaches and immunotherapy.

Colorectal cancer cells suppress CD4+ T cells immunity through canonical Wnt signaling.

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Sun, Xuan; Liu, Suoning; Wang, Daguang; Zhang, Yang; Li, Wei; Guo, Yuchen; Zhang, Hua; Suo, Jian

2017-02-28

Understanding how colorectal cancer escapes from immunosurveillance and immune attack is important for developing novel immunotherapies for colorectal cancer. In this study we evaluated the role of canonical Wnt signaling in the regulation of T cell function in a mouse colorectal cancer model. We found that colorectal cancer cells expressed abundant Wnt ligands, and intratumoral T cells expressed various Frizzled proteins. Meanwhile, both active β-catenin and total β-catenin were elevated in intratumoral T cells. In vitro study indicated that colorectal cancer cells suppressed IFN-γ expression and increased IL-17a expression in activated CD4+ T cells. However, the cytotoxic activity of CD8+ T cells was not altered by colorectal cancer cells. To further evaluate the importance of Wnt signaling for CD4+ T cell-mediated cancer immunity, β-catenin expression was enforced in CD4+ T cells using lentiviral transduction. In an adoptive transfer model, enforced expression of β-catenin in intratumoral CD4+ T cells increased IL-17a expression, enhanced proliferation and inhibited apoptosis of colorectal cancer cells. Taken together, our study disclosed a new mechanism by which colorectal cancer impairs T cell immunity.

TGF-β's delay skeletal muscle progenitor cell differentiation in an isoform-independent manner

International Nuclear Information System (INIS)

Schabort, Elske J.; Merwe, Mathilde van der; Loos, Benjamin; Moore, Frances P.; Niesler, Carola U.

2009-01-01

Satellite cells are a quiescent heterogenous population of mononuclear stem and progenitor cells which, once activated, differentiate into myotubes and facilitate skeletal muscle repair or growth. The Transforming Growth Factor-β (TGF-β) superfamily members are elevated post-injury and their importance in the regulation of myogenesis and wound healing has been demonstrated both in vitro and in vivo. Most studies suggest a negative role for TGF-β on satellite cell differentiation. However, none have compared the effect of these three isoforms on myogenesis in vitro. This is despite known isoform-specific effects of TGF-β1, -β2 and -β3 on wound repair in other tissues. In the current study we compared the effect of TGF-β1, -β2 and -β3 on proliferation and differentiation of the C2C12 myoblast cell-line. We found that, irrespective of the isoform, TGF-β increased proliferation of C2C12 cells by changing the cellular localisation of PCNA to promote cell division and prevent cell cycle exit. Concomitantly, TGF-β1, -β2 and -β3 delayed myogenic commitment by increasing MyoD degradation and decreasing myogenin expression. Terminal differentiation, as measured by a decrease in myosin heavy chain (MHC) expression, was also delayed. These results demonstrate that TGF-β promotes proliferation and delays differentiation of C2C12 myoblasts in an isoform-independent manner

General Information about Small Cell Lung Cancer

Science.gov (United States)

... Lung Cancer Prevention Lung Cancer Screening Research Small Cell Lung Cancer Treatment (PDQ®)–Patient Version General Information About Small Cell Lung Cancer Go to Health Professional Version Key Points Small ...

Mechanisms of Cancer Cell Dormancy--Another Hallmark of Cancer?

Science.gov (United States)

Yeh, Albert C; Ramaswamy, Sridhar

2015-12-01

Disease relapse in cancer patients many years after clinical remission, often referred to as cancer dormancy, is well documented but remains an incompletely understood phenomenon on the biologic level. Recent reviews have summarized potential models that can explain this phenomenon, including angiogenic, immunologic, and cellular dormancy. We focus on mechanisms of cellular dormancy as newer biologic insights have enabled better understanding of this process. We provide a historical context, synthesize current advances in the field, and propose a mechanistic framework that treats cancer cell dormancy as a dynamic cell state conferring a fitness advantage to an evolving malignancy under stress. Cellular dormancy appears to be an active process that can be toggled through a variety of signaling mechanisms that ultimately downregulate the RAS/MAPK and PI(3)K/AKT pathways, an ability that is preserved even in cancers that constitutively depend on these pathways for their growth and survival. Just as unbridled proliferation is a key hallmark of cancer, the ability of cancer cells to become quiescent may be critical to evolving malignancies, with implications for understanding cancer initiation, progression, and treatment resistance. ©2015 American Association for Cancer Research.

Invasive cancer cells and metastasis

Science.gov (United States)

Mierke, Claudia Tanja

2013-12-01

The physics of cancer is a relatively new emerging field of cancer research. In the last decade it has become a focus of biophysical research as well as becoming a novel focus for classical cancer research. This special section of Physical Biology focusing on invasive cancer cells and metastasis (physical oncology) will give greater insight into the different subfields where physical approaches are being applied to cancer research. This focus on the physical aspects of cancer is necessary because novel approaches in the field of genomics and proteomics have not altered the field of cancer research dramatically, due to the fact that few breakthroughs have been made. It is still not understood why some primary tumors metastasize and thus have a worse outcome compared to others that do not metastasize. As biophysicists, we and others suggest that the mechanical properties of the cancer cells, which possess the ability to transmigrate, are quite different compared to non-metastatic and non-invasive cancer cells. Furthermore, we hypothesize that these cancer cells undergo a selection process within the primary tumor that enables them to weaken their cell-cell adhesions and to alter their cell-matrix adhesions in order to be able to cross the outermost boundary of the primary tumor, as well as the surrounding basement membrane, and to invade the connective tissue. This prerequisite may also help the cancer cells to enter blood or lymph vessels, get transported with the vessel flow and form secondary tumors either within the vessel, directly on the endothelium, or in a different organ after crossing the endothelial lining a second time. This special section begins with a paper by Mark F Coughlin and Jeffrey J Fredberg on the changes in cytoskeletal dynamics and nonlinear rheology due to the metastatic capability of cancer cells from different cancer tissue types such as skin, bladder, prostate and kidney [1]. The hypothesis was that the metastatic outcome is impacted by

Extracellular ATP drives breast cancer cell migration and metastasis via S100A4 production by cancer cells and fibroblasts.

Science.gov (United States)

Liu, Ying; Geng, Yue-Hang; Yang, Hui; Yang, Han; Zhou, Yan-Ting; Zhang, Hong-Quan; Tian, Xin-Xia; Fang, Wei-Gang

2018-05-04

Our previous work has demonstrated that extracellular ATP is an important pro-invasive factor, and in this study, we tapped into a possible mechanism involved. We discovered that ATP could upregulate both the intracellular expression and secretion of S100A4 in breast cancer cells and fibroblasts. Apart from stimulating breast cancer cell motility via intracellular S100A4, ATP enhanced the ability of breast cancer cells to transform fibroblasts into cancer-associated fibroblast (CAF)-like cells, which in turn secreted S100A4 to further promote cancer cell motility. Both apyrase and niclosamide treatments could inhibit metastasis of inoculated tumors to lung, liver and kidney in mice model, and CAFs from these treated tumors exhibited weakened migration-stimulating capacity for breast cancer cells. Collectively, our data indicate that extracellular ATP promotes the interactions between breast cancer cells and fibroblasts, which work collaboratively via production of S100A4 to exacerbate breast cancer metastasis. Copyright © 2018. Published by Elsevier B.V.

Chronic Alcohol Ingestion Delays T Cell Activation and Effector Function in Sepsis.

Science.gov (United States)

Margoles, Lindsay M; Mittal, Rohit; Klingensmith, Nathan J; Lyons, John D; Liang, Zhe; Serbanescu, Mara A; Wagener, Maylene E; Coopersmith, Craig M; Ford, Mandy L

2016-01-01

Sepsis is the leading cause of death in intensive care units in the US, and it is known that chronic alcohol use is associated with higher incidence of sepsis, longer ICU stays, and higher mortality from sepsis. Both sepsis and chronic alcohol use are associated with immune deficits such as decreased lymphocyte numbers, impaired innate immunity, delayed-type hypersensitivity reactions, and susceptibility to infections; however, understanding of specific pathways of interaction or synergy between these two states of immune dysregulation is lacking. This study therefore sought to elucidate mechanisms underlying the immune dysregulation observed during sepsis in the setting of chronic alcohol exposure. Using a murine model of chronic ethanol ingestion followed by sepsis induction via cecal ligation and puncture, we determined that while CD4+ and CD8+ T cells isolated from alcohol fed mice eventually expressed the same cellular activation markers (CD44, CD69, and CD43) and effector molecules (IFN-γ, TNF) as their water fed counterparts, there was an overall delay in the acquisition of these phenotypes. This early lag in T cell activation was associated with significantly reduced IL-2 production at a later timepoint in both the CD4+ and CD8+ T cell compartments in alcohol sepsis, as well as with a reduced accumulation of CD8dim activated effectors. Taken together, these data suggest that delayed T cell activation may result in qualitative differences in the immune response to sepsis in the setting of chronic alcohol ingestion.

CD44 and SSEA-4 positive cells in an oral cancer cell line HSC-4 possess cancer stem-like cell characteristics.

Science.gov (United States)

Noto, Zenko; Yoshida, Toshiko; Okabe, Motonori; Koike, Chika; Fathy, Moustafa; Tsuno, Hiroaki; Tomihara, Kei; Arai, Naoya; Noguchi, Makoto; Nikaido, Toshio

2013-08-01

Cancer may be derived from cancer stem-like cells (CSCs), which are tumor-initiating cells that have properties similar to those of stem cells. Identification and isolation of CSCs needs to be improved further. CSCs markers were examined in human oral cancer cell lines by flow cytometry. The stem cell properties of subpopulations expressing different markers were assessed further by in vitro sphere formation assays, expression of stemness genes, drug resistance assays, and the ability to form tumors in nude mice. We demonstrated that CSCs could be isolated by the cell surface markers CD44 and stage-specific embryonic antigen-4 (SSEA-4). CD44+SSEA-4+ cells exhibited cancer stem-like properties, including extensive self-renewal into the bulk of cancer cells. In vivo xenograft experiments indicated that CD44+SSEA-4+ cells exhibit the highest tumorigenic capacity compared with the remaining subpopulations and parental cells. Double-positive cells for CD44 and SSEA-4 exhibited preferential expression of some stemness genes and were more resistant to the anticancer drugs, cisplatin and 5-fluorouracil (5-FU). In addition, cells expressing CD44 and SSEA-4 were detected in all tumor specimens analyzed, while coexpression of CD44 and SSEA-4 was not detectable in normal oral mucosa. Our findings suggest that CD44+SSEA-4+ cells exhibit the characteristics of CSCs in oral squamous cell carcinoma and provide a target for the development of more effective therapies. Copyright © 2013 Elsevier Ltd. All rights reserved.

