Notch通路在肿瘤相关巨噬细胞促前列腺癌增殖中的作用及机制研究

Tumor-associated macrophages (TAM), an important inflammatory cell in "tumor microenvironment", can promote tumor proliferation. But the mechanism is still not entirely explained. At present, most of the research are concentrated in TAM-secreted cytokines promoting cancer cell proliferation. Our previous work found that, compared with non-contact co-culture model, TAM and prostate cancer cell contact can up-regulate the expression of Notch1 receptor in cancer cells, as well as their proliferation ability. This suggests: besides to paracrine pathway, TAM and prostate cancer cells direct contact induces higher Notch pathway signals in cancer cells, which may be another new mechanism of "TAM promoting cancer cells proliferation". In this project, using TAM-prostate cancer cell contact model, we inhibit Notch pathway in cancer cells to demonstrate the role of Notch pathway in "TAM promoting cancer cells proliferation". Moreover, we examine the expression of growth factor receptors in high Notch pathway cancer cells, to elucidate that high Notch pathway signal, induced by TAM direct contact, can make cancer cells more sensitive to TAM-secreted cytokines. We also design in vivo experiments using inhibitors, paving potential way for prostate cancer treatment.

肿瘤相关巨噬细胞(Tumor associated macrophage，TAM)作为 “肿瘤微环境”中重要的炎症细胞，其促肿瘤增殖的作用机制尚不完全明确。目前绝大部分的研究均集中于TAM分泌细胞因子促进癌细胞增殖。我们前期工作发现，相较于非接触式共培养模式，接触式共培养TAM和前列腺癌细胞后，癌细胞Notch1受体表达明显上调，且增殖能力更强。这提示：有别于旁分泌途径，直接接触TAM后，癌细胞Notch通路信号增强可能是“TAM促癌增殖”的另一种新机制。本课题采用TAM和前列腺癌细胞接触式共培养模式，通过抑制癌细胞中Notch通路的功能，明确Notch通路在“TAM促癌增殖”中的作用。此外，通过研究Notch通路影响生长因子受体的表达，试图阐明直接接触引发的高活性Notch通路能“放大”癌细胞对TAM分泌因子的应答。我们还利用抑制剂进行体内验证，期望为前列腺癌治疗提供潜在的新方案。

肿瘤相关巨噬细胞(Tumor associated macrophage，TAM)是“肿瘤微环境”中重要的炎症细胞，其对肿瘤进展有显著的影响。本课题详细探讨了其促肿瘤增殖转移的作用机制。在此研究中，我们发现，相较了非接触式共培养模式，TAM和前列腺癌细胞接触式共培养后，TAM促进癌细胞增殖和转移能力均明显上调。这依赖于接触培养后癌细胞中Notch1通路信号增强，进而上皮间质转化增多。同时，在动物实验中，我们联合TAM聚集抑制剂和Notch通路抑制剂，使得前列腺癌的皮下成瘤和远处转移能力明显下降。另外，在临床标本中，我们同样发现TAM与N1ICD共定位增多的患者明显有着更差的预后。综上，我们认为除了常规的“TAM旁分泌途径”，TAM直接接触癌细胞促进Notch通路活化也是其促癌进展中不能忽视的机制。这为前列腺的治疗提供了可能的分子机制和初期动物实验数据。