MicroRNAs as the critical regulators of Cisplatin resistance in ovarian cancer cells

Abstract Background Ovarian cancer (OC) is one of the leading causes of cancer related deaths among women. Due to the asymptomatic tumor progression and lack of efficient screening methods, majority of OC patients are diagnosed in advanced tumor stages. A combination of surgical resection and platinum based-therapy is the common treatment option for advanced OC patients. However, tumor relapse is observed in about 70% of cases due to the treatment failure. Cisplatin is widely used as an efficient first-line treatment option for OC; however cisplatin resistance is observed in a noticeable ratio of cases. Regarding, the severe cisplatin side effects, it is required to clarify the molecular biology of cisplatin resistance to improve the clinical outcomes of OC patients. Cisplatin resistance in OC is associated with abnormal drug transportation, increased detoxification, abnormal apoptosis, and abnormal DNA repair ability. MicroRNAs (miRNAs) are critical factors involved in cell proliferation, apoptosis, and chemo resistance. MiRNAs as non-invasive and more stable factors compared with mRNAs, can be introduced as efficient markers of cisplatin response in OC patients. Main body In present review, we have summarized all of the miRNAs that have been associated with cisplatin resistance in OC. We also categorized the miRNAs based on their targets to clarify their probable molecular mechanisms during cisplatin resistance in ovarian tumor cells. Conclusions It was observed that miRNAs mainly exert their role in cisplatin response through regulation of apoptosis, signaling pathways, and transcription factors in OC cells. This review highlighted the miRNAs as important regulators of cisplatin response in ovarian tumor cells. Moreover, present review paves the way of suggesting a non-invasive panel of prediction markers for cisplatin response among OC patients.

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Preparation and Characterization of Platinum(II) and (IV) Complexes of 1,3-Diaminepropane and 1,4-Diaminebutane: Circumvention of Cisplatin Resistance and DNA Interstrand Cross-Link Formation in CH1cisR Ovarian Tumor Cells

Journal of Medicinal Chemistry ◽

10.1021/jm010968l ◽

2002 ◽

Vol 45 (9) ◽

pp. 1835-1844 ◽

Cited By ~ 27

Author(s):

Amparo Alvarez-Valdés ◽

José Manuel Pérez ◽

Isabel López-Solera ◽

Raúl Lannegrand ◽

José Manuel Continente ◽

...

Keyword(s):

Tumor Cells ◽

Ovarian Tumor ◽

Cisplatin Resistance ◽

Cross Link ◽

Link Formation ◽

Ovarian Tumor Cells

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Immune evasion by melanoma and ovarian tumor cells through upregulation of the immunosuppressive molecule CD200

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.2545 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 2545-2545

Author(s):

A. Siva ◽

H. Xin ◽

F. Qin ◽

A. Mickel ◽

S. Faas ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Cells ◽

Cell Lines ◽

Ovarian Tumor ◽

Cytokine Production ◽

Ovarian Cancer Cell ◽

Ovarian Adenocarcinoma ◽

Ovarian Cancer Cell Lines ◽

Th1 Cytokine ◽

Ovarian Tumor Cells

2545 Background: Immune escape by tumors can occur by multiple mechanisms, each a significant barrier to immunotherapy. Upregulation of the immunosuppressive molecule CD200 on chronic lymphocytic leukemia cells inhibits Th1 cytokine production required for an effective cytotoxic T cell response. CD200 expression on human tumor cells in animal models prevents human lymphocytes from rejecting the tumor; treatment with an antagonistic anti-CD200 antibody restored lymphocyte-mediated tumor growth inhibition. This study evaluated CD200 expression on other cancers, and its effect on immune response. Methods: CD200 levels in ovarian adenocarcinoma and metastatic melanoma samples were evaluated by RT-QPCR and immunohistochemistry. Cell-surface CD200 on melanoma and ovarian cancer cell lines was assessed by flow cytometry. The effect of CD200 on cytokine production in mixed lymphocyte reactions (MLR) was assessed by adding the cells to cultures containing human monocyte-derived dendritic cells and allogeneic T cells. Th1 and Th2 cytokines in culture supernatants were detected by ELISA. Results: RT-QPCR showed CD200 expression levels upregulated in serous ovarian adenocarcinoma compared to normal samples. In malignant melanoma, CD200 expression in jejunum metastases was significantly higher than in normal samples, and 2 of 6 lung metastases showed CD200 upregulation. IHC showed strong, membrane-associated CD200 staining on malignant cells of two melanoma patients. Three ovarian cancer patients showed varying levels of CD200 tumor staining; all showed strong stromal staining. CD200 was highly expressed on the cell surface of SK-MEL-24 and SK-MEL-28 melanoma and OV-CAR-3 ovarian cancer cell lines and moderately expressed on the melanoma cell line SK-MEL-5. Addition of these cell lines to MLRs downregulated the production of Th1 cytokines; addition of CD200-negative cell lines did not. Inclusion of an antagonistic anti-CD200 antibody during the culture restored Th1 cytokine responses. Conclusion: Melanoma and ovarian tumor cells can upregulate CD200, thereby potentially suppressing anti-tumor immune responses. Therapy with an antagonistic anti-CD200 antibody may permit an effective cytotoxic immune response against the tumor cells. [Table: see text]