Enhancing endogenous stem cells in the newbornvia delayed umbilical cord clamping

Institute of Scientific and Technical Information of China (English)

Christopher Lawton; Sandra Acosta; Nate Watson; Chiara Gonzales-Portillo; hTeo Diamandis; Naoki Tajiri; Yuji Kaneko; Paul R. Sanberg; Cesar V. Borlongan

2015-01-01

There is currently no consensus among clinicians and scientists over the appropriate or optimal timing for umbilical cord clamping. However, many clinical studies have suggested that delayed cord clamping is associated with various neonatal beneifts including increased blood volume, reduced need for blood transfusion, increased cerebral oxygenation in pre-term infants, and decreased frequency of iron deifciency anemia in term infants. Human umbilical cord blood con-tains signiifcant amounts of stem and progenitor cells and is currently used in the treatment of several life-threatening diseases. We propose that delayed cord clamping be encouraged as it en-hances blood lfow from the placenta to the neonate, which is accompanied by an increase supply of valuable stem and progenitor cells, as well as may improve blood oxygenation and increase blood volume, altogether reducing the infant’s susceptibility to both neonatal and age-related diseases.

Starvation-induced activation of ATM/Chk2/p53 signaling sensitizes cancer cells to cisplatin

Directory of Open Access Journals (Sweden)

Shi Yandong

2012-12-01

Full Text Available Abstract Background Optimizing the safety and efficacy of standard chemotherapeutic agents such as cisplatin (CDDP is of clinical relevance. Serum starvation in vitro and short-term food starvation in vivo both stress cells by the sudden depletion of paracrine growth stimulation. Methods The effects of serum starvation on CDDP toxicity were investigated in normal and cancer cells by assessing proliferation, cell cycle distribution and activation of DNA-damage response and of AMPK, and were compared to effects observed in cells grown in serum-containing medium. The effects of short-term food starvation on CDDP chemotherapy were assessed in xenografts-bearing mice and were compared to effects on tumor growth and/or regression determined in mice with no diet alteration. Results We observed that serum starvation in vitro sensitizes cancer cells to CDDP while protecting normal cells. In detail, in normal cells, serum starvation resulted in a complete arrest of cellular proliferation, i.e. depletion of BrdU-incorporation during S-phase and accumulation of the cells in the G0/G1-phase of the cell cycle. Further analysis revealed that proliferation arrest in normal cells is due to p53/p21 activation, which is AMPK-dependent and ATM-independent. In cancer cells, serum starvation also decreased the fraction of S-phase cells but to a minor extent. In contrast to normal cells, serum starvation-induced p53 activation in cancer cells is both AMPK- and ATM-dependent. Combination of CDDP with serum starvation in vitro increased the activation of ATM/Chk2/p53 signaling pathway compared to either treatment alone resulting in an enhanced sensitization of cancer cells to CDDP. Finally, short-term food starvation dramatically increased the sensitivity of human tumor xenografts to cisplatin as indicated not only by a significant growth delay, but also by the induction of complete remission in 60% of the animals bearing mesothelioma xenografts, and in 40% of the

T Cells in Gastric Cancer: Friends or Foes

Science.gov (United States)

Amedei, Amedeo; Della Bella, Chiara; Silvestri, Elena; Prisco, Domenico; D'Elios, Mario M.

2012-01-01

Gastric cancer is the second cause of cancer-related deaths worldwide. Helicobacter pylori is the major risk factor for gastric cancer. As for any type of cancer, T cells are crucial for recognition and elimination of gastric tumor cells. Unfortunately T cells, instead of protecting from the onset of cancer, can contribute to oncogenesis. Herein we review the different types, “friend or foe”, of T-cell response in gastric cancer. PMID:22693525

Xylitol induces cell death in lung cancer A549 cells by autophagy.

Science.gov (United States)

Park, Eunjoo; Park, Mi Hee; Na, Hee Sam; Chung, Jin

2015-05-01

Xylitol is a widely used anti-caries agent that has anti-inflammatory effects. We have evaluated the potential of xylitol in cancer treatment. It's effects on cell proliferation and cytotoxicity were measured by MTT assay and LDH assay. Cell morphology and autophagy were examined by immunostaining and immunoblotting. Xylitol inhibited cell proliferation in a dose-dependent manner in these cancer cells: A549, Caki, NCI-H23, HCT-15, HL-60, K562, and SK MEL-2. The IC50 of xylitol in human gingival fibroblast cells was higher than in cancer cells, indicating that it is more specific for cancer cells. Moreover, xylitol induced autophagy in A549 cells that was inhibited by 3-methyladenine, an autophagy inhibitor. These results indicate that xylitol has potential in therapy against lung cancer by inhibiting cell proliferation and inducing autophagy of A549 cells.

Adipose-derived stromal cells inhibit prostate cancer cell proliferation inducing apoptosis

Energy Technology Data Exchange (ETDEWEB)

Takahara, Kiyoshi [Department of Urology, Faculty of Medicine, Osaka Medical College, Osaka (Japan); Ii, Masaaki, E-mail: masaii@art.osaka-med.ac.jp [Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Osaka (Japan); Inamoto, Teruo; Komura, Kazumasa; Ibuki, Naokazu; Minami, Koichiro; Uehara, Hirofumi; Hirano, Hajime; Nomi, Hayahito; Kiyama, Satoshi [Department of Urology, Faculty of Medicine, Osaka Medical College, Osaka (Japan); Asahi, Michio [Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Osaka (Japan); Azuma, Haruhito [Department of Urology, Faculty of Medicine, Osaka Medical College, Osaka (Japan)

2014-04-18

Highlights: • AdSC transplantation exhibits inhibitory effect on tumor progressions of PCa cells. • AdSC-induced PCa cell apoptosis may occur via the TGF-β signaling pathway. • High expression of the TGF-β1 gene in AdSCs. - Abstract: Mesenchymal stem cells (MSCs) have generated a great deal of interest in the field of regenerative medicine. Adipose-derived stromal cells (AdSCs) are known to exhibit extensive proliferation potential and can undergo multilineage differentiation, sharing similar characteristics to bone marrow-derived MSCs. However, as the effect of AdSCs on tumor growth has not been studied sufficiently, we assessed the degree to which AdSCs affect the proliferation of prostate cancer (PCa) cell. Human AdSCs exerted an inhibitory effect on the proliferation of androgen-responsive (LNCaP) and androgen-nonresponsive (PC3) human PCa cells, while normal human dermal fibroblasts (NHDFs) did not, and in fact promoted PCa cell proliferation to a degree. Moreover, AdSCs induced apoptosis of LNCaP cells and PC3 cells, activating the caspase3/7 signaling pathway. cDNA microarray analysis suggested that AdSC-induced apoptosis in both LNCaP and PC3 cells was related to the TGF-β signaling pathway. Consistent with our in vitro observations, local transplantation of AdSCs delayed the growth of tumors derived from both LNCaP- and PC3-xenografts in immunodeficient mice. This is the first preclinical study to have directly demonstrated that AdSC-induced PCa cell apoptosis may occur via the TGF-β signaling pathway, irrespective of androgen-responsiveness. Since autologous AdSCs can be easily isolated from adipose tissue without any ethical concerns, we suggest that therapy with these cells could be a novel approach for patients with PCa.

Adipose-derived stromal cells inhibit prostate cancer cell proliferation inducing apoptosis

International Nuclear Information System (INIS)

Takahara, Kiyoshi; Ii, Masaaki; Inamoto, Teruo; Komura, Kazumasa; Ibuki, Naokazu; Minami, Koichiro; Uehara, Hirofumi; Hirano, Hajime; Nomi, Hayahito; Kiyama, Satoshi; Asahi, Michio; Azuma, Haruhito

2014-01-01

Highlights: • AdSC transplantation exhibits inhibitory effect on tumor progressions of PCa cells. • AdSC-induced PCa cell apoptosis may occur via the TGF-β signaling pathway. • High expression of the TGF-β1 gene in AdSCs. - Abstract: Mesenchymal stem cells (MSCs) have generated a great deal of interest in the field of regenerative medicine. Adipose-derived stromal cells (AdSCs) are known to exhibit extensive proliferation potential and can undergo multilineage differentiation, sharing similar characteristics to bone marrow-derived MSCs. However, as the effect of AdSCs on tumor growth has not been studied sufficiently, we assessed the degree to which AdSCs affect the proliferation of prostate cancer (PCa) cell. Human AdSCs exerted an inhibitory effect on the proliferation of androgen-responsive (LNCaP) and androgen-nonresponsive (PC3) human PCa cells, while normal human dermal fibroblasts (NHDFs) did not, and in fact promoted PCa cell proliferation to a degree. Moreover, AdSCs induced apoptosis of LNCaP cells and PC3 cells, activating the caspase3/7 signaling pathway. cDNA microarray analysis suggested that AdSC-induced apoptosis in both LNCaP and PC3 cells was related to the TGF-β signaling pathway. Consistent with our in vitro observations, local transplantation of AdSCs delayed the growth of tumors derived from both LNCaP- and PC3-xenografts in immunodeficient mice. This is the first preclinical study to have directly demonstrated that AdSC-induced PCa cell apoptosis may occur via the TGF-β signaling pathway, irrespective of androgen-responsiveness. Since autologous AdSCs can be easily isolated from adipose tissue without any ethical concerns, we suggest that therapy with these cells could be a novel approach for patients with PCa

Syncytin is involved in breast cancer-endothelial cell fusions

DEFF Research Database (Denmark)

Bjerregaard, Bolette; Holck, S.; Christensen, I.J.

2006-01-01

Cancer cells can fuse spontaneously with normal host cells, including endothelial cells, and such fusions may strongly modulate the biological behaviour of tumors. However, the underlying mechanisms are unknown. We now show that human breast cancer cell lines and 63 out of 165 (38%) breast cancer...... specimens express syncytin, an endogenous retroviral envelope protein, previously implicated in fusions between placental trophoblast cells. Additionally, endothelial and cancer cells are shown to express ASCT-2, a receptor for syncytin. Syncytin antisense treatment decreases syncytin expression...... and inhibits fusions between breast cancer cells and endothelial cells. Moreover, a syncytin inhibitory peptide also inhibits fusions between cancer and endothelial cells. These results are the first to show that syncytin is expressed by human cancer cells and is involved in cancer-endothelial cell fusions....

Sunscreens for delay of ultraviolet induction of skin tumors

International Nuclear Information System (INIS)

Wulf, H.C.; Poulsen, T.; Brodthagen, H.; Hou-Jensen, K.

