Undifferentiated cells and embryos express high levels of endogenous non-telomerase reverse transcriptase (RT) of retroposon/retroviral origin. We previously found that RT inhibitors modulate cell growth and differentiation in several cell lines. We have now sought to establish whether high levels of RT activity are directly linked to cell transformation. To address this possibility, we have employed two different approaches to inhibit RT activity in melanoma and prostate carcinoma cell lines: pharmacological inhibition by two characterized RT inhibitors, nevirapine and efavirenz, and downregulation of expression of RT-encoding LINE-1 elements by RNA interference (RNAi). Both treatments reduced proliferation, induced morphological differentiation and reprogrammed gene expression. These features are reversible upon discontinuation of the anti-RT treatment, suggesting that RT contributes to an epigenetic level of control. Most importantly, inhibition of RT activity in vivo antagonized tumor growth in animal experiments. Moreover, pretreatment with RT inhibitors attenuated the tumorigenic phenotype of prostate carcinoma cells inoculated in nude mice. Based on these data, the endogenous RT can be regarded as an epigenetic regulator of cell differentiation and proliferation and may represent a novel target in cancer therapy.
Neoadjuvant therapy with irinotecan combined with 5-FU/FA enabled a significant proportion of patients with initially unresectable liver metastases to undergo surgical resection. The effects of treatment on survival have yet to be determined.
Objective: The combined assessment of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP) gene expressions in metastatic colorectal cancer has been reported to be able to predict the efficacy of fluoropyrimidine-based chemotherapy. In order to evaluate the prognostic role in the adjuvant setting, we investigated the TS, DPD and TP expression in primary tumors of colorectal cancer patients treated with 5-fluorouracil (5-FU). Methods: TS, DPD and TP expression levels were determined by immunohistochemistry in paraffin-embedded primary tumor tissues from 62 patients with Dukes’ stage B and C colorectal cancers who underwent surgery and received adjuvant systemic chemotherapy with 5-FU. The median follow-up was 90 months (range 17–127). Results: Dukes’ stage C cancer and high TS expression were independent markers of poor prognosis for disease-free survival (DFS; p = 0.0009 and p = 0.007, respectively) and overall survival (OS; p = 0.0005 and p = 0.011, respectively). By multivariate analysis, patients with high DPD expression had significantly shorter DFS (p = 0.007) and OS (p = 0.005) compared to patients with low DPD expression. In the combined analysis of 2 markers, patients with low TS and low DPD had the best outcome in terms of DFS (p = 0.007) and OS (p = 0.03). The analysis of all 3 proteins showed that the patients with low expression of all 3 markers had significantly longer DFS (p = 0.04) and OS (p = 0.01) than patients with a high value of any one of the protein expressions. However, the joint analysis of 3 markers (group with TS–/DPD–/TP–) could not identify a subgroup of patients with a better prognosis compared to the analysis of 2 markers (group with TS–/DPD–). The analysis of Dukes’ stage C cancer patients confirmed a significant benefit in terms of DFS and OS (p = 0.001 and p = 0.006, respectively) when all 3 markers had low expression. We also found a positive significant correlation between TS and TP protein expression (p = 0.033). Conclusions: This retrospective investigation suggests that the combined assessment of TS and DPD may be useful to evaluate the prognosis of patients with Dukes’ B and C colon carcinoma receiving 5-FU adjuvant chemotherapy. The role of TP as a predictor for 5-FU-based therapy needs further investigations.
Taken together, these results support a possible anti-cancer and anti-angiogenetic activity of Zol. Our data may not only provide a basis for the clinical use of this drug as preventive agent of bone metastases but also suggest that Zol deserves attention as an anti-cancer agent in non-small-cell lung cancer.
S100 proteins are Ca(2+)-binding polypeptides involved in the tumourigenesis of several human neoplasms. S100A13 is a key regulator of the stress-dependent release of FGF1, the prototype of the FGF protein family involved in angiogenesis. Indeed, S100A13 is a copper binding protein able to enhance the export of FGF1 in response to stress in vitro and to induce the formation of a multiprotein aggregate responsible for FGF1 release. We investigated the expression of S100A13 in human astrocytic gliomas in relation to tumour grading and vascularization. A series of 26 astrocytic gliomas was studied to evaluate microvessel density and to assess FGF1, S100A13 and VEGF-A expression. FGF1 was equally expressed in the vast majority of tumours, whereas S100A13 and VEGF-A were significantly up-regulated in high-grade vascularized gliomas. Moreover, both S100A13 and VEGF-A expression significantly correlated with microvessel density and tumour grading. These data suggest that the up-regulation of S100A13 and VEGF-A expression correlates with the activation of angiogenesis in high-grade human astrocytic gliomas.
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