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

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.

Keywords: DNA methylation; chromatin remodeling; epigenetics; histone modifications; non-coding RNAs; ovarian cancer; tumor microenvironment.

Figure 1

Ovarian tumor-stroma bidirectional crosstalk. (A) Schematic representation of cellular diversity within the complex ovarian tumor bulk; and, (B) Reciprocal communication between ovarian cancer cells and intraperitoneally residing cancer-associated cellular milieu components via molecular signaling pathways and epigenetic regulation. CAAs—cancer-associated adipocytes; CAFs—cancer-associated fibroblasts; CSCs—cancer stem cells; EOC—epithelial ovarian cancer; MCs—mesothelial cells; MSCs—mesenchymal stem cells; PDCs—plasmacytoid dendritic cells; TAMs—tumor-associated macrophages; TECs—tumor-associated endothelial cells; TILs—tumor-infiltrating lymphocytes; TME—tumor microenvironment (see main text for details).

Figure 2

Epigenetic regulation of gene expression. (A) DNA packing in a eukaryotic cell: a DNA molecule (chromosome) located inside the cell nucleus is composed of chromatin fibers which are made of nucleosomes—histone octamers wrapped by a DNA helix. Condensed chromatin (heterochromatin) is transcriptionally silent; loosely packed euchromatin allows access to DNA and active transcription into mRNA, followed by translation into protein; (B) Major epigenetic mechanisms of gene expression include: (1) DNA methylation; (2) histone modifications, such as histone acetylation, methylation, phosphorylation, etc.; (3) chromatin remodeling, including nucleosome sliding, nucleosome ejection and histone eviction; and, (4) mRNA interference with miRNAs and lncRNAs (see main text for details).

Figure 3

Ovarian TME: potential epigenomic-based therapeutic strategies. (A) Main epigenetic therapy mechanisms include: (1) DNA demethylation with hypomethylating agents (HMAs) to re-activate transcription of silenced genes; (2) restoration of open, transcription-permissive euchromatin state with histone deacetylase (HDAC) inhibitors preventing removal of acetyl groups from the histone tails; (3) targeting non-coding RNA-mediated epigenetic perturbations via delivery of exogenous miRNA inhibitors (antagomirs/blockmirs/sponges) or mimics, lncRNA siRNAs, small molecules or peptide nucleic acid aptamers; (B) Multifaceted epigenomic targeting approach suggests simultaneous targeting of several malignant and TME cell types using one epigenetic drug; (C) Combinatorial epigenomic targeting involves employment of multiple epigenetic mechanisms to revert cancer-associated phenotype in TME cells and inhibit their tumor-promoting effect on EOC cells; (D) Epigenomic potentiation of immunotherapy involves epigenetic stimulation of cancer cell immune gene/pathway representation which allows for increased immune surveillance efficacy. CAA—cancer-associated adipocyte; HMA—hypomethylating agent; HDACi—histone deacetylase inhibitor; EOC—epithelial ovarian cancer cell; MSC—mesenchymal stem cell; OCSC—ovarian cancer stem cell; PNA—peptide nucleic acid; TAM—tumor-associated macrophage; TEC—tumor-associated endothelial cell; TIL—tumor-infiltrating lymphocyte. Black arrows represent interactions reported in EOC; dashed arrows designate patterns that were observed in other cancer types and may potentially be applicable towards ovarian cancer (see main text for details).