1982-01-01

Sunscreens with different sun protection factors (SPFs) have been tested for their capability of delaying or preventing actinic damage and skin cancer development in groups of hairless, pigmented mice exposed to artificial ultraviolet (UV) light of increasing intensity. The dose delivered was less than or equal to 1 minimal erythema dose (MED) in the group of untreated mice, so that the mice to which sunscreens were applied never obtained a sunburn after UV exposure. The quality of UV light was similar to bright midday sun at a latitude of 56 degrees (city of Copenhagen). Tumorigenesis was demonstrated to be delayed corresponding to the SPF claimed by the manufacturer, but almost all of the UV-irradiated mice developed skin tumors. Histologic examination revealed actinic degeneration and tumors of squamous cell type with marked variation in differentiation. Metastases to lymph nodes and lungs were found in only 10%. Toxic reactions, such as eczematous-like skin reactions, dark coloring, and amyloidosis, were observed predominantly in the group treated with the sunscreen of highest SPF value. Long-term investigations seem to be necessary to unveil these problems--in particular, the specific SPF value, in sunscreens, that should be recommended to the public for prevention or delay of actinic damage and/or cancer development

Ell3 stimulates proliferation, drug resistance, and cancer stem cell properties of breast cancer cells via a MEK/ERK-dependent signaling pathway

Energy Technology Data Exchange (ETDEWEB)

Ahn, Hee-Jin [Department of Biomedical Science, College of Life Science, CHA University, Seoul (Korea, Republic of); Kim, Gwangil [Department of Pathology, CHA Bundang Medical Center, CHA University, Seoul (Korea, Republic of); Park, Kyung-Soon, E-mail: kspark@cha.ac.kr [Department of Biomedical Science, College of Life Science, CHA University, Seoul (Korea, Republic of)

2013-08-09

Highlights: •Ell3 enhances proliferation and drug resistance of breast cancer cell lines. •Ell3 is related to the cancer stem cell characteristics of breast cancer cell lines. •Ell3 enhances oncogenicity of breast cancer through the ERK1/2 signaling pathway. -- Abstract: Ell3 is a RNA polymerase II transcription elongation factor that is enriched in testis. The C-terminal domain of Ell3 shows strong similarities to that of Ell (eleven−nineteen lysine-rich leukemia gene), which acts as a negative regulator of p53 and regulates cell proliferation and survival. Recent studies in our laboratory showed that Ell3 induces the differentiation of mouse embryonic stem cells by protecting differentiating cells from apoptosis via the promotion of p53 degradation. In this study, we evaluated the function of Ell3 in breast cancer cell lines. MCF-7 cell lines overexpressing Ell3 were used to examine cell proliferation and cancer stem cell properties. Ectopic expression of Ell3 in breast cancer cell lines induces proliferation and 5-FU resistance. In addition, Ell3 expression increases the cancer stem cell population, which is characterized by CD44 (+) or ALDH1 (+) cells. Mammosphere-forming potential and migration ability were also increased upon Ell3 expression in breast cancer cell lines. Through biochemical and molecular biological analyses, we showed that Ell3 regulates proliferation, cancer stem cell properties and drug resistance in breast cancer cell lines partly through the MEK−extracellular signal-regulated kinase signaling pathway. Murine xenograft experiments showed that Ell3 expression promotes tumorigenesis in vivo. These results suggest that Ell3 may play a critical role in promoting oncogenesis in breast cancer by regulating cell proliferation and cancer stem cell properties via the ERK1/2 signaling pathway.

Ell3 stimulates proliferation, drug resistance, and cancer stem cell properties of breast cancer cells via a MEK/ERK-dependent signaling pathway

International Nuclear Information System (INIS)

Ahn, Hee-Jin; Kim, Gwangil; Park, Kyung-Soon

2013-01-01

Highlights: •Ell3 enhances proliferation and drug resistance of breast cancer cell lines. •Ell3 is related to the cancer stem cell characteristics of breast cancer cell lines. •Ell3 enhances oncogenicity of breast cancer through the ERK1/2 signaling pathway. -- Abstract: Ell3 is a RNA polymerase II transcription elongation factor that is enriched in testis. The C-terminal domain of Ell3 shows strong similarities to that of Ell (eleven−nineteen lysine-rich leukemia gene), which acts as a negative regulator of p53 and regulates cell proliferation and survival. Recent studies in our laboratory showed that Ell3 induces the differentiation of mouse embryonic stem cells by protecting differentiating cells from apoptosis via the promotion of p53 degradation. In this study, we evaluated the function of Ell3 in breast cancer cell lines. MCF-7 cell lines overexpressing Ell3 were used to examine cell proliferation and cancer stem cell properties. Ectopic expression of Ell3 in breast cancer cell lines induces proliferation and 5-FU resistance. In addition, Ell3 expression increases the cancer stem cell population, which is characterized by CD44 (+) or ALDH1 (+) cells. Mammosphere-forming potential and migration ability were also increased upon Ell3 expression in breast cancer cell lines. Through biochemical and molecular biological analyses, we showed that Ell3 regulates proliferation, cancer stem cell properties and drug resistance in breast cancer cell lines partly through the MEK−extracellular signal-regulated kinase signaling pathway. Murine xenograft experiments showed that Ell3 expression promotes tumorigenesis in vivo. These results suggest that Ell3 may play a critical role in promoting oncogenesis in breast cancer by regulating cell proliferation and cancer stem cell properties via the ERK1/2 signaling pathway

Cancer Stem Cells of Differentiated B-Cell Malignancies: Models and Consequences

Directory of Open Access Journals (Sweden)

Jean-Jacques Fournie

2011-03-01

Full Text Available The concept of cancer stem cells has revolutionized our current vision of cancer development and was validated in solid tumors and cancers of the primitive hematopoietic compartment. Proof of the principle is still lacking, however, in malignancies of differentiated B-cells. We review here the current literature, which nevertheless suggests hierarchical organizations of the tumor clone for mostly incurable B-cell cancers such as multiple myeloma, lymphomas and B-chronic lymphocytic leukemia. We propose two models accounting for cancer stem cells in these contexts: a “top-to-bottom” clonal hierarchy from memory B-cells and a “bottom-to-top” model of clonal reprogramming. Selection pressure on the growing tumor can drive such reprogramming and increase its genetic diversity.

Cancer Stem Cells of Differentiated B-Cell Malignancies: Models and Consequences

International Nuclear Information System (INIS)

Gross, Emilie; Quillet-Mary, Anne; Ysebaert, Loic; Laurent, Guy; Fournie, Jean-Jacques

2011-01-01

The concept of cancer stem cells has revolutionized our current vision of cancer development and was validated in solid tumors and cancers of the primitive hematopoietic compartment. Proof of the principle is still lacking, however, in malignancies of differentiated B-cells. We review here the current literature, which nevertheless suggests hierarchical organizations of the tumor clone for mostly incurable B-cell cancers such as multiple myeloma, lymphomas and B-chronic lymphocytic leukemia. We propose two models accounting for cancer stem cells in these contexts: a “top-to-bottom” clonal hierarchy from memory B-cells and a “bottom-to-top” model of clonal reprogramming. Selection pressure on the growing tumor can drive such reprogramming and increase its genetic diversity

The stem cell division theory of cancer.

Science.gov (United States)

López-Lázaro, Miguel

2018-03-01

All cancer registries constantly show striking differences in cancer incidence by age and among tissues. For example, lung cancer is diagnosed hundreds of times more often at age 70 than at age 20, and lung cancer in nonsmokers occurs thousands of times more frequently than heart cancer in smokers. An analysis of these differences using basic concepts in cell biology indicates that cancer is the end-result of the accumulation of cell divisions in stem cells. In other words, the main determinant of carcinogenesis is the number of cell divisions that the DNA of a stem cell has accumulated in any type of cell from the zygote. Cell division, process by which a cell copies and separates its cellular components to finally split into two cells, is necessary to produce the large number of cells required for living. However, cell division can lead to a variety of cancer-promoting errors, such as mutations and epigenetic mistakes occurring during DNA replication, chromosome aberrations arising during mitosis, errors in the distribution of cell-fate determinants between the daughter cells, and failures to restore physical interactions with other tissue components. Some of these errors are spontaneous, others are promoted by endogenous DNA damage occurring during quiescence, and others are influenced by pathological and environmental factors. The cell divisions required for carcinogenesis are primarily caused by multiple local and systemic physiological signals rather than by errors in the DNA of the cells. As carcinogenesis progresses, the accumulation of DNA errors promotes cell division and eventually triggers cell division under permissive extracellular environments. The accumulation of cell divisions in stem cells drives not only the accumulation of the DNA alterations required for carcinogenesis, but also the formation and growth of the abnormal cell populations that characterize the disease. This model of carcinogenesis provides a new framework for understanding the

Simultaneous Expression of Cancer Stem Cell-Like Properties and Cancer-Associated Fibroblast-Like Properties in a Primary Culture of Breast Cancer Cells

Energy Technology Data Exchange (ETDEWEB)

Ishikawa, Mami; Inoue, Takahiro; Shirai, Takuma; Takamatsu, Kazuhiko; Kunihiro, Shiori; Ishii, Hirokazu [Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, Kobe 650-0047 (Japan); Nishikata, Takahito, E-mail: nisikata@konan-u.ac.jp [Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, Kobe 650-0047 (Japan); Frontier Institute for Biomolecular Engineering Research (FIBER), Konan University, Kobe 650-0047 (Japan)

2014-07-31

The importance of cancer-associated fibroblasts (CAFs) in cancer biology has been recently highlighted owing to their critical roles in cancer growth, progression, metastasis, and therapeutic resistance. We have previously established a primary culture of breast cancer cells, which showed epithelial-mesenchymal transition and cancer stem cell-like properties. In this study, we found that the primary culture also showed CAF-like properties. For example, hypoxia inducible factor 1α (HIF1A) and its downstream genes, nuclear factor-kappa B2 (NF-κB2) and BCL2/adenovirus E1B 19 kd-interacting protein 3 (BNIP3), and many enzymes involved in glycolysis, such as GAPDH, LDH, PGAM1, and PKM2, were highly overexpressed in the primary culture. Moreover, media conditioned with the primary culture cells enhanced the growth of breast cancer cells. Similar to previous CAF studies, this enhancement suggested to be occurred through fibroblast growth factor signaling. This MCKH primary culture cell, which showed simultaneous expression of tumorigenic and CAF properties, offers a unique experimental system for studying the biology of CAFs.

Compensatory role of Neuroglobin in nervous and non-nervous cancer cells in response to the nutrient deprivation.

