Abstract
AbstractMost ovarian high-grade serous carcinomas (HGSC) arise from Serous Tubal Intraepithelial Carcinoma (STIC) lesions in the distal end of the fallopian tube (FT). Formation of STIC lesions from FT secretory cells leads to seeding of the ovarian surface, with rapid tumor dissemination to other abdominal structures thereafter. It remains unclear how nascent malignant cells leave the FT to colonize the ovary. This report provides evidence that the L1 cell adhesion molecule (L1CAM) contributes to the ability of transformed FT secretory cells (FTSEC) to detach from the tube, survive under anchorage-independent conditions, and seed the ovarian surface. L1CAM was highly expressed on the apical cells of STIC lesions and contributed to ovarian colonization by upregulating integrins and fibronectin in malignant cells and activating the AKT and ERK pathways. These changes increased cell survival under ultra-low attachment conditions that mimic transit from the FT to the ovary. To study dissemination to the ovary, we developed a tumor-ovary co-culture model. We showed that L1CAM expression was important for FT cells to invade the ovary as a cohesive group. Our results indicate that in the early stages of HGSC development, transformed FTSECs disseminate from the FT to the ovary in a L1CAM-dependent manner.
Funder
U.S. Department of Health & Human Services | NIH | National Cancer Institute
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
Honorable Tina Brozman Foundation
Claneil Foundation
Ovarian Cancer Research Fund Alliance
Deutsche Forschungsgemeinschaft
Foundation for the Improvement of Research in Gynecology and Obstetrics in Lausanne University Hospital. Stanley Parker Foundation.
Publisher
Springer Science and Business Media LLC
Subject
General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)
Reference61 articles.
1. Ferlay, J. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J. Cancer 136, E359–E386 (2015).
2. Kroeger, P. T. Jr. & Drapkin, R. Pathogenesis and heterogeneity of ovarian cancer. Curr. Opin. Obstet. Gynecol. 29, 26–34 (2017).
3. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer Statistics, 2017. CA: A cancer J. Clinicians. 67, 7–30 (2017).
4. Wild CP, W. E., Stewart BW. Vol. Available from: http://publications.iarc.fr/586. (ed International Agency for Research on Cancer) (2020).
5. Karst, A. M. & Drapkin, R. Ovarian cancer pathogenesis: a model in evolution. J. Oncol. 2010, 932371 (2010).
Cited by
5 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献