Abstract
Tumour resistance to chemo- and radiotherapy, as well as molecularly targeted therapies, limits the effectiveness of current cancer treatments. We previously reported that the radiation response of human prostate tumours is critically regulated by CAV1 expression in stromal fibroblasts and that loss of stromal CAV1 expression in advanced tumour stages may contribute to tumour radiotherapy resistance. Here we investigated whether fibroblast secreted anti-apoptotic proteins could induce radiation resistance of prostate cancer cells in a CAV1-dependent manner and identified TRIAP1 (TP53 Regulated Inhibitor of Apoptosis 1) as a resistance-promoting CAV1-dependent factor. TRIAP1 expression and secretion was significantly higher in CAV1-deficient fibroblasts and secreted TRIAP1 was able to induce radiation resistance of PC3 and LNCaP prostate cancer cells in vitro, as well as of PC3 prostate xenografts derived from co-implantation of PC3 cells with TRIAP1-expressing fibroblasts in vivo. Immunohistochemical analyses of irradiated PC3 xenograft tumours, as well as of human prostate tissue specimen, confirmed that the characteristic alterations in stromal-epithelial CAV1 expression were accompanied by increased TRIAP1 levels after radiation in xenograft tumours and within advanced prostate cancer tissues, potentially mediating resistance to radiation treatment. In conclusion, we have determined the role of CAV1 alterations potentially induced by the CAV1-deficient, and more reactive, stroma in radio sensitivity of prostate carcinoma at a molecular level. We suggest that blocking TRIAP1 activity and thus avoiding drug resistance may offer a promising drug development strategy for inhibiting resistance-promoting CAV1-dependent signals.
Highlights
IntroductionCancer therapeutic resistance occurs through many different mechanisms, including specific genetic and epigenetic changes in the cancer cell itself and/or the respective microenvironment.The tumour stroma is recognized as a key player in cancer cell invasiveness, progression and therapy resistance [1,2,3]
Cancer therapeutic resistance occurs through many different mechanisms, including specific genetic and epigenetic changes in the cancer cell itself and/or the respective microenvironment.The tumour stroma is recognized as a key player in cancer cell invasiveness, progression and therapy resistance [1,2,3]
We previously reported that the radiation response of human prostate tumours is critically regulated by CAV1 expression in stromal fibroblasts and that loss of stromal CAV1 expression in advanced tumour stages may contribute to tumour radiotherapy resistance
Summary
Cancer therapeutic resistance occurs through many different mechanisms, including specific genetic and epigenetic changes in the cancer cell itself and/or the respective microenvironment.The tumour stroma is recognized as a key player in cancer cell invasiveness, progression and therapy resistance [1,2,3]. The exact mechanisms of fibroblast activation remain elusive, the activation or repression of specific genes or proteins within stromal cells has been correlated with clinical outcome. The membrane protein Caveolin-1 (CAV1) came into focus as it is highly expressed in many tumours and high CAV1 levels in tumour cells, as well as the downregulation of stromal CAV1, were shown to correlate with cancer progression, invasion and metastasis and a worse clinical outcome [4,5]. Data on the CAV1-dependent epithelia-stroma crosstalk indicates that stromal CAV1 possesses tumour-suppressor properties, whereas loss of stromal CAV1 fosters malignant epithelial cell resistance by evading apoptosis [5,10]. A detailed mechanism explaining how CAV1-deficient fibroblasts foster therapy resistance of malignant prostate cancer cells remains elusive. An improved understanding of the molecular basis of resistance will inevitably lead to the clinical assessment of rational drug combinations in selected patient populations
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