Directory of Open Access Journals (Sweden)

Marco Fiocchetti

Full Text Available Environmental factors or adverse growth conditions that may reduce cell function or viability are considered stress. The cell ability to sense and respond to environmental stresses determine its function and survival destiny. We recently defined Neuroglobin (NGB, a heme-protein, as a compensatory protein in the 17β-Estradiol (E2 anti-apoptotic activity and as a sensor of oxidative stress in both neurons and breast cancer cells. Here, the possibility that NGB levels could represent a pivotal regulator of integrated response of cancer cells to stress has been evaluated. Data obtained in neuroblastoma and in breast cancer cell lines evidence that nutrient deprivation significantly up-regulated NGB levels at different time points. However, the analysis of autophagy activation led to exclude any possible role of stress- or E2-induced NGB in the upstream regulation of general autophagy. However, the over-expression of Flag-NGB in ERα stable transfected HEK-293 cells completely affects nutrient deprivation-induced decrease in cell number. In addition, reported results indicate that modulation of the anti-apoptotic Bcl-2 level may play a key role in the protective NGB function against energetic stress. Overall, these data define a role of NGB as compensatory protein in the cell machinery activated in response to stress and as general stress adaptation marker of cancer cells susceptible to oxidative stress, oxygen and, as demonstrated here for the first time, even to nutrient willingness. Despite the lacking of any direct NGB role on autophagic flux activated by energetic stress, NGB upregulation appears functional in delaying stress-related cell death allowing an appropriate cell response and adaptation to the changing extracellular conditions.

Up-regulated microRNA-143 in cancer stem cells differentiation promotes prostate cancer cells metastasis by modulating FNDC3B expression

International Nuclear Information System (INIS)

Fan, Xinlan; Chen, Xu; Deng, Weixi; Zhong, Guangzheng; Cai, Qingqing; Lin, Tianxin

2013-01-01

Metastatic prostate cancer is a leading cause of cancer-related death in men. Cancer stem cells (CSCs) are involved in tumor progression and metastasis, including in prostate cancer. There is an obvious and urgent need for effective cancer stem cells specific therapies in metastatic prostate cancer. MicroRNAs (miRNAs) are an important class of pervasive genes that are involved in a variety of biological functions, especially in cancer. The goal of this study was to identify miRNAs involved in prostate cancer metastasis and cancer stem cells. A microarray and qRT-PCR were performed to investigate the miRNA expression profiles in PC-3 sphere cells and adherent cells. A transwell assay was used to evaluate the migration of PC-3 sphere cells and adherent cells. MiR-143 was silenced with antisense oligonucleotides in PC-3, PC-3-M and LNCaP cells. The role of miR-143 in prostate cancer metastasis was measured by wound-healing and transwell assays in vitro and bioluminescence imaging in vivo. Bioinformatics and luciferase report assays were used to identify the target of miR-143. The expression of miR-143 and the migration capability were reduced in PC-3 sphere cells and progressively increased during sphere re-adherent culture. Moreover, the down-regulation of miR-143 suppressed prostate cancer cells migration and invasion in vitro and systemically inhibited metastasis in vivo. Fibronectin type III domain containing 3B (FNDC3B), which regulates cell motility, was identified as a target of miR-143. The inhibition of miR-143 increased the expression of FNDC3B protein but not FNDC3B mRNA in vitro and vivo. These data demonstrate for the first time that miR-143 was up-regulated during the differentiation of prostate cancer stem cells and promoted prostate cancer metastasis by repressing FNDC3B expression. This sheds a new insight into the post-transcriptional regulation of cancer stem cells differentiation by miRNAs, a potential approach for the treatment of prostate cancer

Association of Knowledge and Cultural Perceptions of Malaysian Women with Delay in Diagnosis and Treatment of Breast Cancer: a Systematic Review.

Science.gov (United States)

Khan, Tahir Mehmood; Leong, Jamie Pik Yan; Ming, Long Chiau; Khan, Amer Hayat

2015-01-01

Breast cancer is the most common cancer and the leading cause of cancer mortality among women of all ethnic and age groups in Malaysia. Delay in seeking help for breast cancer symptoms is preventable and by identifying possible factors for delayed diagnosis, patient prognosis and survival rates could be improved. This narrative review aimed to understand and evaluate the level of in-depth breast cancer knowledge in terms of clinical breast examination and breast self-examination, and other important aspects such as side-effects and risk factors in Malaysian females. Since Malaysia is multicultural, this review assessed social perceptions, cultural beliefs and help-seeking behaviour in respect to breast cancer among different ethnic groups, since these may impinge on efforts to 'avoid' the disease. A comprehensive literature search of seven databases was performed from December 2015 to January 2015. Screening of relevant published journals was also undertaken to identify available information related to the knowledge, perception and help-seeking behaviour of Malaysian women in relation to breast cancer. A total of 42 articles were appraised and included in this review. Generally, women in Malaysia had good awareness of breast cancer and its screening tools, particularly breast self-examination, but only superficial in-depth knowledge about the disease. Women in rural areas had lower levels of knowledge than those in urban areas. It was also shown that books, magazines, brochures and television were among the most common sources of breast cancer information. Delay in presentation was attributed mainly to a negative social perception of the disease, poverty, cultural and religion practices, and a strong influence of complementary and alternative medicine, rather than a lack of knowledge. This review highlighted the need for an intensive and in-depth breast cancer education campaigns using media and community health programmes, even with the existing good awareness of

Fingerprints in cancer cells

International Nuclear Information System (INIS)

Servomaa, K.

1994-01-01

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

Delayed cell death associated with mitotic catastrophe in γ-irradiated stem-like glioma cells

International Nuclear Information System (INIS)

Firat, Elke; Gaedicke, Simone; Tsurumi, Chizuko; Esser, Norbert; Weyerbrock, Astrid; Niedermann, Gabriele

2011-01-01

Stem-like tumor cells are regarded as highly resistant to ionizing radiation (IR). Previous studies have focused on apoptosis early after irradiation, and the apoptosis resistance observed has been attributed to reduced DNA damage or enhanced DNA repair compared to non-stem tumor cells. Here, early and late radioresponse of patient-derived stem-like glioma cells (SLGCs) and differentiated cells directly derived from them were examined for cell death mode and the influence of stem cell-specific growth factors. Primary SLGCs were propagated in serum-free medium with the stem-cell mitogens epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF-2). Differentiation was induced by serum-containing medium without EGF and FGF. Radiation sensitivity was evaluated by assessing proliferation, clonogenic survival, apoptosis, and mitotic catastrophe. DNA damage-associated γH2AX as well as p53 and p21 expression were determined by Western blots. SLGCs failed to apoptose in the first 4 days after irradiation even at high single doses up to 10 Gy, but we observed substantial cell death later than 4 days postirradiation in 3 of 6 SLGC lines treated with 5 or 10 Gy. This delayed cell death was observed in 3 of the 4 SLGC lines with nonfunctional p53, was associated with mitotic catastrophe and occurred via apoptosis. The early apoptosis resistance of the SLGCs was associated with lower γH2AX compared to differentiated cells, but we found that the stem-cell culture cytokines EGF plus FGF-2 strongly reduce γH2AX levels. Nonetheless, in two p53-deficient SLGC lines examined γIR-induced apoptosis even correlated with EGF/FGF-induced proliferation and mitotic catastrophe. In a line containing CD133-positive and -negative stem-like cells, the CD133-positive cells proliferated faster and underwent more γIR-induced mitotic catastrophe. Our results suggest the importance of delayed apoptosis, associated mitotic catastrophe, and cellular proliferation for γIR-induced death of

Cell plasticity and heterogeneity in cancer.

Science.gov (United States)

Marjanovic, Nemanja D; Weinberg, Robert A; Chaffer, Christine L

2013-01-01

Heterogeneity within a given cancer arises from diverse cell types recruited to the tumor and from genetic and/or epigenetic differences amongst the cancer cells themselves. These factors conspire to create a disease with various phenotypes. There are 2 established models of cancer development and progression to metastatic disease. These are the clonal evolution and cancer stem cell models. The clonal evolution theory suggests that successive mutations accumulating in a given cell generate clonal outgrowths that thrive in response to microenvironmental selection pressures, dictating the phenotype of the tumor. The alternative cancer stem cell (CSC) model suggests that cancer cells with similar genetic backgrounds can be hierarchically organized according to their tumorigenic potential. Accordingly, CSCs reside at the apex of the hierarchy and are thought to possess the majority of a cancer's tumor-initiating and metastatic ability. A defining feature of this model is its apparent unidirectional nature, whereby CSCs undergo symmetric division to replenish the CSC pool and irreversible asymmetric division to generate daughter cells (non-CSCs) with low tumorigenic potential. However, evolving evidence supports a new model of tumorigenicity, in which considerable plasticity exists between the non-CSC and CSC compartments, such that non-CSCs can reacquire a CSC phenotype. These findings suggest that some tumors may adhere to a plastic CSC model, in which bidirectional conversions are common and essential components of tumorigenicity. Accumulating evidence surrounding the plasticity of cancer cells, in particular, suggests that aggressive CSCs can be created de novo within a tumor. Given the current focus on therapeutic targeting of CSCs, we discuss the implications of non-CSC-to-CSC conversions on the development of future therapies. © 2012 American Association for Clinical Chemistry

Dynamics of an HBV/HCV infection model with intracellular delay and cell proliferation

Science.gov (United States)

Zhang, Fengqin; Li, Jianquan; Zheng, Chongwu; Wang, Lin

2017-01-01

A new mathematical model of hepatitis B/C virus (HBV/HCV) infection which incorporates the proliferation of healthy hepatocyte cells and the latent period of infected hepatocyte cells is proposed and studied. The dynamics is analyzed via Pontryagin's method and a newly proposed alternative geometric stability switch criterion. Sharp conditions ensuring stability of the infection persistent equilibrium are derived by applying Pontryagin's method. Using the intracellular delay as the bifurcation parameter and applying an alternative geometric stability switch criterion, we show that the HBV/HCV infection model undergoes stability switches. Furthermore, numerical simulations illustrate that the intracellular delay can induce complex dynamics such as persistence bubbles and chaos.

Cellular responses to a prolonged delay in mitosis are determined by a DNA damage response controlled by Bcl-2 family proteins.

Science.gov (United States)

Colin, Didier J; Hain, Karolina O; Allan, Lindsey A; Clarke, Paul R

2015-03-01

Anti-cancer drugs that disrupt mitosis inhibit cell proliferation and induce apoptosis, although the mechanisms of these responses are poorly understood. Here, we characterize a mitotic stress response that determines cell fate in response to microtubule poisons. We show that mitotic arrest induced by these drugs produces a temporally controlled DNA damage response (DDR) characterized by the caspase-dependent formation of γH2AX foci in non-apoptotic cells. Following exit from a delayed mitosis, this initial response results in activation of DDR protein kinases, phosphorylation of the tumour suppressor p53 and a delay in subsequent cell cycle progression. We show that this response is controlled by Mcl-1, a regulator of caspase activation that becomes degraded during mitotic arrest. Chemical inhibition of Mcl-1 and the related proteins Bcl-2 and Bcl-xL by a BH3 mimetic enhances the mitotic DDR, promotes p53 activation and inhibits subsequent cell cycle progression. We also show that inhibitors of DDR protein kinases as well as BH3 mimetics promote apoptosis synergistically with taxol (paclitaxel) in a variety of cancer cell lines. Our work demonstrates the role of mitotic DNA damage responses in determining cell fate in response to microtubule poisons and BH3 mimetics, providing a rationale for anti-cancer combination chemotherapies.

