肿瘤微环境中间充质干细胞通过细胞间接触对前列腺癌细胞干性的影响及机制研究

Tumor microenvironment plays a crucial role in cancer development and tumor resistance to therapy in prostate cancer, but the influence of tumor microenvironment on prostate cancer stem cell (PCSC) remains unclear. Mesenchymal stem cell (MSC) is an important member of tumor microenvironment. Our previous study showed that MSC sometimes was close to PCSC in human prostate cancer tissues. And in vitro experiments demonstrated that MSC promoted the stemness of PCSC by cell-cell contact. Based on these previous researches and the latest associated research developments, we attempt to carry out the following studies. 1. Through various detections of stemness of prostate cancer cells, we will further verify the influence of MSC on the stemness of prostate cancer cells by cell-cell contact; 2. After direct coculture between MSC and prostate cancer cells, detecting the activities of two candidate pathways and their downstream stemness-associated pathway; 3. Verifying the role of the significantly changed pathway by regulating the key factor of this pathway in vitro and vivo experiments; 4. Lastly, we will verify the above mechanisms in clinical prostate cancer samples, and will analyze the correlation between the expression of key genes of these mechanisms in clinical prostate cancer samples and the prognosis of patients aided by the corresponding clinical and pathological data. This study will contribute to enhance the understanding of the impact of MSC on PCSC in tumor environment, and will provide the promising novel targets in PCSC-targeted therapy in the clinic.

肿瘤微环境在前列腺癌发生发展及治疗抵抗中发挥重要作用，但它对前列腺癌干细胞（PCSC）的作用尚未阐明。间充质干细胞（MSC）是肿瘤微环境的重要组分，我们在前期研究中观察到前列腺癌组织中MSC有邻近PCSC的现象，体外实验也提示MSC能通过细胞间接触促进前列腺癌细胞的干性。我们拟在前期研究的基础上，通过多种检测前列腺癌细胞干性的实验，进一步验证MSC通过细胞间接触对前列腺癌细胞干性的影响；前列腺癌细胞和MSC直接共培养后，针对可能参与调控的候选通路及其下游干性相关通路在这两类细胞内可能的活性变化进行检测；对显著变化的通路，通过调控关键因子表达在体内外验证其作用，并关注可能的各通路间的相互影响；最后在前列腺癌临床样本中验证上述机制，并结合病理资料分析其对患者预后的影响。本课题的实施将有助于增强对前列腺癌微环境中MSC对CSC的影响的理论认识，并为临床上靶向PCSC的治疗提供具有前景的新靶点

肿瘤微环境在前列腺癌发生发展及治疗抵抗中发挥重要作用，但具体机制一直没有阐明，间充质干细胞（MSCs）存在于肿瘤微环境中，在其中发挥着重要的作用影响着恶性肿瘤的发生发展。我们的科研团队一直从事间MSCs的相关研究，发现MSCs与癌症干细胞高度相关，并在人类前列腺癌（PCa）的进程中发挥关键作用。但是，人们对PCa细胞直接与MSC（PCaMSCs）接触对PCa细胞潜在干性的影响了解甚少。在主要研究中，我们调查了PCa细胞直接与MSC接触对PCa恶性肿瘤的作用及其可能的机制。首先，我们证明了即使有限稀释后，MSC也可以增强PCa细胞的干性，并表现出增强的菌落和球形成能力。 PCaMSC中CD133 +和前列腺CSC标记（Sox-2，Oct-4和Nanog）升高。然后，我们证明PCaMSCs增强的干性与CCL5 / CCR5途径无关。除此之外，我们发现PCaMSCs上调了Notch信号相关基因的表达。此外，在PCaMSCs细胞中抑制Jagged1-Notch1信号传导可在体外和体内显着抑制MSCs诱导的干性和肿瘤发生。我们的研究结果揭示了通过激活Jagged1-Notch1途径促进肿瘤发生的MSC和PCa细胞之间的新型相互作用。我们次要的一些研究也正是MSCs在肿瘤微环境中可以参与前列腺癌的内分泌耐药形成的机制。总体实验结果有助于增强对前列腺癌微环境中MSC对CSC的影响的理论认识，并为临床上靶向PCSC的治疗提供具有前景的新靶点。