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Generation and regulation of human CD4+ IL-17-producing T cells in ovarian cancer

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0710686105 ◽

2008 ◽

Vol 105 (40) ◽

pp. 15505-15510 ◽

Cited By ~ 188

Author(s):

Yoshihiro Miyahara ◽

Kunle Odunsi ◽

Wenhao Chen ◽

Guangyong Peng ◽

Junko Matsuzaki ◽

...

Keyword(s):

Ovarian Cancer ◽

T Cells ◽

Tumor Cells ◽

Ovarian Tumor ◽

Th17 Cells ◽

Mononuclear Cells ◽

Peripheral Blood Mononuclear ◽

Healthy Donors ◽

Immune Response To Cancer ◽

Ovarian Tumor Cells

Despite the important role of Th17 cells in the pathogenesis of many autoimmune diseases, their prevalence and the mechanisms by which they are generated and regulated in cancer remain unclear. Here, we report the presence of a high percentage of CD4+ Th17 cells at sites of ovarian cancer, compared with a low percentage of Th17 cells in peripheral blood mononuclear cells from healthy donors and cancer patients. Analysis of cytokine production profiles revealed that ovarian tumor cells, tumor-derived fibroblasts, and antigen-presenting cells (APCs) secreted several key cytokines including IL-1β, IL-6, TNF-α and TGF-β, which formed a cytokine milieu that regulated and expanded human IL-17-producing T-helper (Th17) cells. We further show that IL-1β was critically required for the differentiation and expansion of human Th17 cells, whereas IL-6 and IL-23 may also play a role in the expansion of memory Th17 cells, even though IL-23 levels are low or undetectable in ovarian cancer. Further experiments demonstrated that coculture of naïve or memory CD4+ T cells with tumor cells, APCs, or both could generate high percentages of Th17 cells. Treatment with anti-IL-1 alone or a combination of anti-IL-1 and anti-IL-6 reduced the ability of tumor cells to expand memory Th17 cells. Thus, we have identified a set of key cytokines secreted by ovarian tumor cells and tumor-associated APCs that favor the generation and expansion of human Th17 cells. These findings should accelerate efforts to define the function of this important subset of CD4+ T cells in the human immune response to cancer.

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Distinct molecular signature of recurrent ovarian tumor cells isolated from the ascites of advanced-stage serous ovarian cancer patients

Journal of Cancer Stem Cell Research ◽

10.14343/jcscr.2014.2e1006 ◽

2014 ◽

Vol 1 (1) ◽

pp. 1 ◽

Cited By ~ 1

Author(s):

Ardian Latifi ◽

Ruth Escalona ◽

Michael A Quinn ◽

Erik W Thompson ◽

Jock K Findlay ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Patients ◽

Tumor Cells ◽

Ovarian Tumor ◽

Molecular Signature ◽

Advanced Stage ◽

Serous Ovarian Cancer ◽

Ovarian Tumor Cells

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Autologous ovarian tumor cells vaccine, modified with the hapten, dinitrophenyl (DNP), in platinum resistant ovarian cancer

Gynecologic Oncology ◽

10.1016/j.ygyno.2014.04.015 ◽

2014 ◽

Vol 134 (2) ◽

pp. 428

Author(s):

M. Taha ◽

D. Berd ◽

S. Williams ◽

G. Del Priore ◽

S. Standiford ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Cells ◽

Ovarian Tumor ◽

Platinum Resistant ◽

Ovarian Tumor Cells

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Inhibition by lenalidomide of growth factor and hypoxia-induced signaling in endothelial and epithelial tumor cells, and effects within the tumor cell microenvironment

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e14620 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e14620-e14620

Author(s):

L. Lu ◽

P. Schafer ◽

J. B. Bartlett

Keyword(s):