Are Mast Cells MASTers in Cancer?

Science.gov (United States)

Varricchi, Gilda; Galdiero, Maria Rosaria; Loffredo, Stefania; Marone, Giancarlo; Iannone, Raffaella; Marone, Gianni; Granata, Francescopaolo

2017-01-01

Prolonged low-grade inflammation or smoldering inflammation is a hallmark of cancer. Mast cells form a heterogeneous population of immune cells with differences in their ultra-structure, morphology, mediator content, and surface receptors. Mast cells are widely distributed throughout all tissues and are stromal components of the inflammatory microenvironment that modulates tumor initiation and development. Although canonically associated with allergic disorders, mast cells are a major source of pro-tumorigenic (e.g., angiogenic and lymphangiogenic factors) and antitumorigenic molecules (e.g., TNF-α and IL-9), depending on the milieu. In certain neoplasias (e.g., gastric, thyroid and Hodgkin's lymphoma) mast cells play a pro-tumorigenic role, in others (e.g., breast cancer) a protective role, whereas in yet others they are apparently innocent bystanders. These seemingly conflicting results suggest that the role of mast cells and their mediators could be cancer specific. The microlocalization (e.g., peritumoral vs intratumoral) of mast cells is another important aspect in the initiation/progression of solid and hematologic tumors. Increasing evidence in certain experimental models indicates that targeting mast cells and/or their mediators represent a potential therapeutic target in cancer. Thus, mast cells deserve focused consideration also as therapeutic targets in different types of tumors. There are many unanswered questions that should be addressed before we understand whether mast cells are an ally, adversary, or innocent bystanders in human cancers.

Cancer stem cells of the digestive system.

Science.gov (United States)

Colvin, Hugh S; Nishida, Naohiro; Koseki, Jun; Konno, Masamitsu; Kawamoto, Koichi; Tsunekuni, Kenta; Doki, Yuichiro; Mori, Masaki; Ishii, Hideshi

2014-12-01

Stem cells of the digestive system are ideal in many ways for research, given they are abundant, highly proliferative and have a uniform structural arrangement. This in turn has enormously aided the research of cancer stem cells of the digestive system, which is now shaping our understanding of cancer stem cells. In this review, the recent advances in the understanding of cancer stem cells of the digestive system have been summarized, including aspects such as their identification, origin, cell-cycle dormancy, relationship with epithelial-mesenchymal transition, cellular metabolism and the underlying molecular mechanisms. Newly acquired knowledge concerning cancer stem cells have led to the development of novel cancer therapeutics with provisional yet encouraging results. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Nucleolar re-activation is delayed in mouse embryos cloned from two different cell lines

DEFF Research Database (Denmark)

Svarcova, Olga; Dinnyes, A.; Polgar, Z.

2009-01-01

displayed early NPBs transformation. In conclusion, despite normal onset of EGA in cloned embryos, activation of functional nucleoli was one cell cycle delayed in NT embryos. NT-MEF embryos displayed normal targeting but delayed activation of nucleolar proteins. Contrary, in NT-HM1 embryos, both......Aim of this study was to evaluate and compare embryonic genome activation (EGA) in mouse embryos of different origin using nucleolus as a marker. Early and late 2-cell and late 4-cell stage embryos, prepared by in vitro fertilization (IVF), parthenogenetic activation (PG), and nuclear transfer...... ofmouse embryonic fibroblast (MEF) and mouse HM1 emryonic stem cells (HM1), were processed for autoradiography following 3H-uridine incubation (transcriptional activity), transmission electron microscopy (ultrastructure) and immunofluorescence (nucleolar proteins; upstream binding factor, UBF...

Multiple Time-Point 68Ga-PSMA I&T PET/CT for Characterization of Primary Prostate Cancer: Value of Early Dynamic and Delayed Imaging.

Science.gov (United States)

Schmuck, Sebastian; Mamach, Martin; Wilke, Florian; von Klot, Christoph A; Henkenberens, Christoph; Thackeray, James T; Sohns, Jan M; Geworski, Lilli; Ross, Tobias L; Wester, Hans-Juergen; Christiansen, Hans; Bengel, Frank M; Derlin, Thorsten

2017-06-01

The aims of this study were to gain mechanistic insights into prostate cancer biology using dynamic imaging and to evaluate the usefulness of multiple time-point Ga-prostate-specific membrane antigen (PSMA) I&T PET/CT for the assessment of primary prostate cancer before prostatectomy. Twenty patients with prostate cancer underwent Ga-PSMA I&T PET/CT before prostatectomy. The PET protocol consisted of early dynamic pelvic imaging, followed by static scans at 60 and 180 minutes postinjection (p.i.). SUVs, time-activity curves, quantitative analysis based on a 2-tissue compartment model, Patlak analysis, histopathology, and Gleason grading were compared between prostate cancer and benign prostate gland. Primary tumors were identified on both early dynamic and delayed imaging in 95% of patients. Tracer uptake was significantly higher in prostate cancer compared with benign prostate tissue at any time point (P ≤ 0.0003) and increased over time. Consequently, the tumor-to-nontumor ratio within the prostate gland improved over time (2.8 at 10 minutes vs 17.1 at 180 minutes p.i.). Tracer uptake at both 60 and 180 minutes p.i. was significantly higher in patients with higher Gleason scores (P dynamic and static delayed Ga-PSMA ligand PET images. The tumor-to-nontumor ratio in the prostate gland improves over time, supporting a role of delayed imaging for optimal visualization of prostate cancer.

Cancer cell-secreted IGF2 instigates fibroblasts and bone marrow-derived vascular progenitor cells to promote cancer progression.

Science.gov (United States)

Xu, Wen Wen; Li, Bin; Guan, Xin Yuan; Chung, Sookja K; Wang, Yang; Yip, Yim Ling; Law, Simon Y K; Chan, Kin Tak; Lee, Nikki P Y; Chan, Kwok Wah; Xu, Li Yan; Li, En Min; Tsao, Sai Wah; He, Qing-Yu; Cheung, Annie L M

2017-02-10

Local interactions between cancer cells and stroma can produce systemic effects on distant organs to govern cancer progression. Here we show that IGF2 secreted by inhibitor of differentiation (Id1)-overexpressing oesophageal cancer cells instigates VEGFR1-positive bone marrow cells in the tumour macroenvironment to form pre-metastatic niches at distant sites by increasing VEGF secretion from cancer-associated fibroblasts. Cancer cells are then attracted to the metastatic site via the CXCL5/CXCR2 axis. Bone marrow cells transplanted from nude mice bearing Id1-overexpressing oesophageal tumours enhance tumour growth and metastasis in recipient mice, whereas systemic administration of VEGFR1 antibody abrogates these effects. Mechanistically, IGF2 regulates VEGF in fibroblasts via miR-29c in a p53-dependent manner. Analysis of patient serum samples showed that concurrent elevation of IGF2 and VEGF levels may serve as a prognostic biomarker for oesophageal cancer. These findings suggest that the Id1/IGF2/VEGF/VEGFR1 cascade plays a critical role in tumour-driven pathophysiological processes underlying cancer progression.

Dynamics of Cancer Cell near Collagen Fiber Chain

Science.gov (United States)

Kim, Jihan; Sun, Bo

Cell migration is an integrated process that is important in life. Migration is essential for embryonic development as well as homeostatic processes such as wound healing and immune responses. When cell migrates through connective extracellular matrix (ECM), it applies cellular traction force to ECM and senses the rigidity of their local environment. We used human breast cancer cell (MDA-MB-231) which is highly invasive and applies strong traction force to ECM. As cancer cell applies traction force to type I collage-based ECM, it deforms collagen fibers near the surface. Patterns of deforming collagen fibers are significantly different with pairs of cancer cells compared to a single cancer cell. While a pair of cancer cells within 60 um creates aligned collagen fiber chains between them permanently, a single cancer cell does not form any fiber chains. In this experiment we measured a cellular response and an interaction between a pair of cells through the chain. Finally, we analyzed correlation of directions between cancer cell migration and the collagen chain alignment.

Angular-dependent light scattering from cancer cells in different phases of the cell cycle.

Science.gov (United States)

Lin, Xiaogang; Wan, Nan; Weng, Lingdong; Zhou, Yong

2017-10-10

Cancer cells in different phases of the cell cycle result in significant differences in light scattering properties. In order to harvest cancer cells in particular phases of the cell cycle, we cultured cancer cells through the process of synchronization. Flow cytometric analysis was applied to check the results of cell synchronization and prepare for light scattering measurements. Angular-dependent light scattering measurements of cancer cells arrested in the G1, S, and G2 phases have been performed. Based on integral calculations for scattering intensities from 5° to 10° and from 110° to 150°, conclusions have been reached. Clearly, the sizes of the cancer cells in different phases of the cell cycle dominated the forward scatter. Accompanying the increase of cell size with the progression of the cell cycle, the forward scattering intensity also increased. Meanwhile, the DNA content of cancer cells in every phase of the cell cycle is responsible for light scattering at large scatter angles. The higher the DNA content of cancer cells was, the greater the positive effect on the high-scattering intensity. As expected, understanding the relationships between the light scattering from cancer cells and cell cycles will aid in the development of cancer diagnoses. Also, it may assist in the guidance of antineoplastic drugs clinically.

A cancer specific cell-penetrating peptide, BR2, for the efficient delivery of an scFv into cancer cells.

Directory of Open Access Journals (Sweden)

Ki Jung Lim

Full Text Available Cell-penetrating peptides (CPPs have proven very effective as intracellular delivery vehicles for various therapeutics. However, there are some concerns about non-specific penetration and cytotoxicity of CPPs for effective cancer treatments. Herein, based on the cell-penetrating motif of an anticancer peptide, buforin IIb, we designed several CPP derivatives with cancer cell specificity. Among the derivatives, a 17-amino acid peptide (BR2 was found to have cancer-specificity without toxicity to normal cells. After specifically targeting cancer cells through interaction with gangliosides, BR2 entered cells via lipid-mediated macropinocytosis. Moreover, BR2 showed higher membrane translocation efficiency than the well-known CPP Tat (49-57. The capability of BR2 as a cancer-specific drug carrier was demonstrated by fusion of BR2 to a single-chain variable fragment (scFv directed toward a mutated K-ras (G12V. BR2-fused scFv induced a higher degree of apoptosis than Tat-fused scFv in K-ras mutated HCT116 cells. These results suggest that the novel cell-penetrating peptide BR2 has great potential as a useful drug delivery carrier with cancer cell specificity.

