Integrin-mediated mechanisms of prostate cancer progression

摘要 考虑到前列腺癌（PrCa）的发病率，旨在治愈前列腺癌（PrCa）的治疗方法仅部分成功。 发生高转移性耐药表型，这些表型通常是对化学去势的反应 PrCa患者最近，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;该分子是理想的靶点，因为与其他整合素不同， 存在于不同类型的癌症中，但不存在于正常组织中。我们已经证明了这种独特的性质， 在PrCa中没有观察到其他整合素的分子：我们已经证明αvβ6促进去势- 通过JNK和雄激素受体（AR）的激活，治疗耐药前列腺癌（CRPC）。此外，我们有 显示αvβ6存在于癌细胞外泌体中，通过 外泌体并在受体细胞中保持活性。我们还证明了αvβ6对 微环境。具体而言，αvβ6阻止供体中Stat 1/Mx 1/2信号通路的诱导。 癌细胞及其外泌体及其在癌细胞外泌体中的下调抑制单核细胞M2 极化最后，我们证明了体内αvβ6抑制导致Stat 1/MxA/B上调， 癌细胞中的信号通路。 基于我们高度严谨的机理研究，我们提出了以下创新假设：αvβ6 表达通过下调供体细胞中Stat 1/Mx 1水平影响微环境， 在癌细胞外泌体和受体细胞中，从而促进单核细胞分化、肿瘤生长， 癌症进展因此，通过下调或抑制癌细胞中的αvβ6， 细胞/外来体/单核细胞中的Stat 1/MxA/B水平将产生抗肿瘤作用。测试 根据这一假设，我们计划实现以下三个具体目标。我们将在体外研究αvβ6整合素在细胞凋亡中的作用。 调节癌细胞-单核细胞串扰（Aim 1），并在体内分析该途径的功能作用 外泌体αvβ6和/或Stat 1介导的癌症进展（目的2），并表征αvβ6 整合素/Stat 1通路（Aim 3）。 创新的方法，高度纯化的外泌体和体内模型将用于测试我们的假设， 整合素及其下游效应物从癌细胞转移到肿瘤中的其它细胞 微环境促进CRPC。该研究将得到多学科研究人员团队的支持 他们在所有必要的技术方面都有广泛的互补性专业知识。根据我们初步的 关于αvβ6/Stat 1通路的数据和本项目计划的实验设计，我们希望我们的研究将 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.