scholarly journals MAPK Signaling Is Required for Generation of Tunneling Nanotube-Like Structures in Ovarian Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 274
Author(s):  
Jennifer M. Cole ◽  
Richard Dahl ◽  
Karen D. Cowden Dahl
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cell Types ◽  
Therapy Resistance ◽  
Mapk Signaling ◽  
Conditioned Media ◽  
Ovarian Cancer Cells ◽  
Tunneling Nanotubes ◽  
Tunneling Nanotube

Ovarian cancer (OC) cells survive in the peritoneal cavity in a complex microenvironment composed of diverse cell types. The interaction between tumor cells and non-malignant cells is crucial to the success of the metastatic process. Macrophages activate pro-metastatic signaling pathways in ovarian cancer cells (OCCs), induce tumor angiogenesis, and orchestrate a tumor suppressive immune response by releasing anti-inflammatory cytokines. Understanding the interaction between immune cells and tumor cells will enhance our ability to combat tumor growth and dissemination. When co-cultured with OCCs, macrophages induce projections consistent with tunneling nanotubes (TnTs) to form between OCCs. TnTs mediate transfer of material between cells, thus promoting invasiveness, angiogenesis, proliferation, and/or therapy resistance. Macrophage induction of OCC TnTs occurs through a soluble mediator as macrophage-conditioned media potently induced TnT formation in OCCs. Additionally, EGFR-induced TnT formation in OCCs through MAPK signaling may occur. In particular, inhibition of ERK and RSK prevented EGFR-induced TnTs. TnT formation in response to macrophage-conditioned media or EGFR signaling required MAPK signaling. Collectively, these studies suggest that inhibition of ERK/RSK activity may dampen macrophage-OCC communication and be a promising therapeutic strategy.

scholarly journals PARP Inhibition Activates STAT3 in Both Tumor and Immune Cells Underlying Therapy Resistance and Immunosuppression In Ovarian Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Antons Martincuks ◽  
Jieun Song ◽  
Adrian Kohut ◽  
Chunyan Zhang ◽  
Yi-Jia Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Immune Cells ◽  
Therapy Resistance ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Ovarian Cancer Cells ◽  
Before And After ◽  
Immunosuppressive Cytokine

Despite the promising activity of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) in many cancer types with defects in the DNA damage response the majority of the treated patients acquire PARPi resistance and succumb to their diseases. Consequently, there is an urgent need to identify the mechanisms of PARPi resistance. Here, we show that PARPi treatment promotes STAT3 activation in ovarian cancer cells, tumor-associated immune cells and fibroblasts, resulting in PARPi resistance and immunosuppression. Comparison of ovarian cancer patient-matched tumor biopsies before and after PARPi therapy revealed that STAT3 activity was significantly higher in tumor cells and tumor-associated immune cells and fibroblasts post PARPi treatment. Moreover, one-time PARPi treatment activated STAT3 both in tumor cells as well as diverse immune subsets and fibroblasts. PARPi-treated immune cells exhibited decreased expression of immunostimulatory interferon (IFN)-γ and Granzyme B while increasing immunosuppressive cytokine IL-10. Finally, we demonstrate that the acquisition of PARPi resistance in ovarian cancer cells was accompanied by increased STAT3 activity. Ablating STAT3 inhibited PARPi-resistant ovarian tumor cell growth and/or restored PARPi sensitivity. Therefore, our study has identified a critical mechanism intrinsic to PARPi that promotes resistance to PARPi and induces immunosuppression during PARPi treatment by activating STAT3 in tumor cells and tumor-associated immune cells/fibroblasts.

scholarly journals Photodynamic Therapy Using a New Folate Receptor-Targeted Photosensitizer on Peritoneal Ovarian Cancer Cells Induces the Release of Extracellular Vesicles with Immunoactivating Properties

2020 ◽  
Vol 9 (4) ◽  
pp. 1185 ◽  
Author(s):  
Martha Baydoun ◽  
Olivier Moralès ◽  
Céline Frochot ◽  
Colombeau Ludovic ◽  
Bertrand Leroux ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Response ◽  
Photodynamic Therapy ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Immune Cells ◽  
Surgical Techniques ◽  
Ovarian Cancer Cells ◽  
The Impact

