子宫平滑肌细胞与肿瘤细胞之间的环式调控: 子宫内膜癌肌层浸润的机制

Endometrial cancer is one of the most common malignancies in female reproductive system. Myometrial invasion is the critical step for endometrial cancer metastasis, the foundation for surgical-pathological staging, and the important evaluation criteria for the treatment and prognosis of endometrial cancer. However, there are few studies on myometrial invasion in endometrial cancer and its molecular mechanism is still unknown. Here, we investigate the role of reciprocal interaction between myometrial smooth muscle cells and endometrial cancer cells in myometrial invasion. Our preliminary results showed that myometrial smooth muscle cells promote the proliferation and invasion of endometrial cancer cells. However, we still do not know if myometrial smooth muscle cells are educated by cancer cells, if a regulatory loop is generated between their reciprocal interaction and if the loop regulates myometrial invasion in endometrial cancer. Therefore, we hope this study will discover the underlying mechanism of myometrial invasion, which would be a breakthrough for understanding the growth and progression of endometrial cancer. This study will also prove smooth muscle cells are critical for tumor microenvironment, which will lead to new direction of tumor microenvironment research. Moreover, clarifying the mechanism of myometrial invasion in endometrial cancer will be a good foundation for the study of cancer-muscle interaction in other tumors.

子宫内膜癌是女性生殖系统最常见的恶性肿瘤之一。肌层浸润是子宫内膜癌转移的关键环节，浸润深度是手术-病理分期的依据，是决定手术方式、术后放化疗和预后的重要评价指标。然而，有关子宫内膜癌发生肌层浸润的机制研究很少，我们仍不清楚肌层浸润的调控机制。在此，我们研究子宫平滑肌细胞与肿瘤细胞之间的相互调控在肌层浸润中的作用。我们发现子宫平滑肌细胞通过分泌的细胞因子促进子宫内膜癌细胞地增生和浸润。然而，子宫内膜癌细胞是否对子宫平滑肌细胞有教育改造的作用、它们之间是否形成一个环路、及此环路是否介导子宫内膜癌发生肌层浸润呢？通过本研究来明确肌层浸润的机理，不仅可以为子宫内膜癌的发生发展机制和靶向治疗提供一个新的理论突破，还将证明平滑肌细胞是肿瘤微环境中的重要一员，从而开启肿瘤微环境研究的新方向。此外，明确子宫内膜癌肌层浸润的机制将会开拓性地为研究发生肌层浸润的其他肿瘤的发展机制及治疗提供示范作用。

子宫内膜癌是女性生殖系统最常见的恶性肿瘤之一。通过荟萃分析我们发现子宫内膜癌肌层浸润深度与淋巴血管间隙浸润、淋巴结转移、复发及其总生存期之间具有相关性。然而，有关子宫内膜癌发生肌层浸润的机制研究很少。在此，我们发现子宫内膜癌细胞可以引起子宫平滑肌细胞上巨噬细胞刺激蛋白（MSP）的分泌增加，并作用于子宫内膜癌细胞上的巨噬细胞刺激蛋白受体（RON），从而介导子宫内膜癌细胞的增生及浸润。子宫内膜癌细胞增生后进一步向肌层浸润，与子宫肌层相互作用，从而子宫内膜癌细胞与子宫平滑肌细胞形成一个环路调控。而在子宫内膜癌细胞的增生中，周期蛋白依赖性激酶（CDK1）发挥着重要作用。因此，通过打破以上环路可以减少子宫内膜癌细胞与子宫平滑肌细胞之间的相互作用和控制子宫内膜癌的进展，鉴于此，我们发现RON抑制剂和CDK1抑制剂可以用于子宫内膜癌治疗的靶向抑制剂。以上研究明确了肌层浸润的机理，不仅为子宫内膜癌的发生发展机制和靶向治疗提供一个新的理论突破，还证明了平滑肌细胞是肿瘤微环境中的重要一员，开启了一个肿瘤微环境研究的新方向。