Abstract TMIM-079: INHIBITION OF TUMOR MICROENVIRONMENT CYTOKINE SIGNALING SENSITIZES OVARIAN CANCER CELLS TO ANTIESTROGEN THERAPY

Background Ovarian cancer progression and invasiveness are promoted by a range of soluble factors released by cancer cells and stromal cells within the tumor microenvironment. Our previous studies demonstrated that resveratrol (RV), a nutraceutical and caloric restriction mimetic with tumor-suppressive properties, counteracts cancer cell motility induced by stromal IL-6 by upregulating autophagy. Lysophosphatidic acid (LPA), a bioactive phospholipid that shows elevated levels in the tumor microenvironment and the ascites of ovarian cancers, stimulates the growth and tissue invasion of cancer cells. Whether LPA elicits these effects by inhibiting autophagy and through which pathway and whether RV can counteract the same remain obscure. Aims To investigate the molecular pathways involved in LPA-induced ovarian cancer malignancy, particularly focusing on the role of autophagy, and the ability of RV to counteract LPA activity. Results LPA stimulated while RV inhibited ovarian cancer cell migration. Transcriptomic and bioinformatic analyses showed an opposite regulation by LPA and RV of genes linked to epithelial-to-mesenchymal transition (EMT) and autophagy with involvement of the PI3K-AKT, JAK-STAT and Hedgehog (Hh) pathways. LPA upregulated the Hh and EMT members GLI1, BMI-1, SNAIL-1 and TWIST1 and inhibited autophagy, while RV did the opposite. Similar to the inhibitors of the Hh pathway, RV inhibited LPA-induced cancer cell migration and 3D growth of ovarian cancer cells. BMI-1 silencing prevented LPA-induced EMT, restored autophagy and hampered cell migration, resembling the effects of RV. TCGA data analyses indicated that patients with low expression of Hh/EMT-related genes together with active autophagy flux tended to have a better prognosis and this correlates with a more effective response to platinum therapy. In in vitro 3D spheroids, LPA upregulated BMI-1, downregulated autophagy and inhibited platinum toxicity while RV and Hh inhibitors restored autophagy and favored BAX-mediated cell death in response to platinum. Conclusions By inhibiting the Hh pathway and restoration of autophagy, RV counteracts LPA-induced malignancy, supporting its inclusion in the therapy of ovarian cancer for limiting metastasis and chemoresistance.

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Shaping Immune Responses in the Tumor Microenvironment of Ovarian Cancer

Frontiers in Immunology ◽

10.3389/fimmu.2021.692360 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xin Luo ◽

Jing Xu ◽

Jianhua Yu ◽

Ping Yi

Keyword(s):

Ovarian Cancer ◽

Tumor Microenvironment ◽

Immune Responses ◽

Cancer Cells ◽

Disease Progression ◽

Immune Cells ◽

Biomarker Discovery ◽

Immune Cell ◽

Ovarian Cancer Cells ◽

Cancer Tumor

Reciprocal signaling between immune cells and ovarian cancer cells in the tumor microenvironment can alter immune responses and regulate disease progression. These signaling events are regulated by multiple factors, including genetic and epigenetic alterations in both the ovarian cancer cells and immune cells, as well as cytokine pathways. Multiple immune cell types are recruited to the ovarian cancer tumor microenvironment, and new insights about the complexity of their interactions have emerged in recent years. The growing understanding of immune cell function in the ovarian cancer tumor microenvironment has important implications for biomarker discovery and therapeutic development. This review aims to describe the factors that shape the phenotypes of immune cells in the tumor microenvironment of ovarian cancer and how these changes impact disease progression and therapy.

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Mimicking the tumor microenvironment: Fibroblasts reduce miR-29b expression and increase the motility of ovarian cancer cells in a co-culture model

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2019.06.001 ◽

2019 ◽

Vol 516 (1) ◽

pp. 96-101

Author(s):

Mariana Medeiros ◽

Amanda Oliveira Ribeiro ◽

Luiz Antônio Lupi ◽

Guilherme Ribeiro Romualdo ◽

Danillo Pinhal ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Ovarian Cancer Cells ◽

Culture Model

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

Cancers ◽

10.3390/cancers10090295 ◽

2018 ◽

Vol 10 (9) ◽

pp. 295 ◽

Cited By ~ 20

Author(s):

Yuliya Klymenko ◽

Kenneth P. Nephew

Keyword(s):

Ovarian Cancer ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Abdominal Cavity ◽

Malignant Ascites ◽

Bioactive Molecules ◽

Ovarian Cancer Cells ◽

Secondary Tumor

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.

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