A cancer specific cell-penetrating peptide, BR2, for the efficient delivery of an scFv into cancer cells.

Science.gov (United States)

Lim, Ki Jung; Sung, Bong Hyun; Shin, Ju Ri; Lee, Young Woong; Kim, Da Jung; Yang, Kyung Seok; Kim, Sun Chang

2013-01-01

Cell-penetrating peptides (CPPs) have proven very effective as intracellular delivery vehicles for various therapeutics. However, there are some concerns about non-specific penetration and cytotoxicity of CPPs for effective cancer treatments. Herein, based on the cell-penetrating motif of an anticancer peptide, buforin IIb, we designed several CPP derivatives with cancer cell specificity. Among the derivatives, a 17-amino acid peptide (BR2) was found to have cancer-specificity without toxicity to normal cells. After specifically targeting cancer cells through interaction with gangliosides, BR2 entered cells via lipid-mediated macropinocytosis. Moreover, BR2 showed higher membrane translocation efficiency than the well-known CPP Tat (49-57). The capability of BR2 as a cancer-specific drug carrier was demonstrated by fusion of BR2 to a single-chain variable fragment (scFv) directed toward a mutated K-ras (G12V). BR2-fused scFv induced a higher degree of apoptosis than Tat-fused scFv in K-ras mutated HCT116 cells. These results suggest that the novel cell-penetrating peptide BR2 has great potential as a useful drug delivery carrier with cancer cell specificity.

Tumor budding cells, cancer stem cells and epithelial-mesenchymal transition-type cells in pancreatic cancer

International Nuclear Information System (INIS)

Karamitopoulou, Eva

2013-01-01

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with a 5-year survival rate of less than 5%. Moreover, PDAC escapes early detection and resists treatment. Multiple combinations of genetic alterations are known to occur in PDAC including mutational activation of KRAS, inactivation of p16/CDKN2A and SMAD4 (DPC4) and dysregulation of PTEN/PI3K/AKT signaling. Through their interaction with Wingless-INT pathway, the downstream molecules of these pathways have been implicated in the promotion of epithelial–mesenchymal transition (EMT). Emerging evidence has demonstrated that cancer stem cells (CSCs), small populations of which have been identified in PDAC, and EMT-type cells play critical roles in drug resistance, invasion, and metastasis in pancreatic cancer. EMT may be histologically represented by the presence of tumor budding which is described as the occurrence of single tumor cells or small clusters (<5) of dedifferentiated cells at the invasive front of gastrointestinal (including colorectal, oesophageal, gastric, and ampullary) carcinomas and is linked to poor prognosis. Tumor budding has recently been shown to occur frequently in PDAC and to be associated with adverse clinicopathological features and decreased disease-free and overall survival. The aim of this review is to present a short overview on the morphological and molecular aspects that underline the relationship between tumor budding cells, CSCs, and EMT-type cells in PDAC.

Tumor budding cells, cancer stem cells and epithelial-mesenchymal transition-type cells in pancreatic cancer.

Science.gov (United States)

Karamitopoulou, Eva

2012-01-01

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with a 5-year survival rate of less than 5%. Moreover, PDAC escapes early detection and resists treatment. Multiple combinations of genetic alterations are known to occur in PDAC including mutational activation of KRAS, inactivation of p16/CDKN2A and SMAD4 (DPC4) and dysregulation of PTEN/PI3K/AKT signaling. Through their interaction with Wingless-INT pathway, the downstream molecules of these pathways have been implicated in the promotion of epithelial-mesenchymal transition (EMT). Emerging evidence has demonstrated that cancer stem cells (CSCs), small populations of which have been identified in PDAC, and EMT-type cells play critical roles in drug resistance, invasion, and metastasis in pancreatic cancer. EMT may be histologically represented by the presence of tumor budding which is described as the occurrence of single tumor cells or small clusters (<5) of dedifferentiated cells at the invasive front of gastrointestinal (including colorectal, oesophageal, gastric, and ampullary) carcinomas and is linked to poor prognosis. Tumor budding has recently been shown to occur frequently in PDAC and to be associated with adverse clinicopathological features and decreased disease-free and overall survival. The aim of this review is to present a short overview on the morphological and molecular aspects that underline the relationship between tumor budding cells, CSCs, and EMT-type cells in PDAC.

Tumor Budding Cells, Cancer Stem Cells and Epithelial-Mesenchymal Transition-type Cells in Pancreatic Cancer

Directory of Open Access Journals (Sweden)

Eva eKaramitopoulou

2013-01-01

Full Text Available Pancreatic ductal adenocarcinoma (PDAC is one of the most lethal cancers with a 5-year survival rate of less than 5%. Moreover, PDAC escapes early detection and resists treatment. Multiple combinations of genetic alterations are known to occur in PDAC including mutational activation of KRAS, inactivation of p16/CDKN2A and SMAD4 (DPC4 and dysregulation of PTEN/PI3K/AKT signaling. Through their interaction with WNT pathway, the downstream molecules of these pathways have been implicated in the promotion of epithelial-mesenchymal transition (EMT. Emerging evidence has demonstrated that cancer stem cells (CSCs, small populations of which have been identified in PDAC, and EMT-type cells play critical roles in drug resistance, invasion and metastasis in pancreatic cancer. EMT may be histologically represented by the presence of tumor budding which is described as the occurrence of single tumor cells or small clusters (<5 of dedifferentiated cells at the invasive front of gastrointestinal (including colorectal, oesophageal, gastric and ampullary carcinomas and is linked to poor prognosis. Tumor budding has recently been shown to occur frequently in PDAC and to be associated with adverse clinicopathological features and decreased disease-free and overall survival. The aim of this review is to present a short overview on the morphological and molecular aspects that underline the relationship between tumor budding cells, CSCs and EMT-type cells in PDAC.

Tubulin binding cofactor C (TBCC) suppresses tumor growth and enhances chemosensitivity in human breast cancer cells

International Nuclear Information System (INIS)

Hage-Sleiman, Rouba; Herveau, Stéphanie; Matera, Eva-Laure; Laurier, Jean-Fabien; Dumontet, Charles

2010-01-01

Microtubules are considered major therapeutic targets in patients with breast cancer. In spite of their essential role in biological functions including cell motility, cell division and intracellular transport, microtubules have not yet been considered as critical actors influencing tumor cell aggressivity. To evaluate the impact of microtubule mass and dynamics on the phenotype and sensitivity of breast cancer cells, we have targeted tubulin binding cofactor C (TBCC), a crucial protein for the proper folding of α and β tubulins into polymerization-competent tubulin heterodimers. We developed variants of human breast cancer cells with increased content of TBCC. Analysis of proliferation, cell cycle distribution and mitotic durations were assayed to investigate the influence of TBCC on the cell phenotype. In vivo growth of tumors was monitored in mice xenografted with breast cancer cells. The microtubule dynamics and the different fractions of tubulins were studied by time-lapse microscopy and lysate fractionation, respectively. In vitro sensitivity to antimicrotubule agents was studied by flow cytometry. In vivo chemosensitivity was assayed by treatment of mice implanted with tumor cells. TBCC overexpression influenced tubulin fraction distribution, with higher content of nonpolymerizable tubulins and lower content of polymerizable dimers and microtubules. Microtubule dynamicity was reduced in cells overexpressing TBCC. Cell cycle distribution was altered in cells containing larger amounts of TBCC with higher percentage of cells in G2-M phase and lower percentage in S-phase, along with slower passage into mitosis. While increased content of TBCC had little effect on cell proliferation in vitro, we observed a significant delay in tumor growth with respect to controls when TBCC overexpressing cells were implanted as xenografts in vivo. TBCC overexpressing variants displayed enhanced sensitivity to antimicrotubule agents both in vitro and in xenografts. These

Delayed K562 cell apoptosis promoted by cleaved LyGDI after 60Co γ-rays irradiation

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Sun Huali; Duan Weiming; Shao Yanyan; Xiao Hainan; Zhou Xinwen

2010-01-01

Objective: To elucidate the function and regulatory mechanism of LyGDI involved delayed cell death in the human K562 cells and HL-60 cells induced by 60 Co γ-rays. Methods: Erythrosine B cells staining was used to count the apoptosis rate. PI staining and flow cytometry were applied to check the cell cycle. The expression of LYGDI and Rac1 was resolved by Western blot by using monoclonal antibody of LyGDI and Rac1. The distribution of Rac1 protein in cells was observed with immunofluorescence by using the confocal microscope. Results: The K562 cells showed G 2 /M phase arrest and the percent age was 71.3%. The apoptosis rate was very low at early post-irradiation stage in the K562 cells. The apoptosis rate was 14% in the K562 cells at 24 h post-irradiation with 8 Gy of γ-rays, and delayed cell apoptosis was present. LyGDI was cleaved in the K562 cells irradiated by 4 Gy 60 Co γ-rays after 24 hours post-irradiation. The expression of Rac1 protein was not altered at all, but the distribution was changed in the irradiated cells while the Rac1 protein moved to cell membrane and a little in cell nucleus. The Rac1 was activated with the losing the binding affinity with the LyGDI. Conclusion: LyGDI could promote the delayed cell apoptosis, which is through the activation of the Rac1. (authors)

Exosomes Promote Ovarian Cancer Cell Invasion through Transfer of CD44 to Peritoneal Mesothelial Cells.

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Nakamura, Koji; Sawada, Kenjiro; Kinose, Yasuto; Yoshimura, Akihiko; Toda, Aska; Nakatsuka, Erika; Hashimoto, Kae; Mabuchi, Seiji; Morishige, Ken-Ichirou; Kurachi, Hirohisa; Lengyel, Ernst; Kimura, Tadashi

2017-01-01

Epithelial ovarian cancer (EOC) cells metastasize within the peritoneal cavity and directly encounter human peritoneal mesothelial cells (HPMC) as the initial step of metastasis. The contact between ovarian cancer cells and the single layer of mesothelial cells involves direct communications that modulate cancer progression but the mechanisms are unclear. One candidate mediating cell-cell communications is exosomes, 30-100 nm membrane vesicles of endocytic origin, through the cell-cell transfer of proteins, mRNAs, or microRNAs. Therefore, the goal was to mechanistically characterize how EOC-derived exosomes modulate metastasis. Exosomes from ovarian cancer cells were fluorescently labeled and cocultured with HPMCs which internalized the exosomes. Upon exosome uptake, HPMCs underwent a change in cellular morphology to a mesenchymal, spindle phenotype. CD44, a cell surface glycoprotein, was found to be enriched in the cancer cell-derived exosomes, transferred, and internalized to HPMCs, leading to high levels of CD44 in HPMCs. This increased CD44 expression in HPMCs promoted cancer invasion by inducing the HPMCs to secrete MMP9 and by cleaning the mesothelial barrier for improved cancer cell invasion. When CD44 expression was knocked down in cancer cells, exosomes had fewer effects on HPMCs. The inhibition of exosome release from cancer cells blocked CD44 internalization in HPMCs and suppressed ovarian cancer invasion. In ovarian cancer omental metastasis, positive CD44 expression was observed in those mesothelial cells that directly interacted with cancer cells, whereas CD44 expression was negative in the mesothelial cells remote from the invading edge. This study indicates that ovarian cancer-derived exosomes transfer CD44 to HPMCs, facilitating cancer invasion. Mechanistic insight from the current study suggests that therapeutic targeting of exosomes may be beneficial in treating ovarian cancer. Mol Cancer Res; 15(1); 78-92. ©2016 AACR. ©2016 American

Chronic Alcohol Ingestion Delays T Cell Activation and Effector Function in Sepsis.

