Cole Jennifer M, Dahl Richard, Cowden Dahl Karen D
Kabara Cancer Research Institute, Gundersen Medical Foundation, La Crosse, WI 54601, USA.
Department of Microbiology and Immunology, Indiana University School of Medicine, South Bend, IN 46617, USA.
Cancers (Basel). 2021 Jan 13;13(2):274. doi: 10.3390/cancers13020274.
Ovarian cancer (OC) cells survive in the peritoneal cavity in a complex microenvironment composed of diverse cell types. The interaction between tumor cells and non-malignant cells is crucial to the success of the metastatic process. Macrophages activate pro-metastatic signaling pathways in ovarian cancer cells (OCCs), induce tumor angiogenesis, and orchestrate a tumor suppressive immune response by releasing anti-inflammatory cytokines. Understanding the interaction between immune cells and tumor cells will enhance our ability to combat tumor growth and dissemination. When co-cultured with OCCs, macrophages induce projections consistent with tunneling nanotubes (TnTs) to form between OCCs. TnTs mediate transfer of material between cells, thus promoting invasiveness, angiogenesis, proliferation, and/or therapy resistance. Macrophage induction of OCC TnTs occurs through a soluble mediator as macrophage-conditioned media potently induced TnT formation in OCCs. Additionally, EGFR-induced TnT formation in OCCs through MAPK signaling may occur. In particular, inhibition of ERK and RSK prevented EGFR-induced TnTs. TnT formation in response to macrophage-conditioned media or EGFR signaling required MAPK signaling. Collectively, these studies suggest that inhibition of ERK/RSK activity may dampen macrophage-OCC communication and be a promising therapeutic strategy.
卵巢癌细胞在由多种细胞类型组成的复杂微环境中在腹腔内存活。肿瘤细胞与非恶性细胞之间的相互作用对于转移过程的成功至关重要。巨噬细胞激活卵巢癌细胞（OCCs）中的促转移信号通路，诱导肿瘤血管生成，并通过释放抗炎细胞因子协调肿瘤抑制性免疫反应。了解免疫细胞与肿瘤细胞之间的相互作用将增强我们对抗肿瘤生长和扩散的能力。当与OCCs共培养时，巨噬细胞诱导与隧道纳米管（TnTs）一致的突起在OCCs之间形成。TnTs介导细胞间物质转移，从而促进侵袭性、血管生成、增殖和/或治疗抗性。巨噬细胞对OCC TnTs的诱导通过一种可溶性介质发生，因为巨噬细胞条件培养基能有效诱导OCCs中TnT的形成。此外，EGFR可能通过MAPK信号通路诱导OCCs中TnT的形成。特别是，抑制ERK和RSK可阻止EGFR诱导的TnTs。响应巨噬细胞条件培养基或EGFR信号的TnT形成需要MAPK信号通路。总体而言，这些研究表明抑制ERK/RSK活性可能会抑制巨噬细胞与OCC之间的通讯，是一种有前景的治疗策略。
