Abstract 4907: Epigenetic treatment of ovarian cancer cells increases immune cell recruitment to the tumor microenvironment: implications for response to immune checkpoint therapy

2016 ◽  
Author(s):  
Meredith L. Stone ◽  
Katherine B. Chiappinelli ◽  
Huili Li ◽  
Lauren Murphy ◽  
Michael Topper ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Ovarian Cancer Cells ◽  
Cell Recruitment ◽  
Immune Cell Recruitment

scholarly journals Shaping Immune Responses in the Tumor Microenvironment of Ovarian Cancer

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.

Adenosine Analogues as Opposite Modulators of the Cisplatin Resistance of Ovarian Cancer Cells

2019 ◽  
Vol 19 (4) ◽  
pp. 473-486 ◽  
Author(s):  
Katarzyna Bednarska-Szczepaniak ◽  
Damian Krzyżanowski ◽  
Magdalena Klink ◽  
Marek Nowak
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cell Biology ◽  
Immune Cell ◽  
Immunosuppressive Agents ◽  
Cell Activity ◽  
Ovarian Cancer Cells ◽  
Adenosine Analogues

Background: Adenosine released by cancer cells in high amounts in the tumour microenvironment is one of the main immunosuppressive agents responsible for the escape of cancer cells from immunological control. Blocking adenosine receptors with adenosine analogues and restoring immune cell activity is one of the methods considered to increase the effectiveness of anticancer therapy. However, their direct effects on cancer cell biology remain unclear. Here, we determined the effect of adenosine analogues on the response of cisplatinsensitive and cisplatin-resistant ovarian cancer cells to cisplatin treatment. Methods: The effects of PSB 36, DPCPX, SCH58261, ZM 241385, PSB603 and PSB 36 on cisplatin cytotoxicity were determined against A2780 and A2780cis cell lines. Quantification of the synergism/ antagonism of the compounds cytotoxicity was performed and their effects on the cell cycle, apoptosis/necrosis events and cisplatin incorporation in cancer cells were determined. Results: PSB 36, an A1 receptor antagonist, sensitized cisplatin-resistant ovarian cancer cells to cisplatin from low to high micromolar concentrations. In contrast to PSB 36, the A2AR antagonist ZM 241385 had the opposite effect and reduced the influence of cisplatin on cancer cells, increasing their resistance to cisplatin cytotoxicity, decreasing cisplatin uptake, inhibiting cisplatin-induced cell cycle arrest, and partly restoring mitochondrial and plasma membrane potentials that were disturbed by cisplatin. Conclusion: Adenosine analogues can modulate considerable sensitivity to cisplatin of ovarian cancer cells resistant to cisplatin. The possible direct beneficial or adverse effects of adenosine analogues on cancer cell biology should be considered in the context of supportive chemotherapy for ovarian cancer.

scholarly journals Resveratrol Contrasts LPA-Induced Ovarian Cancer Cell Migration and Platinum Resistance by Rescuing Hedgehog-Mediated Autophagy

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3213
Author(s):  
Alessandra Ferraresi ◽  
Andrea Esposito ◽  
Carlo Girone ◽  
Letizia Vallino ◽  
Amreen Salwa ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Migration ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Ovarian Cancer Cells ◽  
Cancer Cell Migration ◽  
Effective Response ◽  
Mesenchymal Transition

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.

scholarly journals Targeting the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jianhuang Lin ◽  
Heng Liu ◽  
Takeshi Fukumoto ◽  
Joseph Zundell ◽  
Qingqing Yan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stress Response ◽  
Er Stress ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Er Stress Response

AbstractCARM1 is often overexpressed in human cancers including in ovarian cancer. However, therapeutic approaches based on CARM1 expression remain to be an unmet need. Cancer cells exploit adaptive responses such as the endoplasmic reticulum (ER) stress response for their survival through activating pathways such as the IRE1α/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1α/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1α/XBP1s pathway was effective against ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model. Our data show that pharmacological inhibition of the IRE1α/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers.

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

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

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

Cancers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 295 ◽  
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.

Interferons alpha and gamma with monocytes as a therapeutic strategy for ovarian cancer.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 9-9
Author(s):  
Christina M. Annunziata ◽  
Anna Duemler ◽  
Franklin Ning
Keyword(s):  
Ovarian Cancer ◽  
Flow Cytometry ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Interferon Alpha ◽  
Immune Cell ◽  
Ovarian Cancer Cells ◽  
Human Monocytes ◽  
Differentiation Markers ◽  
Monocyte Differentiation

9 Background: In the presence of pro-inflammatory cytokines, monocytes are cytotoxic to tumor cells. We previously showed that monocytes stimulated with interferon alpha and gamma result in synergistic killing of ovarian cancer cells in vitro. Here we better characterize monocyte differentiation and their ability to induce cell death through co-culture experiments with spheroids and in mouse xenografts. Methods: OVCAR8 cells were grown in ultra-low attachment conditions for three days before being co-cultured with human monocytes as well as interferon gamma and interferon alpha. Monocytes and OVCAR8s were assayed by flow cytometry for markers of differentiation and viability, respectively. Mouse studies were performed to confirm the viability of human monocytes stimulated with interferon alpha and gamma within the peritoneal cavity seventy-two hours after injection. Subsequent mouse experiments analyzed monocyte differentiation towards M1 or M2 phenotypes by flow cytometry with or without exposure to tumor cells and/or interferons. Results: OVCAR8 spheroids showed decreased viability in the presence of monocytes combined with interferon. We show that monocytes also express a hybrid M1/M2 phenotype when stimulated to IFN and exposed to tumor cells. In mice, monocytes demonstrated a unique differentiation towards both M1 and M2 macrophages as well as plasmacytoid and classic DCs. Various immune cell subsets also differed when comparing peritoneal washes versus tissue digests. Mouse survival studies are ongoing. Conclusions: Monocytes with the combination of interferons alpha and gamma are effective at killing ovarian cancer cells in laboratory models. Phenotypic analyses show a novel pattern of differentiation markers. Our ongoing clinical trial with these agents will incorporate similar studies to correlate monocyte differentiation with anti-tumor activity.

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