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Lindsay M Margoles

Full Text Available Sepsis is the leading cause of death in intensive care units in the US, and it is known that chronic alcohol use is associated with higher incidence of sepsis, longer ICU stays, and higher mortality from sepsis. Both sepsis and chronic alcohol use are associated with immune deficits such as decreased lymphocyte numbers, impaired innate immunity, delayed-type hypersensitivity reactions, and susceptibility to infections; however, understanding of specific pathways of interaction or synergy between these two states of immune dysregulation is lacking. This study therefore sought to elucidate mechanisms underlying the immune dysregulation observed during sepsis in the setting of chronic alcohol exposure. Using a murine model of chronic ethanol ingestion followed by sepsis induction via cecal ligation and puncture, we determined that while CD4+ and CD8+ T cells isolated from alcohol fed mice eventually expressed the same cellular activation markers (CD44, CD69, and CD43 and effector molecules (IFN-γ, TNF as their water fed counterparts, there was an overall delay in the acquisition of these phenotypes. This early lag in T cell activation was associated with significantly reduced IL-2 production at a later timepoint in both the CD4+ and CD8+ T cell compartments in alcohol sepsis, as well as with a reduced accumulation of CD8dim activated effectors. Taken together, these data suggest that delayed T cell activation may result in qualitative differences in the immune response to sepsis in the setting of chronic alcohol ingestion.

Pancreatic Cancer-Derived Exosomes Cause Paraneoplastic β-cell Dysfunction.

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Javeed, Naureen; Sagar, Gunisha; Dutta, Shamit K; Smyrk, Thomas C; Lau, Julie S; Bhattacharya, Santanu; Truty, Mark; Petersen, Gloria M; Kaufman, Randal J; Chari, Suresh T; Mukhopadhyay, Debabrata

2015-04-01

Pancreatic cancer frequently causes diabetes. We recently proposed adrenomedullin as a candidate mediator of pancreatic β-cell dysfunction in pancreatic cancer. How pancreatic cancer-derived adrenomedullin reaches β cells remote from the cancer to induce β-cell dysfunction is unknown. We tested a novel hypothesis that pancreatic cancer sheds adrenomedullin-containing exosomes into circulation, which are transported to β cells and impair insulin secretion. We characterized exosomes from conditioned media of pancreatic cancer cell lines (n = 5) and portal/peripheral venous blood of patients with pancreatic cancer (n = 20). Western blot analysis showed the presence of adrenomedullin in pancreatic cancer-exosomes. We determined the effect of adrenomedullin-containing pancreatic cancer exosomes on insulin secretion from INS-1 β cells and human islets, and demonstrated the mechanism of exosome internalization into β cells. We studied the interaction between β-cell adrenomedullin receptors and adrenomedullin present in pancreatic cancer-exosomes. In addition, the effect of adrenomedullin on endoplasmic reticulum (ER) stress response genes and reactive oxygen/nitrogen species generation in β cells was shown. Exosomes were found to be the predominant extracellular vesicles secreted by pancreatic cancer into culture media and patient plasma. Pancreatic cancer-exosomes contained adrenomedullin and CA19-9, readily entered β cells through caveolin-mediated endocytosis or macropinocytosis, and inhibited insulin secretion. Adrenomedullin in pancreatic cancer exosomes interacted with its receptor on β cells. Adrenomedullin receptor blockade abrogated the inhibitory effect of exosomes on insulin secretion. β cells exposed to adrenomedullin or pancreatic cancer exosomes showed upregulation of ER stress genes and increased reactive oxygen/nitrogen species. Pancreatic cancer causes paraneoplastic β-cell dysfunction by shedding adrenomedullin(+)/CA19-9(+) exosomes into

The usefulness of three-dimensional cell culture in induction of cancer stem cells from esophageal squamous cell carcinoma cell lines

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Fujiwara, Daisuke; Kato, Kazunori; Nohara, Shigeo; Iwanuma, Yoshimi; Kajiyama, Yoshiaki

2013-01-01

Highlights: •Spheroids were created from esophageal carcinoma cells using NanoCulture® Plates. •The proportion of strongly ALDH-positive cells increased in 3-D culture. •Expression of cancer stem cell-related genes was enhanced in 3-D culture. •CA-9 expression was enhanced, suggesting hypoxia had been induced in 3-D culture. •Drug resistance was increased. 3-D culture is useful for inducing cancer stem cells. -- Abstract: In recent years, research on resistance to chemotherapy and radiotherapy in cancer treatment has come under the spotlight, and researchers have also begun investigating the relationship between resistance and cancer stem cells. Cancer stem cells are assumed to be present in esophageal cancer, but experimental methods for identification and culture of these cells have not yet been established. To solve this problem, we created spheroids using a NanoCulture® Plate (NCP) for 3-dimensional (3-D) cell culture, which was designed as a means for experimentally reproducing the 3-D structures found in the body. We investigated the potential for induction of cancer stem cells from esophageal cancer cells. Using flow cytometry we analyzed the expression of surface antigen markers CD44, CD133, CD338 (ABCG2), CD318 (CDCP1), and CD326 (EpCAM), which are known cancer stem cell markers. None of these surface antigen markers showed enhanced expression in 3-D cultured cells. We then analyzed aldehyde dehydrogenase (ALDH) enzymatic activity using the ALDEFLUOR reagent, which can identify immature cells such as stem cells and precursor cells. 3-D-cultured cells were strongly positive for ALDH enzyme activity. We also analyzed the expression of the stem cell-related genes Sox-2, Nanog, Oct3/4, and Lin28 using RT-PCR. Expression of Sox-2, Nanog, and Lin28 was enhanced. Analysis of expression of the hypoxic surface antigen marker carbonic anhydrase-9 (CA-9), which is an indicator of cancer stem cell induction and maintenance, revealed that CA-9 expression

FREQUENCY CATASTROPHE AND CO-EXISTING ATTRACTORS IN A CELL Ca2+ NONLINEAR OSCILLATION MODEL WITH TIME DELAY*

Institute of Scientific and Technical Information of China (English)

应阳君; 黄祖洽

2001-01-01

Frequency catastrophe is found in a cell Ca2+ nonlinear oscillation model with time delay. The relation of the frequency transition to the time delay is studied by numerical simulations and theoretical analysis. There is a range of parameters in which two kinds of attractors with great frequency differences co-exist in the system. Along with parameter changes, a critical phenomenon occurs and the oscillation frequency changes greatly. This mechanism helps us to deepen the understanding of the complex dynamics of delay systems, and might be of some meaning in cell signalling.

Analysis of cell-cycle regulation following exposure of lung-derived cells to γ-rays

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Trani, D.; Lucchetti, C.; Cassone, M.; D'Agostino, L.; Caputi, M.; Giordano, A.

Acute exposure of mammalian cells to ionizing radiation results in a delay of cell-cycle progression and/or augmentation of apoptosis. Following ionizing radiation-induced DNA damage, cell-cycle arrest in the G1- or G2-phase of the cell-cycle prevents or delays DNA replication or mitosis, providing time for the DNA repair machinery to exert its function. Deregulation or failing of cell-cycle checkpoints and/or DNA repair mechanisms may lead normal cells bearing chromosome mutations to acquire neoplastic autonomy, which in turn can trigger the onset of cancer. Existing studies have focused on the impact of p53 status on the radiation response of lung cancer (LC) cell lines in terms of both cell-cycle regulation and apoptosis, while no comparative studies have been performed on the radiation response of lung derived normal and cancerous epithelial cells. To investigate the radiation response in normal and cancerous phenotypes, along with the role and impact of p53 status, and possible correlations with pRb/p105 or other proteins involved in carcinogenesis and cell-cycle regulation, we selected two lung-derived epithelial cell lines, one normal (NL20, p53 wild-type) and one non-small cell lung cancer (NSCLC), H358 (known to be p53-deficient). We compared the levels of γ-induced cell proliferation ability, cell-cycle arrest, apoptotic index, and expression levels of cell-cycle regulating and regulated proteins. The different cell sensitivity, apoptotic response and protein expression profiles resulting from our study for NL20 and H358 cells suggest that still unknown mechanisms involving p53, pRb/p105 and their target molecules might play a pivotal role in determining cell sensitivity and resistance upon exposure to ionizing radiation.

