Journal of Experimental & Clinical Cancer Research - Most accessed articles

Circulating microRNAs in cancer: origin, function and application

Ruimin Ma — 2012-04-30T00:00:00Z

MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression at the posttranscriptional level. The dysregulation of miRNAs has been linked to a series of diseases, including various types of cancer. Since their discovery in the circulation of cancer patients, there has been a steady increase in the study of circulating miRNAs as stable, non-invasive biomarkers. However, the origin and function of circulating miRNAs has not been systematically elucidated. In this review, we summarize the discovery of circulating miRNAs and their potential as biomarkers. We further emphasize their possible origin and function. Finally, we discuss the application and existing questions surrounding circulating miRNAs in cancer diagnostics. Although several challenges remain to be concerned, circulating miRNAs could be useful, non-invasive biomarkers for cancer diagnosis.

Chromophobe renal cell cancer - review of the literature and potential methods of treating metastatic disease

Rafal Stec — 2009-10-07T00:00:00Z

Chromophobe renal cell carcinoma (ChRCC) is a subtype of renal cell carcinoma (RCC). ChRCC is diagnosed mainly in 6th decade of life. An incidence of ChRCC is similar in both men and woman. Eighty six percent of ChRCCs cases are diagnosed in stage 1 or 2. Prognosis of ChRCC is better than in other types of RCC. Five- and 10-year disease free survival (DFS) for ChRCC was 83.9% and 77.9%, respectively. Expression of immunohistological markers: cytokeratins (CK), vimentin, epithelial membrane antigen (EMA), CD10 could be potentially helpful in diagnosis of different subtypes of RCC. From all conventional RCC, CD 117 was detected (overexpression) in membrane of cells ChRCC.Overexpression of CD117 on cellular membranes of ChRCC could be a potential target for kinase inhibitors like: imatinib, dasatinib, nilotinib. The potential targets for other kinase inhibitors (sunitinib and sorafenib) in ChRCC seem to be VEGFR and PDGFR. On the basis for formulating research hypotheses which should be verified by prospective studies.

Knockdown of glucose-regulated protein 78 decreases the invasion, metalloproteinase expression and ECM degradation in hepatocellular carcinoma cells

Hongdan Li — 2012-04-30T00:00:00Z

Background: We have reported previously that overexpression of glucose-regulated protein 78 (GRP78) promotes the invasion of hepatocellular carcinoma. However, whether GRP78 knockdown affects the extracellular matrix degradation has not been elucidated. Here we are going to determine whether GRP78 knockdown affect the ECM degradation and the role of MMP-2 and MMP-9 in these process in hepatocellular carcinoma cells. Methods: Human hepatocellular carcinoma cell line SMMC7721 and HepG2 were cultured in DMEM supplemented with 10% FBS, RT-PCR and western blot were used to detect the endogenous expression of GRP78, MMP-2, MMP-9 and TIMP-2 in SMMC7721 and HepG2. GRP78 shRNAs were transfected using lipofection2000. Transwell assay and wound healing assay were used to analyze the invasion of each transfectant. Gelatin zymography and FITC-gelatin degradation assay were employed to investigate the capabilities of ECM degradation of each transfectant. MTT assay was used to determine the proliferation status. Western blot were employed to detect the expression of matrix metalloproteinase 2(MMP-2), MMP-9, MMP-14, and tissue inhibitor of metalloproteinases 2(TIMP-2), focal adhesion kinase (FAK), ERK1/2, JNK and Src. Results: According to the expression levels of GRP78, MMP-2, MMP-9, MMP-14 and TIMP-1 in hepatocellular carcinoma cell lines SMMC7721 and hepG2, we used SMMC7721 as the in vitro invasion model for further functional analysis. Using this model, we found that GRP78 knockdown decreased the invasion of tumor cells, and this inhibitory effect was independent of cell proliferation. In hepatocellular carcinoma cells, Grp78 knockdown inhibited ECM degradation and the decreased activity and expression of MMP-2, but not MMP-9 contributed largely to this impact. Further analysis revealed that the decreased activity and expression of MMP-2 is mediated by JNK. Conclusion: Knockdown of GRP78 decreases ECM degradation, and downregulates the expression and activity of MMP-2 and TIMP-2. These results further demonstrate that GRP78 is a potential target for inhibiting the invasion of hepatocellular carcinoma cells.

