Abstract
Despite good treatment results in localized prostate tumors, advanced disease stages usually have a pronounced resistance to chemotherapy and radiotherapy. The membrane protein caveolin-1 (Cav1) functions here as an important oncogene. Therefore we examined the impact of stromal Cav1 expression for tumor growth and sensitivity to ionizing radiation (IR). Silencing of Cav1 expression in PC3 cells resulted in increased tumor growth and a reduced growth delay after IR when compared to tumors generated by Cav1-expressing PC3 cells. The increased radiation resistance was associated with increasing amounts of reactive tumor stroma and a Cav1 re-expression in the malignant epithelial cells. Mimicking the human situation these results were confirmed using co-implantation of Cav1-silenced PC3 cells with Cav1-silenced or Cav1-expressing fibroblasts. Immunohistochemically analysis of irradiated tumors as well as human prostate tissue specimen confirmed that alterations in stromal-epithelial Cav1 expressions were accompanied by a more reactive Cav1-reduced tumor stroma after radiation and within advanced prostate cancer tissues which potentially mediates the resistance to radiation treatment. Conclusively, the radiation response of human prostate tumors is critically regulated by Cav1 expression in stromal fibroblasts. Loss of stromal Cav1 expression in advanced tumor stages may thus contribute to resistance of these tumors to radiotherapy.
Highlights
The clinical relevance of the tumor microenvironment in modulating the response of solid tumors to chemotherapy and radiotherapy has been documented[1,2,3,4,5]
Using long-term assays measuring the surviving fraction after irradiation revealed that the number of epithelial PC3 cells able to re-grow and form a colony after irradiation was considerably diminished in shCav[1] PC3(−) cells as compared to the shCtrl PC3(+) cells with normal Cav[1] expression (Fig. 1A)
Lowering Cav[1] levels in tumor epithelial cells may be suited to increase the efficiency of ionizing radiation (IR) in prostate cancer (PCa)
Summary
The clinical relevance of the tumor microenvironment in modulating the response of solid tumors to chemotherapy and radiotherapy has been documented[1,2,3,4,5]. Though levels of Cav[1] increased in epithelial cancer cells during PCa progression, Cav[1] expression was decreased in the tumor stroma in advanced and metastatic PCa, an effect that was found to be functionally relevant to tumor progression and to correlate with reduced relapse-free survival[10,19]. The accelerated growth of untreated prostate tumors in the Cav1-deficient background hinted to a potential risk of treatment strategies targeting endothelial Cav[1] for radiosensitization in these tumors making careful validation of such treatment strategies with respect to adverse growth promoting effects absolutely necessary[19]. We investigated the role of stromal Cav[1] for growthand resistance-promoting tumor-stroma interactions during PCa progression with a focus on the impact of stromal fibroblasts
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