Ovarian Cancer ◽

Endothelial Cells ◽

Growth Factor ◽

Tumor Cells ◽

Ovarian Tumor ◽

Epithelial Tumor ◽

Akt Phosphorylation ◽

Tumor Invasiveness ◽

Epithelial Tumor Cells ◽

Ovarian Tumor Cells

e14620 Background: Lenalidomide, an immunomodulatory and anti-angiogenic agent, has activity in many hematological malignancies. It has direct anti-proliferative activity in hematological cells but there is no evidence of direct activity in solid tumor cells. In solid tumors, lenalidomide is being advanced in combination with other agents to take advantage of its immune-enhancing properties in combination with direct anti-tumor agents. Lenalidomide studies in CLL and MM suggest that it may also attenuate pro-survival signals generated by interaction of stroma with the malignant cell itself. Lysophosphatidic acid (LPA) is a key pro-survival factor present at high levels within the ascites of ovarian cancer patients which confers increased tumor invasiveness and reduced survival. Hypoxia-induced factor (HIF)-1α is the key initiator of angiogenesis and tumor invasiveness. Methods: The effect of lenalidomide on growth factor-induced Akt phosphorylation was investigated in endothelial cells, NHL cells, and ovarian cancer cells in vitro. Ovarian cancer cell lines SKOV-3 and OVCAR-3 were treated with LPA and the effect of lenalidomide on invasiveness via enhanced p-Akt was investigated. The effect of lenalidomide on HIF-1α expression by endothelial cells and epithelial cells was also investigated. Results: Lenalidomide inhibited growth factor-induced Akt phosphorylation. Treatment of ovarian tumor cells with LPA increased tumor cell invasiveness via enhanced p-Akt. Lenalidomide strongly inhibited invasion and p-Akt (at S308 but not T473) in a dose-dependent manner. Hypoxic endothelial cells and epithelial tumor cells showed enhanced HIF-1α expression. Lenalidomide inhibited hypoxia-induced HIF-1α expression by endothelial cells and by epithelial tumor cells, including prostate, breast, pancreatic, renal and ovarian tumor cells. Conclusions: Lenalidomide may act within the tumor microenvironment to inhibit key signals of tumor cells survival, growth, and invasiveness. These studies support the potential utility of lenalidomide in combination with other agents in the treatment of patients with solid tumors. [Table: see text]

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ST6Gal-I sialyltransferase confers cisplatin resistance in ovarian tumor cells

Journal of Ovarian Research ◽

10.1186/1757-2215-6-25 ◽

2013 ◽

Vol 6 (1) ◽

pp. 25 ◽

Cited By ~ 57

Author(s):

Matthew J Schultz ◽

Amanda F Swindall ◽

John W Wright ◽

Elizabeth S Sztul ◽

Charles N Landen ◽

...

Keyword(s):

Tumor Cells ◽

Ovarian Tumor ◽

Cisplatin Resistance ◽

St6gal I ◽

Ovarian Tumor Cells

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B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma

Journal of Experimental Medicine ◽

10.1084/jem.20050930 ◽

2006 ◽

Vol 203 (4) ◽

pp. 871-881 ◽

Cited By ~ 445

Author(s):

Ilona Kryczek ◽

Linhua Zou ◽

Paulo Rodriguez ◽

Gefeng Zhu ◽

Shuang Wei ◽

...

Keyword(s):

Ovarian Cancer ◽

T Cell ◽

Tumor Microenvironment ◽

Tumor Cells ◽

Ovarian Tumor ◽

Tumor Regression ◽

Ectopic Expression ◽

Cell Immunity ◽

Ovarian Tumor Cells

Tumor-associated macrophages are a prominent component of ovarian cancer stroma and contribute to tumor progression. B7-H4 is a recently identified B7 family molecule. We show that primary ovarian tumor cells express intracellular B7-H4, whereas a fraction of tumor macrophages expresses surface B7-H4. B7-H4+ tumor macrophages, but not primary ovarian tumor cells, suppress tumor-associated antigen-specific T cell immunity. Blocking B7-H4-, but not arginase-, inducible nitric oxide synthase or B7-H1 restored the T cell stimulating capacity of the macrophages and contributes to tumor regression in vivo. Interleukin (IL)-6 and IL-10 are found in high concentrations in the tumor microenvironment. These cytokines stimulate macrophage B7-H4 expression. In contrast, granulocyte/macrophage colony-stimulating factor and IL-4, which are limited in the tumor microenvironment, inhibit B7-H4 expression. Ectopic expression of B7-H4 makes normal macrophages suppressive. Thus, B7-H4+ tumor macrophages constitute a novel suppressor cell population in ovarian cancer. B7-H4 expression represents a critical checkpoint in determining host responses to dysfunctional cytokines in ovarian cancer. Blocking B7-H4 or depleting B7-H4+ tumor macrophages may represent novel strategies to enhance T cell tumor immunity in cancer.

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