Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China.
Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China.
Cell Death Dis. 2022 Aug 4;13(8):675. doi: 10.1038/s41419-022-05129-5.
As the predominant stroma cells of tumor microenvironment (TME), cancer associated fibroblasts (CAFs) are robust tumor player of different malignancies. However, less is known about the regulatory mechanism of CAFs on promoting progression of ovarian cancer (OvCA). In the present study, the conditioned medium of primary CAFs (CAF-CM) from OvCA was used to culture cell lines of epithelial ovarian cancer (EOC), and showed a potent role in promoting proliferation, migration and invasion of cancer cells. Mass spectrum (MS) analysis identified that Collapsin response mediator protein-2 (CRMP2), a microtubule-associated protein involved in diverse malignancies, derived from CAFs was a key regulator responsible for mediating these cell events of OvCA. In vitro study using recombinant CRMP2 (r-CRMP2) revealed that the protein promoted proliferation, invasion, and migration of OvCA cells through activation of hypoxia-inducible factor (HIF)-1α-glycolysis signaling pathway. The CRMP2 was abundantly expressed in OvCA, with a well correlation with metastasis and poor prognosis, as analyzed from 118 patients' samples. Inhibition of the CRMP2 derived from CAFs by neutralizing antibodies significantly attenuated the tumor size, weights, and metastatic foci numbers of mice in vivo. Our finding has provided a novel therapeutic clue for OvCA based on TME.
作为肿瘤微环境（TME）的主要基质细胞，癌症相关成纤维细胞（CAFs）是多种恶性肿瘤中强大的肿瘤参与者。然而，关于 CAFs 促进卵巢癌（OvCA）进展的调控机制知之甚少。在本研究中，使用源自 OvCA 的原代 CAFs（CAF-CM）的条件培养基来培养上皮性卵巢癌（EOC）细胞系，结果显示其在促进癌细胞增殖、迁移和侵袭方面具有强大作用。质谱（MS）分析鉴定出 Collapsin 反应介质蛋白-2（CRMP2），一种参与多种恶性肿瘤的微管相关蛋白，源自 CAFs，是负责介导 OvCA 这些细胞事件的关键调节剂。使用重组 CRMP2（r-CRMP2）进行的体外研究表明，该蛋白通过激活缺氧诱导因子（HIF）-1α-糖酵解信号通路促进 OvCA 细胞的增殖、侵袭和迁移。从 118 名患者的样本中分析发现，CRMP2 在 OvCA 中大量表达，与转移和预后不良密切相关。通过中和抗体抑制来自 CAFs 的 CRMP2 显著减弱了体内小鼠的肿瘤大小、重量和转移灶数量。我们的发现为基于 TME 的 OvCA 提供了一种新的治疗线索。
