肿瘤微环境应激反应蛋白PAGE4在间质细胞中的激活对前列腺癌进展的影响

Prostate cancer (PCa) is the most diagnosed cancer in men in the United States, and its incidence is increasing rapidly in Asia countries recently. Androgens are well-established risk factors for the development and progression of PCa. However, they alone are not single causative factors; estrogen dysregulation, chronic inflammation, and in particular, oxidative stress induced by diet, environmental carcinogens, and inflammatory factors, are also proffered to contribute to the development and progression of PCa. On the other hand, PCa is a typical multicentric cancer, which is believed to be attributed to the "cancer field effect", which represents the compliance of microenvironment where the cancer cells exist to cancerous behavior. In this context, cancer microenvironment and cancer-stroma interaction signaling may have the potential to become valuable targets for cancer therapy or biomarkers to reveal the immediate consequence of cancer progression and thereby indicate its invasive or metastatic potential.Prostate associated gene 4 (PAGE4) is a cancer-testis antigen that is expressed in the normal testis and fetal prostate but not in adult prostate. PAGE4 has been described as a stroma-specific gene; however, for the first time we show that it is also expressed in the inflammation-related epithelia of PIA lesions, suggesting an association with stress-enriched microenvironment of diseased prostate. While the expression of PAGE4 has been partially described, its function remains unclear. Our preliminary studies indicate that PAGE4 is activated in the microenvironment of PCa, suppress reactive oxidative species (ROS) production, and protects cells from stress-induced cellular damage. Thus, PAGE4 may be involved in the cellular response to stress in the microenvironment associated with PCa, and better understanding its functional roles in the interactions between stromal cells and cancer cells could provide new insight into the mechanisms underlying the progression of PCa and help to identify novel biomarker(s) to predicate cancer prognosis. To this end, we propose to investigate the effect of PAGE4 expression in PCa microenvironment on cancer progression by a co-culture system in vitro and a tissue recombinant model in vivo. Further, the mechanisms by which PAGE4 regulates the interactions between prostatic stromal cells and PCa cells will be determined by cytokine screening system, and the modulation of PAGE4 on cytoskeleton as well as on extracellular matrix remodeling will be evaluated.Thus, the successful completion of this project will likely lead to the discovery of a novel PAGE4-associated pathway that will in turn lead to identification of targets for cancer therapy, and also may help to develop biomarkers to predict PCa progression.

前列腺癌是多中心发病肿瘤，"癌场效应"表明组织微环境对肿瘤的发生、发展具有重要作用。前列腺癌间质的氧化应激因素是肿瘤微环境重建的重要动力，而癌相关间质细胞是肿瘤微环境的重要建造者之一。我们前期的研究表明，前列腺胚胎发育相关基因PAGE4在前列腺癌组织微环境内的激活与炎症、氧化应激及细胞保护密切相关，并可能参与调控前列腺癌-间质细胞间相互作用。本研究拟利用2D、3D共培养体系和体内组织重组技术来揭示PAGE4对癌-间质细胞间相互作用的影响，并运用细胞因子抗体芯片、PCR芯片和荧光素酶报告系统等手段在共培养系统中筛选和鉴定PAGE4调节的细胞因子和信号转导通路，以及PAGE4对间质细胞骨架和细胞外基质的影响，从而阐明PAGE4调节肿瘤微环境的作用机制和作用方式，为进一步从前列腺癌病理微环境中筛选新的治疗靶点和诊断标记物打下基础。

本研究针对PAGE4这一应激反应蛋白在前列腺癌的发生发展的过程中的作用加以探讨。肿瘤细胞暴露于其特殊的微环境中，其炎症、氧化应激等水平均与正常组织中不同。而前期的实验结果发现PAGE4在前列腺间质细胞及前列腺癌细胞中在肿瘤发生发展的不同时期表达量发生有趣的变化。这种变化是否有意义值得探讨。本研究发现，在前列腺间质中过表达PAGE4基因会抑制前列腺癌上皮细胞的增殖及迁移水平，也就是说在癌症早期，PAGE4在间质中表达量上升，一定程度的遏制了肿瘤的发生发展。随着癌症的进展，这种升高消失。而在前列腺癌上皮细胞中过表达PAGE4基因，可以减少癌细胞暴露于氧化应激中产生的DNA损伤、减少凋亡，并促进了肿瘤细胞在小鼠体内的生长。PAGE4在前列腺不同细胞中的高表达所表现出的对癌症的不同的影响为我们认识单一基因在癌症发生发展中起到的作用开辟了新的思路。