Integrin-mediated mechanisms of prostate cancer progression

摘要 旨在治愈前列腺癌(PrCa)的治疗方法只取得了部分成功，因为 高转移性耐药表型的出现，这些表型经常因化学去势而发展 在PrCa患者中。最近，我们首次描述了整合素家族的表面受体αvβ6。 作为PrCa治疗的新治疗靶点，该分子是一个理想的靶点，因为与其他整合素不同的是，它 在不同类型的癌症中发现，但在正常组织中不存在。我们已经证明了这一点的独特性质 PrCa中其他整合素没有观察到的分子：我们已经证明αvβ6促进去势- 耐药前列腺癌(CRPC)通过激活JNK和雄激素受体(AR)。此外，我们还拥有 研究表明，αvβ6存在于癌细胞外体中，通过以下途径从癌细胞转移到受体细胞 外体并在受体细胞中保持活性。我们还证明了αvβ6对 微环境。具体地说，αvβ6可阻止供体中STAT1/Mx1/2信号通路的诱导 癌细胞及其外切体及其在癌细胞外切体中的下调抑制单核细胞M2 极化。最后，我们证明了体内抑制αvβ6导致STAT1/MXA/B上调 癌细胞中的信号通路。 基于我们高度严谨的机制研究，我们提出了以下创新假设：αvβ6 表达通过下调供体细胞中的STAT1/Mx1水平来影响微环境，并随后 在癌细胞外体和受体细胞中，从而促进单核细胞分化，肿瘤生长，以及 癌症进展。因此，通过下调或抑制癌细胞中的αvβ6，增加了 将在细胞/外切体/单核细胞中产生STAT1/MXA/B水平，从而产生抗肿瘤作用。为了测试 在这一假设下，我们计划实现以下三个具体目标。我们将在体外检测αvβ6整合素在 调节癌细胞-单核细胞串扰(AIM 1)，并在体内分析该通路的功能作用 由胞外体αvβ6和/或STAT1介导的肿瘤进展(目标2)和αvβ6的特征 PrCa细胞中的整合素/STAT1通路(目标3)。 创新的方法、高度提纯的外切体和体内模型将被用来检验我们的假设 整合素及其下游效应因子从癌细胞向肿瘤中其他细胞的转移 微环境促进CRPC。这项研究将由一个多学科的调查小组提供支持 他们在所有所需技术方面拥有广泛和互补的专业知识。根据我们的初步调查 关于αvβ6/STAT1通路的数据和该项目的计划实验设计，我们预计我们的研究将 阐明促进PrCa的新机制，并验证PrCa治疗方法的新靶点。

ABSTRACT Therapeutic approaches aimed at curing prostate cancer (PrCa) are only partially successful given the occurrence of highly metastatic resistant phenotypes that frequently develop in response to chemical castration of PrCa patients. Recently, we have, for the first time, described αvβ6, a surface receptor of the integrin family as a novel therapeutic target for PrCa treatment; this molecule is an ideal target since, unlike other integrins, it is found in different types of cancer but not in normal tissues. We have demonstrated unique properties of this molecule in PrCa that are not observed for other integrins: we have shown that αvβ6 promotes castrate- resistant prostate cancer (CRPC) via activation of JNK and androgen receptor (AR). Furthermore, we have shown that αvβ6 is found in cancer cell exosomes, is transferred from cancer cells to recipient cells by exosomes and remains active in the recipient cells. We also demonstrate that αvβ6 has profound effects on the microenvironment. Specifically, αvβ6 prevents induction of the Stat1/Mx1/2 signaling pathway in donor cancer cells, and their exosomes, and its down-regulation in cancer cell exosomes inhibits monocyte M2 polarization. Finally, we demonstrate that αvβ6 inhibition in vivo causes upregulation of the Stat1/MxA/B signaling pathway in cancer cells. Based on our highly rigorous mechanistic studies, we propose the following innovative hypothesis: αvβ6 expression affects the microenvironment by down-regulating Stat1/Mx1 levels in donor cells, and subsequently in cancer cell exosomes and recipient cells, thereby promoting monocyte differentiation, tumor growth, and cancer progression. Consequently, by down-regulating or inhibiting αvβ6 in cancer cells, increased Stat1/MxA/B levels in cells/ exosomes/ monocytes will be generated producing an anti-tumor effect. To test this hypothesis, we plan the following three specific aims. We will examine in vitro the role of αvβ6 integrin in regulating cancer cell - monocyte crosstalk (Aim 1), and analyze in vivo the functional role of the pathway mediated by exosomal αvβ6 and/or Stat1 in cancer progression (Aim 2) and characterize the αvβ6 integrin/Stat1 pathway in PrCa cells (Aim 3). Innovative approaches, highly purified exosomes and in vivo models will be used to test our hypothesis that transfer of integrins and their downstream effectors from cancer cells to other cells in the tumor microenvironment promotes CRPC. The study will be supported by a multidisciplinary team of investigators who have extensive and complementary expertise in all the required technologies. Based on our preliminary data on the αvβ6/Stat1 pathway and planned experimental design for this project, we expect that our study will elucidate new mechanisms that promote PrCa and validate new targets for PrCa therapeutic approaches.