Differential expression of RBM5, EGFR and KRAS mRNA and protein in non-small cell lung cancer tissues

Hong Liang — 2012-04-26T00:00:00Z

Background: RNA binding motif 5 (RBM5) is a tumor suppressor gene that modulates apoptosis through the regulation of alternative splicing of apoptosis-related genes. This study aimed to detect RBM5 expression in non-small cell lung cancer (NSCLC) and to associate RBM5 expression with clinicopathological data from NSCLC patients and EGFR and KRAS expression to better understand the potential role of RBM5 in NSCLC.MethodSemi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were performed to detect expression of mRNA and protein, respectively, of RBM5, EGFR and KRAS in 120 paired non-tumor and tumor samples of NSCLC. Results: The data showed that expression of RBM5 mRNA and protein was significantly reduced in NSCLC compared to normal tissues, whereas expression of both EGFR and KRAS genes was increased in NSCLC compared to normal tissues. Furthermore, the reduced RBM5 protein expression correlated with smoking status, tumor stage and lymph node metastasis of NSCLC, while overexpression of EGFR and KRAS proteins correlated with tumor stage and lymph node metastasis of NSCLC. Overexpression of KRAS protein was more frequent in smokers with NSCLC. In addition, expression of RBM5 mRNA and protein was negatively correlated with expression of EGFR and KRAS mRNA and protein in NSCLC tissues. Conclusion: This study suggests further evaluation of RBM5 expression is warranted for use of RBM5 as a biomarker for NSCLC patients.

Health-related quality of life in breast cancer patients: a bibliographic review of the literature from 1974 to 2007

Ali Montazeri — 2008-08-29T00:00:00Z

Background: Quality of life in patients with breast cancer is an important outcome. This paper presents an extensive overview on the topic ranging from descriptive findings to clinical trials. Methods: This was a bibliographic review of the literature covering all full publications that appeared in English language biomedical journals between 1974 and 2007. The search strategy included a combination of key words 'quality of life' and 'breast cancer' or 'breast carcinoma' in titles. A total of 971 citations were identified and after exclusion of duplicates, the abstracts of 606 citations were reviewed. Of these, meetings abstracts, editorials, brief commentaries, letters, errata and dissertation abstracts and papers that appeared online and were indexed ahead of publication were also excluded. The remaining 477 papers were examined. The major findings are summarized and presented under several headings: instruments used, validation studies, measurement issues, surgical treatment, systemic therapies, quality of life as predictor of survival, psychological distress, supportive care, symptoms and sexual functioning. Results: Instruments-Several valid instruments were used to measure quality of life in breast cancer patients. The European Organization for Research and Treatment of Cancer Core Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and its breast cancer specific complementary measure (EORTC QLQ-BR23) and the Functional Assessment Chronic Illness Therapy General questionnaire (FACIT-G) and its breast cancer module (FACIT-B) were found to be the most common and well developed instruments to measure quality of life in breast cancer patients. Surgery-different surgical procedures led to relatively similar results in terms of quality of life assessments, although mastectomy patients compared to conserving surgery patients usually reported a lower body image and sexual functioning. Systemic therapies-almost all studies indicated that breast cancer patients receiving chemotherapy might experience several side-effects and symptoms that negatively affect their quality of life. Adjuvant hormonal therapies also were found to have similar negative impact on quality of life, although in general they were associated with improved survival. Quality of life as predictor of survival-similar to known medical factors, quality of life data in metastatic breast cancer patients was found to be prognostic and predictive of survival time. Psychological distress-anxiety and depression were found to be common among breast cancer patients even years after the disease diagnosis and treatment. Psychological factors also were found to predict subsequent quality of life or even overall survival in breast cancer patients. Supportive care-clinical treatments to control emesis, or interventions such as counseling, providing social support and exercise could improve quality of life. Symptoms-Pain, fatigue, arm morbidity and postmenopausal symptoms were among the most common symptoms reported by breast cancer patients. As recommended, recognition and management of these symptoms is an important issue since such symptoms impair health-related quality of life. Sexual functioning-breast cancer patients especially younger patients suffer from poor sexual functioning that negatively affect quality of life. Conclusion: There was quite an extensive body of the literature on quality of life in breast cancer patients. These papers have made a considerable contribution to improving breast cancer care, although their exact benefit was hard to define. However, quality of life data provided scientific evidence for clinical decision-making and conveyed helpful information concerning breast cancer patients' experiences during the course of the disease diagnosis, treatment, disease-free survival time, and recurrences; otherwise finding patient-centered solutions for evidence-based selection of optimal treatments, psychosocial interventions, patient-physician communications, allocation of resources, and indicating research priorities were impossible. It seems that more qualitative research is needed for a better understanding of the topic. In addition, issues related to the disease, its treatment side effects and symptoms, and sexual functioning should receive more attention when studying quality of life in breast cancer patients.

UP-regulation of hypoxia inducible factor-1alpha by cobalt chloride correlates with proliferation and apoptosis in PC-2 cells

