Epigenetic Crosstalk between the Tumor Microenvironment and Ovarian Cancer Cells: A Therapeutic Road Less Traveled.

Yuliya Klymenko,Kenneth P Nephew

doi:10.3390/cancers10090295

Abstract

Metastatic dissemination of epithelial ovarian cancer (EOC) predominantly occurs through direct cell shedding from the primary tumor into the intra-abdominal cavity that is filled with malignant ascitic effusions. Facilitated by the fluid flow, cells distribute throughout the cavity, broadly seed and invade through peritoneal lining, and resume secondary tumor growth in abdominal and pelvic organs. At all steps of this unique metastatic process, cancer cells exist within a multidimensional tumor microenvironment consisting of intraperitoneally residing cancer-reprogramed fibroblasts, adipose, immune, mesenchymal stem, mesothelial, and vascular cells that exert miscellaneous bioactive molecules into malignant ascites and contribute to EOC progression and metastasis via distinct molecular mechanisms and epigenetic dysregulation. This review outlines basic epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA regulators, and summarizes current knowledge on reciprocal interactions between each participant of the EOC cellular milieu and tumor cells in the context of aberrant epigenetic crosstalk. Promising research directions and potential therapeutic strategies that may encompass epigenetic tailoring as a component of complex EOC treatment are discussed.

Highlights

Epithelial ovarian cancer (EOC), a histopathologically, morphologically, and molecularly heterogeneous group of neoplasms [1], is the leading cause of gynecological malignancy-related deaths in women, with >14,000 deaths in the United States (US) and ~152,000 deaths worldwide yearly [2,3,4]
While lymph node and hematogenous metastasis of ovarian cancer have been reported in human epithelial ovarian cancer (EOC) cancer and/or model systems [19,20], the current consensus is that expansion of ovarian neoplastic masses occurs primarily via transcoelomic route, including the direct exfoliation of anoikis-resistant cancer cells and multi-cellular clusters from the original tumor, ascitic fluid-facilitated intraperitoneal dissemination, subsequent mesothelial adhesion and retraction, submesothelial extracellular matrix invasion, and ultimate establishment of secondary lesions in peritoneum-sheathed surfaces and organs [18,21,22,23]
Ovarian cancer cells are confined to and nurtured by the complex host intraperitoneal cellular milieu, encompassing cells co-existing within the tumor bulk, freely available in ascitic effusions, and residing in peritoneal and adipose tissues—fibroblasts, mesothelial cells, adipocytes, infiltrating lymphocytes, macrophages, plasmacytoid dendritic cells, mesenchymal stem cells, and others (Figure 1) [24,25,26,27,28,29]