Often discovered at an advanced stage, ovarian cancer progresses to peritoneal carcinoma, which corresponds to the invasion of the serosa by multiple tumor implants. The current treatment is based on the combination of chemotherapy and tumor cytoreduction surgery. Despite the progress and standardization of surgical techniques combined with effective chemotherapy, post-treatment recurrences affect more than 60% of women in remission. Photodynamic therapy (PDT) has been particularly indicated for the treatment of superficial lesions on large surfaces and appears to be a relevant candidate for the treatment of microscopic intraperitoneal lesions and non-visible lesions. However, the impact of this therapy on immune cells remains unclear. Hence, the objective of this study is to validate the efficacy of a new photosensitizer [pyropheophorbide a-polyethylene glycol-folic acid (PS)] on human ovarian cancer cells and to assess the impact of the secretome of PDT-treated cells on human peripheral blood mononuclear cells (PBMC). We show that PS, upon illumination, can induce cell death of different ovarian tumor cells. Furthermore, PDT using this new PS seems to favor activation of the immune response by inducing the secretion of effective cytokines and inhibiting the pro-inflammatory and immunosuppressive ones, as well as releasing extracellular vesicles (EVs) prone to activating immune cells. Finally, we show that PDT can activate CD4+ and CD8+ T cells, resulting in a potential immunostimulating process. The results of this pilot study therefore indicate that PS-PDT treatment may not only be effective in rapidly and directly destroying target tumor cells but also promote the activation of an effective immune response; notably, by EVs. These data thus open up good prospects for the treatment of micrometastases of intraperitoneal ovarian carcinosis which are currently inoperable.

Tunneling nanotubes and intercellular communication: Differences between platinum-resistant and platinum-sensitive ovarian cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22007-e22007
Author(s):  
Elizabeth Louise Dickson ◽  
Venugopal Thayanithy ◽  
Rachel Isaksson Vogel ◽  
Peter Argenta ◽  
Melissa Ann Geller ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cell Lines ◽  
Ovarian Cancer Cells ◽  
Platinum Resistance ◽  
Skov3 Cell ◽  
Continuous Exposure ◽  
Tunneling Nanotubes ◽  
Platinum Sensitive

e22007 Background: Preliminary evidence suggests that cell-to-cell communication may be responsible for the development of chemotherapy resistance in ovarian cancer. We propose tunneling nanotubes (TnTs) – long, thin actin-based cell extensions – as novel candidates to explain direct communication between treatment-refractory malignant ovarian cells. The purpose of this study was to investigate TnT formation between ovarian cancer cells in vitro. Methods: Using platinum-sensitive (A2780) and resistant (C200 and SKOV3, as well as ES2) ovarian cancer cell lines, we tested various conditions to assess factors affecting TnT formation. Scratch assays were utilized as a 2-dimensional simulation of ovarian cancer invasion. To assess TnTs as a conduit for transmission of therapeutic drugs between connected cells, we used doxorubicin, which auto-fluoresces in cell culture. Results: We determined that a hyperglycemic, low-serum, acidic medium stimulated TnT formation between all ovarian cancer cells studied, and more significantly, formed direct connections between A2780 to both C200 and SKOV3 cell lines. Conversely, Everolimus or Metformin decreased TnT formation in all cell lines with continuous exposure up to 96 hours; most prominently for the platinum-sensitive cell line. Time-lapse microscopy was used to assess chronologic formation of TnTs at the advancing front of the scratch wound. Cell proliferation assays were performed and confirmed the decrease in TnTs was not due to decreased cell proliferation. We directly observed fluorescing doxorubicin within the TnTs, suggesting TnTs act as a transport mechanism for cellular communication. Conclusions: TnT formation is stimulated in conditions of cellular stress similar to those experienced in vivo and results in direct connections between cells. Our data suggests that these conduits are a potential means of cellular exchange between platinum-sensitive and resistant ovarian cancer cells. Using currently available agents to target TnTs and disrupt this communication provides a novel approach to understanding and treating the problem of platinum resistance in ovarian cancer.

