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• W4247248935 abstract "Marra et al., pp. 2004–2013 Zoledronic acid is commonly used to treat the pathologic fractures associated with cancers such as multiple myeloma and pancreatic carcinoma. Chemically a biphosphonate, the drug has unique affinities to bone tissue, where it blocks the enzyme farnesyl diphosphate synthase. This prevents the formation of two metabolites that are essential for protein prenylation and proper subcellular trafficking of lipid-anchored proteins, such as Ras, Rho and Rac. The study by Marra and colleagues follows up on recent in vitro experiments that uncovered unique therapeutic effects of zoledronic acid on the binding of breast and prostate cancer cells to bone surfaces. Previous studies also demonstrated that the drug directly induces growth inhibition and apoptosis in prostate cancer cell lines. To identify the molecular targets of these effects of zoledronic acid, the authors performed gene expression profiling studies in PC3 prostate cancer cells. They identified Cyr61 as a gene product that is downregulated by zoledronic acid treatment. Cyr61 is a secreted matrix-associated protein that promotes adhesion of endothelial cells through interactions with integrins. Downregulation of Cyr61 by zoledronic acid occurred at the transcriptional level and was only partially explained by known effects of the drug on the Ras-Raf-Erk pathway. Knockdown of Cyr61 by small hairpin RNAs potentiated the growth inhibition mediated by zoledronic acid and suppressed cell motility in PC3 cells. The authors speculate that zoledronic acid in combination with other Cyr61-targeting modalities may uniquely benefit prostate cancer patients. Cullmann et al., pp. 2014–2020 Human papillomavirus (HPV) transforms human cells by inactivating two key tumor suppressor pathways via the activity of its main oncogenic proteins: HPV E6 inactivates the p53 pathway while HPV E7 inactivates the Rb pathway. Reduced BTG2 protein expression in cervical cancer. Immunohistochemical staining of a normal ectocervical tissue (upper panel) and of a cervical carcinoma (lower panel) for expression of BTG2 and p16 (a surrogate marker for HPV oncogene expression). Magnification is 40-fold. To identify other cellular pathways that might be modulated by these two viral proteins, Cullmann and colleagues analyzed transcriptional changes occurring in cell lines carrying HPV following inactivation of E6/E7 via RNA interference. In this issue of IJC, they report the identification of the tumor suppressor B-cell translocation gene 2 (BTG2) as a specific target of E6. BTG2 exhibits properties of a tumor suppressor and was recently linked to human carcinogenesis. The authors show that BTG2 is specifically repressed by the HPV E6 protein in a p53-dependent manner. This repression occurs at the transcriptional level via specific p53-binding sites in the BTG2 promoter. Importantly, high-grade HPV-positive cervical carcinomas showed lower expression of BTG2 in comparison to normal cervical epithelium and forced re-expression of BTG2 in cervical cancer cells suppressed their proliferation. These observations collectively support an important role for the suppressive activity of E6 against BTG2 in the pathogenesis of HPV-induced cervical carcinoma. Zieger et al., pp. 2095–2103 Genetic profiling of different cancers deepens our understanding of the biology of these cancers and identifies novel subtypes beyond the common histopathological classifications. Carcinoma-in-situ (CIS) is a frequent, but molecularly poorly understood bladder cancer subtype. These flat, noninvasive, but high-grade intraurothelial lesions are often found in coexistence with invasive tumors. Zieger and colleagues performed laser-capture microdissection and SNP microarrays in 12 CIS samples and accompanying invasive tumors. They detected characteristic chromosomal instabilities in 8 of the 12 CIS cases. These included gains of chromosomes 5p, 5p22.3 and 10p15.1 and losses of chromosome 5q and 13q13-q14. Because in early papillary bladder cancer the fibroblast growth factor receptor 3 (FGFR3) is known to act as a molecular “speeder,” activating FGFR3 mutations were also analyzed. However, no FGFR3 mutations were found in CIS samples. In a cohort of high-risk non-muscle-invasive bladder cancers, gains of chromosome 5p and FGFR3 mutations were mutually exclusive, suggesting that they represent markers of different pathways. Interestingly, although 5p gains were associated with CIS lesions, they were never found as the only chromosomal change in any sample. This indicates that 5p gain is a characteristic, but probably later change in CIS-type lesions. Based on these findings the authors propose a revised model of bladder tumor development that proceeds through two mutually exclusive early stage pathways: a papillary and a CIS-type pathway. The primary difference is that in the papillary pathway self-sufficiency to growth signals appears before chromosomal instabilities, while CIS-type tumors lose genomic stability prior to unlimited proliferation." @default.
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• W4247248935 date "2009-08-28" @default.
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• W4247248935 title "Spotlight" @default.
• W4247248935 doi "https://doi.org/10.1002/ijc.24843" @default.
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