Zhi-Jun Dai — 2012-03-27T00:00:00Z

Background: The exact mechanism of the effects of hypoxia on the proliferation and apoptosis in carcinoma cells is still conflicting. This study investigated the variation of hypoxia-inducible factor-1alpha( HIF-1alpha) expression and the apoptosis effect of hypoxia stimulated by cobalt chloride (CoCl2) in pancreatic cancer PC-2 cells. Methods: PC-2 cells were cultured with different concentration (50-200 mumol/L) of CoCl2 after 24-120 hours to simulate hypoxia in vitro. The proliferation of PC-2 cells was examined by MTT assay. The cellular morphology of PC-2 cells were observed by light inverted microscope and transmission electron microscope(EM). The expression of HIF-1alpha on mRNA and protein level was measured by semi-quantitive RT-PCR and Western blot analysis. Apoptosis of PC-2 cells were demonstrated by flow cytometry with Annexin V-FITC/PI double staining. Results: MTT assay showed that the proliferation of PC-2 cells were stimulated in the first 72 h, while after treated over 72 h, a dose- dependent inhibition of cell growth could be observed. By using transmission electron microscope, swollen chondrosomes, accumulated chromatin under the nuclear membrane and apoptosis bodies were observed. Flow cytometer(FCM) analysis showed the apoptosis rate was correlated with the dosage of CoCl2. RT-PCR and Western blot analysis indicated that hypoxia could up-regulate the expression of HIF-1alpha on both mRNA and protein levels. Conclusion: Hypoxic microenvironment stimulated by CoCl2 could effectively induce apoptosis and influence cell proliferation in PC-2 cells, the mechanism could be related to up-expression of HIF-1alpha.

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

Jiang Zhinong — 2012-05-03T00:00:00Z

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

In vitro the behaviors of metastasis with suppression of VEGF in human bone metastatic LNCaP-derivative C4-2B prostate cancer cell line

Lei Yang — 2012-05-01T00:00:00Z

Background: Vascular endothelial growth factor (VEGF) is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. VEGF is believed to implicate poor prognosis in various cancers. The overexpression of VEGF may be an early step in the process of metastasis. Methods: ELISA was used to investigate the levels of VEGF, bFGF and IL8 in human bone metastatic LNCaP-derivative C4-2B prostate cancer cell line and its parental cell line, LNCa-P, and to determine the effect of bevacizumab on reducing the level of VEGF. Cell proliferation assay, invasion assay and in vitro angiogenesis assay were performed under the condition with bevacizumab or control IgG. Results: Human bone metastatic LNCaP-derivative C4-2B prostate cancer cell line expressed a higher level of VEGF than its parental primary prostate cancer cell line LNCaP. The effect of bevacizumab is dose-dependent and time-dependent: 100 ug/mL of bevacizumab and 3-day treatment was more effective than low-dose and lesser-day treatment for decreasing the level of VEGF. Bevacizumab is able to suppress cell proliferation, angiogenesis and invasion in human bone metastatic C4-2B prostatic cancer cell line. Conclusions: The overexpression of VEGF can be inhibited by bevacizumab in human bone metastatic cancer cell line. The behaviors of metastasis involving proliferation, angiogenesis and invasion are suppressed by anti-VEGF therapy.

Sexual function in breast cancer patients: a prospective study from Iran

Iraj Harirchi — 2012-03-09T00:00:00Z

Background: Sexual function in patients with breast cancer especially in younger patients is an important issue from clinical and psychosocial perspectives. This study aimed to assess sexual function among Iranian breast cancer patients. Methods: This was a prospective study of sexual function in breast cancer patients attending the Cancer Institute of Iran. Sexual function was assessed using the Female Sexual Function Index (FSFI) at two points in time: baseline (pre-treatment) and after completion of cancer treatment at follow-up visits (post-treatment). Pre- and post-treatment data were compared. In addition logistic regression analysis was performed to find out factors that contributing to post-treatment sexual dysfunction. Results: In all 277 breast cancer patients were approached. Of these, 231 patients (83%) were sexually active and data for 216 patients (93.5% of sexually active patients) were available at pre-and post-treatment. Overall pre- and post-treatment sexual dysfunction was found to be 52% and 84%, respectively indicating a significant deterioration in sexual function among breast cancer patients. The results obtained from multiple logistic regression analysis indicated that younger age [OR = 0.95, 95% CI = 0.93-0.98; P = 0.04], receiving endocrine therapy [OR = 3.34, 95% CI = 1.37-7.91; P = 0.007] and poor sexual function at pre-treatment [OR = 12.3, 95% CI = 3.93-39.0; P < 0.0001] were the most significant contributing factors to post-treatment sexual disorders. Conclusion: A significant number of breast cancer patients experience deterioration in sexual function over time. The findings from this study indicated that younger age, receiving endocrine therapy, and poor sexual function at diagnosis were the most significant predicting factors for sexual disorders following treatment.

Stem cells in clinical practice: applications and warnings

Daniele Lodi — 2011-01-17T00:00:00Z

Stem cells are a relevant source of information about cellular differentiation, molecular processes and tissue homeostasis, but also one of the most putative biological tools to treat degenerative diseases. This review focuses on human stem cells clinical and experimental applications. Our aim is to take a correct view of the available stem cell subtypes and their rational use in the medical area, with a specific focus on their therapeutic benefits and side effects. We have reviewed the main clinical trials dividing them basing on their clinical applications, and taking into account the ethical issue associated with the stem cell therapy. Methods: We have searched Pubmed/Medline for clinical trials, involving the use of human stem cells, using the key words "stem cells" combined with the key words "transplantation", "pathology", "guidelines", "properties" and "risks". All the relevant clinical trials have been included. The results have been divided into different categories, basing on the way stem cells have been employed in different pathological conditions.