scholarly journals Dual Knockdown of Musashi RNA-Binding Proteins MSI-1 and MSI-2 Attenuates Putative Cancer Stem Cell Characteristics and Therapy Resistance in Ovarian Cancer Cells

2021 ◽  
Vol 22 (21) ◽  
pp. 11502
Author(s):  
Maria T. Löblein ◽  
Isabel Falke ◽  
Hans Theodor Eich ◽  
Burkhard Greve ◽  
Martin Götte ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Ovarian Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Cancer Cells ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Therapy Resistance ◽  
Ovarian Cancer Cells

In ovarian cancer, therapy resistance mechanisms complicate cancer cell eradication. Targeting Musashi RNA-binding proteins (MSI) may increase therapeutic efficacy. Database analyses were performed to identify gene expression associations between MSI proteins and key therapy resistance and cancer stem cell (CSC) genes. Then, ovarian cancer cells were subjected to siRNA-based dual knockdown of MSI-1 and MSI-2. CSC and cell cycle gene expression was investigated using quantitative polymerase chain reaction (qPCR), western blots, and flow cytometry. Metabolic activity and chemoresistance were assessed by MTT assay. Clonogenic assays were used to quantify cell survival post-irradiation. Database analyses demonstrated positive associations between MSI proteins and putative CSC markers NOTCH, MYC, and ALDH4A1 and negative associations with NOTCH inhibitor NUMB. MSI-2 expression was negatively associated with the apoptosis regulator p21. MSI-1 and MSI-2 were positively correlated, informing subsequent dual knockdown experiments. After MSI silencing, CSC genes were downregulated, while cell cycle progression was reduced. Metabolic activity was decreased in some cancer cells. Both chemo- and radioresistance were reduced after dual knockdown, suggesting therapeutic potential. Dual knockdown of MSI proteins is a promising venue to impede tumor growth and sensitize ovarian cancer cells to irradiation and chemotherapy.

scholarly journals CD83, a Novel MAPK Signaling Pathway Interactor, Determines Ovarian Cancer Cell Fate

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2269
Author(s):  
Aalia Batool ◽  
Hao Liu ◽  
Yi-Xun Liu ◽  
Su-Ren Chen
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Mapk Signaling ◽  
Migration And Invasion ◽  
Integrated Analysis ◽  
Ovarian Cancer Cells ◽  
Spheroid Formation ◽  
Regulation Of Proliferation

Ovarian cancer is a leading cause of death from gynecologic malignancies worldwide. Although CD83 is widely described as a solid marker for mature dendritic cells, emerging pieces of evidence indicate the expression of membrane protein CD83 by various tumor cells, including ovarian cancer cells. However, the potential role of CD83 in ovarian cancer cell properties and development remains absolutely unknown. By using human CD83 stable overexpression and knockdown sublines of several ovarian cancer cells, we observed that CD83 advanced the growth proliferation, colony formation ability, spheroid formation, and in vivo tumorigenicity of ovarian cancer cells; surprisingly, CD83 limited their migration and invasion potentials. Positive regulation of proliferation/stemness factors (e.g., cyclin-CDKs and KIT/CD44) but negative regulation of matrix metallopeptidases (e.g., MMP1 and 7) by CD83 were revealed by the integrated analysis of transcriptome and proteome. Furthermore, immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP) first identified the association of CD83 with MAP3K7 (also known as TAK1) and MAP3K7-binding protein TAB1 on the cell membrane. Moreover, CD83 functions through the activation of MAP3K7-MEK1/2-ERK1/2 cascades to further regulate downstream FOXO1/p21/CDK2/CCNB1 and STAT3/DKK1 signaling pathways, thus activating proliferation and spheroid formation of ovarian cancer cells, respectively. Collectively, our findings define a CD83-MAPK pathway in the regulation of proliferation and stemness in ovarian cancer cells, with potential therapeutic applications in blocking their progression.

