Cacciotti Paola, Barbone Dario, Porta Camillo, Altomare Deborah A, Testa Joseph R, Mutti Luciano, Gaudino Giovanni
Department of Medical Sciences, University of Piemonte Orientale A. Avogadro, Novara, Italy.
Cancer Res. 2005 Jun 15;65(12):5256-62. doi: 10.1158/0008-5472.CAN-05-0127.
Human malignant mesothelioma is an aggressive cancer generally associated with exposure to asbestos, although SV40 virus has been involved as a possible cofactor by a number of studies. Asbestos fibers induce cytotoxicity in human mesothelial cells (HMC), although cell survival activated by key signaling pathways may promote transformation. We and others previously reported that SV40 large T antigen induces autocrine loops in HMC and malignant mesothelioma cells, leading to activation of growth factor receptors. Now we show that SV40 induces cell survival via Akt activation in malignant mesothelioma and HMC cells exposed to asbestos. Consequently, prolonged exposure to asbestos fibers progressively induces transformation of SV40-positive HMC. As a model of SV40/asbestos cocarcinogenesis, we propose that malignant mesothelioma originates from a subpopulation of transformed stem cells and that Akt signaling is a novel therapeutic target to overcome malignant mesothelioma resistance to conventional therapies.
人类恶性间皮瘤是一种侵袭性癌症，通常与接触石棉有关，尽管多项研究表明SV40病毒可能是一种辅助致癌因素。石棉纤维可诱导人胸膜间皮细胞（HMC）产生细胞毒性，不过由关键信号通路激活的细胞存活可能会促进细胞转化。我们和其他人之前报道过，SV40大T抗原可在HMC和恶性间皮瘤细胞中诱导自分泌环，从而导致生长因子受体的激活。现在我们发现，在暴露于石棉的恶性间皮瘤和HMC细胞中，SV40通过激活Akt诱导细胞存活。因此，长期暴露于石棉纤维会逐渐诱导SV40阳性HMC发生转化。作为SV40/石棉协同致癌作用的模型，我们提出恶性间皮瘤起源于转化干细胞亚群，并且Akt信号传导是克服恶性间皮瘤对传统疗法耐药性的一个新的治疗靶点。
