Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA; Department of Surgery, Harvard Medical School, Boston, MA, USA.
Indiana University School of Medicine-Bloomington, Indiana University, Bloomington, IN, USA.
Cell Rep. 2023 Jul 25;42(7):112730. doi: 10.1016/j.celrep.2023.112730. Epub 2023 Jul 14.
Cancer-associated mesothelial cells (CAMCs) in the tumor microenvironment are thought to promote growth and immune evasion. We find that, in mouse and human ovarian tumors, cancer cells express anti-Müllerian hormone (AMH) while CAMCs express its receptor AMHR2, suggesting a paracrine axis. Factors secreted by cancer cells induce AMHR2 expression during their reprogramming into CAMCs in mouse and human in vitro models. Overexpression of AMHR2 in the Met5a mesothelial cell line is sufficient to induce expression of immunosuppressive cytokines and growth factors that stimulate ovarian cancer cell growth in an AMH-dependent way. Finally, syngeneic cancer cells implanted in transgenic mice with Amhr2 CAMCs grow significantly slower than in wild-type hosts. The cytokine profile of Amhr2 tumor-bearing mice is altered and their tumors express less immune checkpoint markers programmed-cell-death 1 (PD1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4). Taken together, these data suggest that the AMH/AMHR2 axis plays a critical role in regulating the pro-tumoral function of CAMCs in ovarian cancer.
肿瘤微环境中的癌相关间皮细胞（CAMCs）被认为可促进肿瘤生长和免疫逃逸。我们发现，在小鼠和人类卵巢肿瘤中，癌细胞表达抗苗勒管激素（AMH），而 CAMCs 表达其受体 AMHR2，提示存在旁分泌轴。在体外小鼠和人类模型中，癌细胞在重编程为 CAMCs 的过程中分泌的因子诱导 AMHR2 的表达。在 Met5a 间皮细胞系中过表达 AMHR2 足以诱导免疫抑制细胞因子和生长因子的表达，以 AMH 依赖的方式刺激卵巢癌细胞生长。最后，在携带有 Amhr2CAMCs 的转基因小鼠中植入同基因癌细胞，其生长速度明显慢于野生型宿主。Amhr2 荷瘤小鼠的细胞因子谱发生改变，其肿瘤表达的免疫检查点标志物程序性细胞死亡 1（PD1）和细胞毒性 T 淋巴细胞相关蛋白 4（CTLA4）较少。综上所述，这些数据表明 AMH/AMHR2 轴在调节卵巢癌中 CAMCs 的促肿瘤功能方面起着关键作用。
