肿瘤相关巨噬细胞表达E-cadherin在其促乳腺癌转移中作用及分子机制研究

The vast majority of breast cancer deaths are due to metastasis and the mechanism of metastasis development still remains uncovered. Tumor-associated macrophages (TAMs) associated with tumor cells and enhance tumor progression to malignancy. Recent studies showed that E-cadherin, which is involved in cell-fusion procession，is a marker expressed on TAMs. Whether E-cadherin is involved in the fusion between TAMs and tumor cells and further promotes tumor metastasis or not needs to be further explored. Our initially study showed that up-regulating expression of E-cadherin in TAMs promotes fusion efficiency between TAMs and MDA-MB-231.Here, we will use breast cancer as the disease model and further explore the function of E-cadherin in fusion between TAMs and breast cancer cell lines. Then, in vivo, in vitro and clinical sample detection experiments will be use to demonstrate the function of E-cadherin in breast cancer metastasis. Further, the mechanisms of E-cadherin function in this process are investigated. Through this study, we are aiming to identify the mechanism of breast cancer metastasis and unearth valid targets for prevention and cure of breast cancer metastasis.

转移是乳腺癌致患者死亡的主要原因，其难以有效防治的关键在于肿瘤转移机制不详。肿瘤原发灶中肿瘤相关巨噬细胞(TAMs)的多少与肿瘤侵袭和转移正相关，且体内外研究显示TAMs可与肿瘤细胞融合形成杂交体。近有报道与细胞融合相关的E-cadherin分子是TAMs表面的标记物，其是否通过促进TAMs与肿瘤细胞融合并参与TAMs促肿瘤转移过程亟待阐明。我们预实验显示，上调TAMs中E-cadherin可促进其与乳腺癌细胞MDA-MB-231融合，提示其可能参与了TAMs与肿瘤细胞融合过程。本研究拟以乳腺癌为疾病模型，明确E-cadherin在TAMs与不同侵袭性乳腺癌细胞融合中作用；在细胞、动物模型、临床病例水平阐明E-cadherin在TAMs促乳腺癌侵袭、转移中作用及机制；以期阐明TAMs表达E-cadherin在其促乳腺癌转移中作用及机制，并为发掘防治乳腺癌转移新靶点奠定理论和实验依据。

转移是乳腺癌致患者死亡的主要原因，其难以有效防治的关键在于肿瘤转移机制不详。肿瘤原发灶中肿瘤相关巨噬细胞(TAMs)的多少与肿瘤侵袭和转移正相关，且体内外研究显示TAMs可与肿瘤细胞融合形成杂交体。我们发现M2型巨噬细胞过表达E-cadherin后，巨噬细胞与乳腺癌细胞MDA-MB-231和MCF-7细胞的融合能力明显增强。体内外研究显示，与未融合细胞相比，融合细胞的增殖能力和转移能力均有增强；提示E-cadherin促进巨噬细胞与乳腺癌细胞的融合并且增强了该融合细胞的增殖和转移能力。进一步研究发现融合细胞中凋亡相关基因Bcl-2表达显著增强，同时P21、P53表达显著降低，MMP-2、MMP-9的表达增高。提示巨噬细胞与乳腺癌细胞融合细胞的转移能力增强与细胞凋亡抑制有关。本研究阐明了巨噬细胞表达E-cadherin可促进其与乳腺癌细胞的融合，并且通过抑制细胞凋亡信号通路、转移相关信号通路MMP-2等促进肿瘤细胞的生长、增殖和转移。研究结果为进一步明确肿瘤微环境中M2巨噬细胞促肿瘤进展提供了一定的理论依据。