MCP-1趋化巨噬细胞在卵巢癌腹腔转移微环境形成中的关键作用及分子机制

Intra-abdominal metastasis, especially omentum metastasis, is the most characteristic clinical manifestation of ovarian cancer patients with advanced stage, and impacts on the recurrence and prognosis directly. It is recognized that omentum plays an important role in the promotion of intra-abdominal metastasis of ovarian cancer. We observed that the adipocytes in the omentum promoted the malignant phenotype of ovarian cancer cells by the secretion of monocyte chemoattractant protein-1 (MCP-1). As a monocyte chemokine, MCP-1 also attracted the macrophages accumulation in the omentum and then promoted the local implantation of cancer cells. So we hypothesized here that the accumulation of macrophages induced by MCP-1 could form a specific pre-metastatic niche, attract the ovarian cancer cells in the ascites fluid adhere to the local, and then promote the metastasis-associated phenotype by some unknown mechanisms. This study tries to clarify the key role of omentum and macrophages in the pre-metastatic niche formations and ovarian cancer intra-abdominal metastasis by the application of knockout mouse models, mice marrow-transplantation models, other experiments in vitro and in vivo, and combined with the clinical specimens validation. The results will provide new theoretical basis and intervention strategies for intra-abdominal metastasis of ovarian cancer .

腹腔内转移、特别是大网膜转移是晚期卵巢癌最具特征性的临床表现，直接影响患者复发和预后。目前认为大网膜在卵巢癌的腹腔内转移中有重要的促进作用。我们前期发现大网膜脂肪细胞分泌的MCP-1可以直接促进卵巢癌细胞的恶性表型；作为单核细胞趋化因子，MCP-1也可以通过大网膜内巨噬细胞的聚集而促进肿瘤细胞在局部的种植，因此我们提出假说：大网膜脂肪细胞分泌MCP-1通过巨噬细胞聚集形成转移前微环境，趋化和吸引腹水中脱落的卵巢癌细胞的局部粘附，进而通过某些机制直接促进粘附肿瘤细胞的转移相关表型，最终形成转移灶。本研究拟利用基因敲除小鼠卵巢癌细胞原位种植大网膜转移模型、小鼠骨髓移植模型等在内的体内外实验，结合临床标本验证，探讨MCP-1对大网膜转移前微环境形成的影响，阐明大网膜和巨噬细胞在卵巢癌转移过程中发挥的关键作用和分子机制，以期为卵巢癌腹腔转移提供新的理论依据和干预策略。

卵巢癌选择性转移至网膜，导致卵巢癌预后差，而导致该现象的机制和相应的治疗方法还没有完全阐明。本研究中，我们发现由大网膜的脂肪细胞分泌的MCP-1蛋白可以与卵巢癌上的同源受体CCR-2相结合，从而促进卵巢癌细胞迁移和网膜的转移，而该现象是通过激活mTOR / PI3K / AKT通路及其下游效应器HIF-1α和VEGF-A来实现的。我们分别从体内外研究中证实了这个机制。我们发现，MCP-1抗体可显著降低小鼠体内肿瘤负担，提高小鼠存活率。有应用价值的研究在于，老药二甲双胍可以通过抑制脂肪细胞分泌MCP-1来减少大网膜转移，而非直接作用于癌细胞。我们的研究确定了一个新的MCP-1/CCR-2轴靶点，可以使卵巢癌患者受益。