Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, 60607, USA.
Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, 60607, USA.
Cancer Lett. 2022 Sep 1;543:215779. doi: 10.1016/j.canlet.2022.215779. Epub 2022 Jun 10.
High grade serous ovarian cancers (HGSOC) predominantly arise in the fallopian tube epithelium (FTE) and colonize the ovary first, before further metastasis to the peritoneum. Ovarian cancer risk is directly related to the number of ovulations, suggesting that the ovary may secrete specific factors that act as chemoattractants for fallopian tube derived tumor cells during ovulation. We found that 3D ovarian organ culture produced a secreted factor that enhanced the migration of FTE non-tumorigenic cells as well as cells harboring specific pathway modifications commonly found in high grade serous cancers. Through size fractionation and a small molecule inhibitors screen, the secreted protein was determined to be 50-100kDa in size and acted through the Epidermal Growth Factor Receptor (EGFR). To correlate the candidates with ovulation, the PREDICT organ-on-chip system was optimized to support ovulation in a perfused microfluidic platform. Versican was found in the correct molecular weight range, contained EGF-like domains, and correlated with ovulation in the PREDICT system. Exogenous versican increased migration, invasion, and enhanced adhesion of both murine and human FTE cells to the ovary in an EGFR-dependent manner. The identification of a protein secreted during ovulation that impacts the ability of FTE cells to colonize the ovary provides new insights into the development of strategies for limiting primary ovarian metastasis.
高级别浆液性卵巢癌（HGSOC）主要起源于输卵管上皮（FTE），并首先在卵巢定植，然后进一步转移到腹膜。卵巢癌风险与排卵次数直接相关，这表明卵巢可能分泌特定的因子，在排卵时作为输卵管来源的肿瘤细胞的趋化因子。我们发现，3D 卵巢器官培养产生了一种分泌因子，可增强 FTE 非肿瘤细胞以及携带高级别浆液性癌中常见特定途径修饰的细胞的迁移。通过大小分级和小分子抑制剂筛选，确定分泌蛋白的大小为 50-100kDa，并通过表皮生长因子受体（EGFR）起作用。为了将候选物与排卵相关联，对 PREDICT 器官芯片系统进行了优化，以在灌注微流控平台上支持排卵。Versican 位于正确的分子量范围内，含有 EGF 样结构域，并与 PREDICT 系统中的排卵相关。外源性 versican 以 EGFR 依赖的方式增加了鼠和人 FTE 细胞的迁移、侵袭和对卵巢的黏附。鉴定出一种在排卵期间分泌的蛋白，该蛋白影响 FTE 细胞定植卵巢的能力，为限制原发性卵巢转移的策略提供了新的见解。
