~ New Findings in the Area of Oncology Detailed

NewsRx.com, 08-17-05

Data on oncology are outlined in reports from Italy, Canada and France.

Study 1: BRCA2 and collagen type I interaction causes prostate cancer to proliferate.

According to a study from Italy, "BRCA2 is a tumor suppressor gene that when mutated confers an increased susceptibility to developing breast and prostate carcinoma. Besides its role in mediating DNA repair, new evidence suggests that BRCA2 may also play a role in suppressing cancer cell growth."

"Because altered interactions between neoplastic cells and the surrounding extracellular matrix (ECM) play a pivotal role in unchecked cancer cell proliferation and metastatic progression, we hypothesized that the ECM may have an effect in BRCA2 expression," L. Moro and colleagues, National Research Council, Bari reported.

"By using normal and prostate carcinoma cell lines, we demonstrated that although normal cells transiently increase BRCA2 protein levels when adhering to the ECM protein collagen type I (COL1), carcinoma cells exhibit a significant reduction in BRCA2 protein. This aberrant effect is independent from de novo protein synthesis and results from COL1-beta1 integrin signaling through phosphatidylinositol (PI) 3-kinase leading to BRCA2 ubiquitination and degradation in the proteasome.

"BRCA2 protein depletion after cancer cell adhesion to COL1 or in small RNA interference assays triggers new DNA synthesis, a trophic effect that is abrogated by recombinant BRCA2 expression," researchers noted. "Blocking or inhibiting beta1 integrin, PI 3-kinase, or proteasome activity all have a negative effect on COL1-mediated DNA synthesis in cancer cells."

"In normal cells, the transient increase in BRCA2 expression is independent from beta1 integrin or PI 3-kinase and has no effect in cell proliferation," researchers reported.

"In summary, these results unravel a novel mechanism whereby prostate carcinoma cell proliferation is enhanced by the down-regulation of BRCA2 expression when interacting with COL1, a major component of the ECM at osseous metastatic sites."

Moro and colleagues published the results of their research in The Journal of Biological Chemistry (Down-regulation of Brca2 expression by collagen type I promotes prostate cancer cell proliferation. J Biol Chem, 2005;280(23):22482-91).

For additional information, contact L. Moro, Institute of Biomembranes and Bioenergetics, National Research Council (Consiglio Nazionale delle Ricerche), Via Amendola 165, A, Bari 70126, Italy.

Study 2: Clusterin inhibition enhances prostate cancer's response to primary therapy.

According to a study from Canada, "the discovery and targeting of genes mediating androgen-independence may lead to the development of novel therapies that delay progression of hormone refractory prostate cancer (HRPC). Clusterin is a stress-associated cell survival gene that increases after androgen ablation."

"Here, we review clusterin's functional role in apoptosis and the use of antisense oligonucleotides (ASOs) against clusterin to enhance apoptosis in prostate cancer models," wrote M. Gleave and colleagues, University of British Columbia, Division of Urology.

"Immunostaining of tissue microarrays constructed from untreated and post-hormone treated radical prostatectomy specimens confirm that clusterin is highly expressed in virtually all HRPC cells, 80% of prostate cancer cells after neoadjuvant hormone therapy, but is low or absent (<20%) in untreated specimens. Overexpression of clusterin in LNCaP cells confers resistance to both androgen ablation and chemotherapy."

"Clusterin ASOs reduced clusterin levels in a dose-dependent and sequence-specific manner. Adjuvant treatment with murine clusterin ASOs after castration of mice bearing Shionogi tumors decreased clusterin levels, accelerated apoptotic tumor regression, and significantly delayed the recurrence of androgen-independent tumors," Gleave and coauthors reported.

"A human clusterin ASO targeting the translation initiation site and incorporating MOE-gapmer backbone (OGX-011) synergistically enhanced the cytotoxic effects of paclitaxel in human xenografts of prostate, renal cell, bladder, and lung cancer."

"Clusterin, is an antiapoptosis protein upregulated in an adaptive cell survival manner by androgen ablation and chemotherapy that confers resistance to various cell death triggers. Suppression of clusterin levels using ASOs enhances cell death following treatment with androgen ablation, radiation, and chemotherapy," researchers concluded.

Gleave and colleagues published the results of their research in World Journal of Urology (Use of antisense oligonucleotides targeting the cytoprotective gene, clusterin, to enhance androgen- and chemo-sensitivity in prostate cancer. World J Urol, 2005;23(1):38-46).

For additional information, contact M. Gleave, University British Columbia, Division Urology, D-9, 2733 Heather St., Vancouver, BC V5Z 3J5, Canada.

Study 3: Angiogenic growth factor receptors predict poor outcomes from breast cancer.

"The degree of angiogenesis in breast cancer has previously been shown to be an indicator of prognosis, and tumor microvasculature is a candidate target for new antiangiogenic therapies. The aim of this study was to investigate the prognostic value of vascular endothelial growth factor (VEGF) receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1), and Tie2/tek receptor tyrosine kinase in breast carcinoma," scientists writing in the International Journal of Oncology report.

"VEGF receptors and Tie2 expression was investigated using immunohistochemical assays with monoclonal antibodies on frozen sections in a series of 918 and 909 patients respectively," said S. Meunier-Carpentier and colleagues, Anatomy and Cytological Pathology Service.

"VEGFR-1 and VEGFR-2 and Tie2 were correlated with long-term (median, 11.3 years) patients' outcome. Univariate (Kaplan-Meier) analysis showed that VEGFR-1 positive tumor surface (cutoff=5%) was significantly correlated with high metastasis risk (p=0.03) and relapse (p<0.01) in all patients, and in those with node negative tumors (p<0.001 and p<0.01 respectively), but not with overall survival.

"In contrast, Tie2 positive tumor surface (cutoff=7%) was significantly correlated with poor overall survival (p=0.025) and also with high metastasis risk, particularly among node negative patients (p<0.01). Moreover, Tie2 immunoexpression was significantly predictive of relapse (p=0.003) in the node negative subgroup (p=0.02). In multivariate analysis (Cox model), VEGFR-1 and Tie2 immunoexpressions were identified as independent prognostic indicators.

"In contrast, univariate analysis showed that VEGFR-2 positive tumor surface (cutoff%) was not correlated with survival or with metastasis and relapse risk," researchers advised.

"Our results suggest that VEGFR-1 and Tie2 immunohistochemical expression permits the identification of patients with poor outcome, and particularly node negative ones with a high risk for metastasis and relapse. VEGFR-1 and Tie2 immunodetection may also be considered as potential tools for selecting patients who could benefit in the future from specific antiangiogenic therapy interfering with VEGFR-1 and Tie2 activation pathways," scientists concluded.

Meunier-Carpentier and colleagues published their study in International Journal of Oncology (Comparison of the prognosis indication of VEGFR-1 and VEGFR-2 and Tie2 receptor expression in breast carcinoma. Int J Oncol, 2005;26(4):977-984).

Additional information can be obtained by contacting C. Charpin, Faculty Med Secteur North Marseille, Service Anatomy & Cytology Pathology, Bd Pierre Dramard, F-13916 Marseille, France.

Keywords: Marseille, France, Angiogenesis, Breast Cancer, Oncology, Women's Health. This article was prepared by Biotech Week editors from staff and other reports. Copyright 2005, Biotech Week via NewsRx.com.

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