scholarly journals Overexpression of BMPER in Ovarian Cancer and the Mechanism by which It Promotes Malignant Biological Behavior in Tumor Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Yong Xi ◽  
Xin Nie ◽  
Jing Wang ◽  
Lingling Gao ◽  
Bei Lin
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Poor Prognosis ◽  
Malignant Tumors ◽  
Biological Behavior ◽  
Ovarian Cancer Cells ◽  
Epithelial Tumor ◽  
Tumor Tissues ◽  
Ovarian Epithelial Tumor

Background. BMPER has been reported to be associated with the biological behavior of a few malignant tumors, but the mechanism is still unclear. We aimed to detect BMPER expression in ovarian epithelial tumor tissues and its effects on their biological behaviors, as well as to elucidate the possible mechanism. Methods. BMPER expression in ovarian epithelial tumor tissues was detected by immunohistochemistry. BMPER expression in ovarian cancer cell lines was inhibited via RNA interference. Changes in the malignant behaviors of ovarian cancer cells were detected by MTT, wound healing, Transwell, and flow cytometry assays. Changes in proteins in the MAPK and autophagy-related signaling pathways were detected by Western blot analysis. Results. The expression of BMPER was significantly upregulated in ovarian epithelial malignant tumors and was related to increased lymph node metastasis and lower survival rate. High BMPER expression is an independent risk factor for poor prognosis in patients. Inhibition of BMPER inhibited the proliferation, invasion, and migration of ovarian cancer cells and promoted apoptosis. In addition, BMPER downregulation decreased the expression of PCNA, Bcl-2, MMP2, and MMP9 and increased the expression of Bax. Moreover, the levels of p-ERK, p-MEK, and the autophagy-related protein p-mTOR were decreased, and Beclin 1 levels and the LC3II/I ratio were increased. Conclusions. Our findings indicated that BMPER is closely related to poor prognosis in ovarian cancer. BMPER plays a role in promoting the malignant biological behavior of tumor cells through the MAPK and autophagy-related signaling pathways.

scholarly journals EGFR-Specific Tyrosine Kinase Inhibitor Modifies NK Cell-Mediated Antitumoral Activity against Ovarian Cancer Cells

2019 ◽  
Vol 20 (19) ◽  
pp. 4693 ◽  
Author(s):  
Nina Mallmann-Gottschalk ◽  
Yvonne Sax ◽  
Rainer Kimmig ◽  
Stephan Lang ◽  
Sven Brandau
Keyword(s):  
Ovarian Cancer ◽  
Nk Cells ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Immune Cells ◽  
Nk Cell ◽  
Ovarian Cancer Cells ◽  
Antitumoral Activity ◽  
Egfr Tkis

The adverse prognosis of most patients with ovarian cancer is related to recurrent disease caused by resistance to chemotherapeutic and targeted therapeutics. Besides their direct activity against tumor cells, monoclonal antibodies and tyrosine kinase inhibitors (TKIs) also influence the antitumoral activity of immune cells, which has important implications for the design of immunotherapies. In this preclinical study, we treated different ovarian cancer cell lines with anti-epidermal growth factor receptor (EGFR) TKIs and co-incubated them with natural killer (NK) cells. We studied treatment-related structural and functional changes on tumor and immune cells in the presence of the anti-EGFR antibody cetuximab and investigated NK-mediated antitumoral activity. We show that long-term exposure of ovarian cancer cells to TKIs leads to reduced responsiveness of intrinsically sensitive cancer cells over time. Inversely, neither long-term treatment with TKIs nor cetuximab could overcome the intrinsic resistance of certain ovarian cancer cells to anti-EGFR agents. Remarkably, tumor cells pretreated with anti-EGFR TKIs showed increased sensitivity towards NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). In contrast, the cytokine secretion of NK cells was reduced by TKI sensitization. Our data suggest that sensitization of tumor cells by anti-EGFR TKIs differentially modulates interactions with NK cells. These data have important implications for the design of chemo-immuno combination therapies in this tumor entity.

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