Curcumin induces chemo/radio-sensitization in ovarian cancer cells and curcumin nanoparticles inhibit ovarian cancer cell growth

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Yallapu Murali M

2010-04-01

Full Text Available Abstract Background Chemo/radio-resistance is a major obstacle in treating advanced ovarian cancer. The efficacy of current treatments may be improved by increasing the sensitivity of cancer cells to chemo/radiation therapies. Curcumin is a naturally occurring compound with anti-cancer activity in multiple cancers; however, its chemo/radio-sensitizing potential is not well studied in ovarian cancer. Herein, we demonstrate the effectiveness of a curcumin pre-treatment strategy for chemo/radio-sensitizing cisplatin resistant ovarian cancer cells. To improve the efficacy and specificity of curcumin induced chemo/radio sensitization, we developed a curcumin nanoparticle formulation conjugated with a monoclonal antibody specific for cancer cells. Methods Cisplatin resistant A2780CP ovarian cancer cells were pre-treated with curcumin followed by exposure to cisplatin or radiation and the effect on cell growth was determined by MTS and colony formation assays. The effect of curcumin pre-treatment on the expression of apoptosis related proteins and β-catenin was determined by Western blotting or Flow Cytometry. A luciferase reporter assay was used to determine the effect of curcumin on β-catenin transcription activity. The poly(lactic acid-co-glycolic acid (PLGA nanoparticle formulation of curcumin (Nano-CUR was developed by a modified nano-precipitation method and physico-chemical characterization was performed by transmission electron microscopy and dynamic light scattering methods. Results Curcumin pre-treatment considerably reduced the dose of cisplatin and radiation required to inhibit the growth of cisplatin resistant ovarian cancer cells. During the 6 hr pre-treatment, curcumin down regulated the expression of Bcl-XL and Mcl-1 pro-survival proteins. Curcumin pre-treatment followed by exposure to low doses of cisplatin increased apoptosis as indicated by annexin V staining and cleavage of caspase 9 and PARP. Additionally, curcumin pre

MicroRNA-196a-5p is a potential prognostic marker of delayed lymph node metastasis in early-stage tongue squamous cell carcinoma

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Maruyama, Tessho; Nishihara, Kazuhide; Umikawa, Masato; Arasaki, Akira; Nakasone, Toshiyuki; Nimura, Fumikazu; Matayoshi, Akira; Takei, Kimiko; Nakachi, Saori; Kariya, Ken-Ichi; Yoshimi, Naoki

2018-01-01

MicroRNAs (miRs) are expected to serve as prognostic tools for cancer. However, many miRs have been reported as prognostic markers of recurrence or metastasis in oral squamous cell carcinoma patients. We aimed to determine the prognostic markers in early-stage tongue squamous cell carcinoma (TSCC). Based on previous studies, we hypothesized that miR-10a, 10b, 196a-5p, 196a-3p, and 196b were prognostic markers and we retrospectively performed miR expression analyses using formalin-fixed paraffin-embedded sections of surgical specimens. Total RNA was isolated from cancer tissues and adjacent normal tissue as control, and samples were collected by laser-capture microdissection. After cDNA synthesis, reverse transcription-quantitative polymerase chain reaction was performed. Statistical analyses for patient clinicopathological characteristics, recurrence/metastasis, and survival rates were performed to discern their relationships with miR expression levels, and the 2−ΔΔCq method was used. miR-196a-5p levels were significantly upregulated in early-stage TSCC, particularly in the lymph node metastasis (LNM) group. The LNM-free survival rate in the low miR-196a-5p ΔΔCq value regulation group was found to be lower than that in the high ΔΔCq value regulation group (P=0.0079). Receiver operating characteristic analysis of ΔΔCq values revealed that miR-196a-5p had a P-value=0.0025, area under the curve=0.740, and a cut-off value=−0.875 for distinguishing LNM. To our knowledge, this is the first study to examine LNM-related miRs in early-stage TSCC as well as miRs and ‘delayed LNM’ in head and neck cancer. miR-196a-5p upregulation may predict delayed LNM. Our data serve as a foundation for future studies to evaluate miR levels and facilitate the prediction of delayed LNM during early-stage TSCC, which prevent metastasis when combined with close follow-up and aggressive adjuvant therapy or elective neck dissection. Moreover, our data will serve as a foundation

Cyclooxygenase-2: A Role in Cancer Stem Cell Survival and Repopulation of Cancer Cells during Therapy

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Lisa Y. Pang

2016-01-01

Full Text Available Cyclooxygenase-2 (COX-2 is an inducible form of the enzyme that catalyses the synthesis of prostanoids, including prostaglandin E2 (PGE2, a major mediator of inflammation and angiogenesis. COX-2 is overexpressed in cancer cells and is associated with progressive tumour growth, as well as resistance of cancer cells to conventional chemotherapy and radiotherapy. These therapies are often delivered in multiple doses, which are spaced out to allow the recovery of normal tissues between treatments. However, surviving cancer cells also proliferate during treatment intervals, leading to repopulation of the tumour and limiting the effectiveness of the treatment. Tumour cell repopulation is a major cause of treatment failure. The central dogma is that conventional chemotherapy and radiotherapy selects resistant cancer cells that are able to reinitiate tumour growth. However, there is compelling evidence of an active proliferative response, driven by increased COX-2 expression and downstream PGE2 release, which contribute to the repopulation of tumours and poor patient outcome. In this review, we will examine the evidence for a role of COX-2 in cancer stem cell biology and as a mediator of tumour repopulation that can be molecularly targeted to overcome resistance to therapy.

Comparative proteomics analysis of oral cancer cell lines: identification of cancer associated proteins

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2014-01-01

Background A limiting factor in performing proteomics analysis on cancerous cells is the difficulty in obtaining sufficient amounts of starting material. Cell lines can be used as a simplified model system for studying changes that accompany tumorigenesis. This study used two-dimensional gel electrophoresis (2DE) to compare the whole cell proteome of oral cancer cell lines vs normal cells in an attempt to identify cancer associated proteins. Results Three primary cell cultures of normal cells with a limited lifespan without hTERT immortalization have been successfully established. 2DE was used to compare the whole cell proteome of these cells with that of three oral cancer cell lines. Twenty four protein spots were found to have changed in abundance. MALDI TOF/TOF was then used to determine the identity of these proteins. Identified proteins were classified into seven functional categories – structural proteins, enzymes, regulatory proteins, chaperones and others. IPA core analysis predicted that 18 proteins were related to cancer with involvements in hyperplasia, metastasis, invasion, growth and tumorigenesis. The mRNA expressions of two proteins – 14-3-3 protein sigma and Stress-induced-phosphoprotein 1 – were found to correlate with the corresponding proteins’ abundance. Conclusions The outcome of this analysis demonstrated that a comparative study of whole cell proteome of cancer versus normal cell lines can be used to identify cancer associated proteins. PMID:24422745

B-cell lymphoma 6 protein stimulates oncogenicity of human breast cancer cells

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Wu, Qiang; Kong, Xiang-jun; Xu, Xiao-chun; Lobie, Peter E; Zhu, Tao; Wu, Zheng-sheng; Liu, Xue; Yan, Hong; He, Yin-huan; Ye, Shan; Cheng, Xing-wang; Zhu, Gui-lu; Wu, Wen-yong; Wang, Xiao-nan

2014-01-01

B-cell lymphoma 6 (BCL6) protein, an evolutionarily conserved zinc finger transcription factor, showed to be highly expressed in various human cancers in addition to malignancies in the lymphoid system. This study investigated the role of BCL6 expression in breast cancer and its clinical significance in breast cancer patients. Expression of BCL6 protein was assessed using in situ hybridization and immunohistochemistry in 127 breast cancer patients and 50 patients with breast benign disease as well as in breast cell lines. Expression of BCL6 was restored or knocked down in two breast cancer cell lines (MCF-7 and T47D) using BCL6 cDNA and siRNA, respectively. The phenotypic change of these breast cancer cell lines was assessed using cell viability MTT, Transwell invasion, colony formation, and flow cytometry assays and in a xenograft mice model. Luciferase reporter gene, immunoblot, and qRT-PCR were used to investigate the molecular events after manipulated BCL6 expression in breast cancer cells. BCL6 protein was highly expressed in breast cancer cell lines and tissue specimens and expression of BCL6 protein was associated with disease progression and poor survival of breast cancer patients. In vitro, the forced expression of BCL6 results in increased proliferation, anchorage-independent growth, migration, invasion and survival of breast cancer cell lines, whereas knockdown of BCL6 expression reduced these oncogenic properties of breast cancer cells. Moreover, forced expression of BCL6 increased tumor growth and invasiveness in a nude mouse xenograft model. At the gene level, BCL6 was a target gene of miR-339-5p. Expression of BCL6 induced expression of CXCR4 and cyclinD1 proteins. The current study demonstrated the oncogenic property of BCL6 in breast cancer and further study could target BCL6 as a novel potential therapeutic strategy for breast cancer

Prostate stromal cells express the progesterone receptor to control cancer cell mobility.

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Yu, Yue; Lee, Jennifer Suehyun; Xie, Ning; Li, Estelle; Hurtado-Coll, Antonio; Fazli, Ladan; Cox, Michael; Plymate, Stephen; Gleave, Martin; Dong, Xuesen

2014-01-01

Reciprocal interactions between epithelium and stroma play vital roles for prostate cancer development and progression. Enhanced secretions of cytokines and growth factors by cancer associated fibroblasts in prostate tumors create a favorable microenvironment for cancer cells to grow and metastasize. Our previous work showed that the progesterone receptor (PR) was expressed specifically in prostate stromal fibroblasts and smooth muscle cells. However, the expression levels of PR and its impact to tumor microenvironment in prostate tumors are poorly understood. Immunohistochemistry assays are applied to human prostate tissue biopsies. Cell migration, invasion and proliferation assays are performed using human prostate cells. Real-time PCR and ELISA are applied to measure gene expression at molecular levels. Immunohistochemistry assays showed that PR protein levels were decreased in cancer associated stroma when compared with paired normal prostate stroma. Using in vitro prostate stromal cell models, we showed that conditioned media collected from PR positive stromal cells inhibited prostate cancer cell migration and invasion, but had minor suppressive impacts on cancer cell proliferation. PR suppressed the secretion of stromal derived factor-1 (SDF-1) and interlukin-6 (IL-6) by stromal cells independent to PR ligands. Blocking PR expression by siRNA or supplementation of exogenous SDF-1 or IL-6 to conditioned media from PR positive stromal cells counteracted the inhibitory effects of PR to cancer cell migration and invasion. Decreased expression of the PR in cancer associated stroma may contribute to the elevated SDF-1 and IL-6 levels in prostate tumors and enhance prostate tumor progression.

Prostate stromal cells express the progesterone receptor to control cancer cell mobility.

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Yue Yu

Full Text Available Reciprocal interactions between epithelium and stroma play vital roles for prostate cancer development and progression. Enhanced secretions of cytokines and growth factors by cancer associated fibroblasts in prostate tumors create a favorable microenvironment for cancer cells to grow and metastasize. Our previous work showed that the progesterone receptor (PR was expressed specifically in prostate stromal fibroblasts and smooth muscle cells. However, the expression levels of PR and its impact to tumor microenvironment in prostate tumors are poorly understood.Immunohistochemistry assays are applied to human prostate tissue biopsies. Cell migration, invasion and proliferation assays are performed using human prostate cells. Real-time PCR and ELISA are applied to measure gene expression at molecular levels.Immunohistochemistry assays showed that PR protein levels were decreased in cancer associated stroma when compared with paired normal prostate stroma. Using in vitro prostate stromal cell models, we showed that conditioned media collected from PR positive stromal cells inhibited prostate cancer cell migration and invasion, but had minor suppressive impacts on cancer cell proliferation. PR suppressed the secretion of stromal derived factor-1 (SDF-1 and interlukin-6 (IL-6 by stromal cells independent to PR ligands. Blocking PR expression by siRNA or supplementation of exogenous SDF-1 or IL-6 to conditioned media from PR positive stromal cells counteracted the inhibitory effects of PR to cancer cell migration and invasion.Decreased expression of the PR in cancer associated stroma may contribute to the elevated SDF-1 and IL-6 levels in prostate tumors and enhance prostate tumor progression.