scholarly journals Host Mesothelin Expression Increases Ovarian Cancer Metastasis in the Peritoneal Microenvironment

2021 ◽  
Vol 22 (22) ◽  
pp. 12443
Author(s):  
Tyvette S. Hilliard ◽  
Brooke Kowalski ◽  
Kyle Iwamoto ◽  
Elizabeth A. Agadi ◽  
Yueying Liu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Peritoneal Cavity ◽  
Cancer Metastasis ◽  
Single Cells ◽  
Mesothelial Cell ◽  
Metastatic Tumor ◽  
Tumor Burden ◽  
Mesothelial Cells ◽  
Stage Disease

Mesothelin (MSLN), a glycoprotein normally expressed by mesothelial cells, is overexpressed in ovarian cancer (OvCa) suggesting a role in tumor progression, although the biological function is not fully understood. OvCa has a high mortality rate due to diagnosis at advanced stage disease with intraperitoneal metastasis. Tumor cells detach from the primary tumor as single cells or multicellular aggregates (MCAs) and attach to the mesothelium of organs within the peritoneal cavity producing widely disseminated secondary lesions. To investigate the role of host MSLN in the peritoneal cavity we used a mouse model with a null mutation in the MSLN gene (MSLNKO). The deletion of host MSLN expression modified the peritoneal ultrastructure resulting in abnormal mesothelial cell surface architecture and altered omental collagen fibril organization. Co-culture of murine OvCa cells with primary mesothelial cells regardless of MSLN expression formed compact MCAs. However, co-culture with MSLNKO mesothelial cells resulted in smaller MCAs. An allograft tumor study, using wild-type mice (MSLNWT) or MSLNKO mice injected intraperitoneally with murine OvCa cells demonstrated a significant decrease in peritoneal metastatic tumor burden in MSLNKO mice compared to MSLNWT mice. Together, these data support a role for host MSLN in the progression of OvCa metastasis.

scholarly journals A systematic CRISPR screen reveals an IL-20/IL20RA-mediated immune crosstalk to prevent the ovarian cancer metastasis

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Jia Li ◽  
Xuan Qin ◽  
Jie Shi ◽  
Xiaoshuang Wang ◽  
Tong Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Peritoneal Cavity ◽  
Cancer Metastasis ◽  
Immune Surveillance ◽  
Mesothelial Cells ◽  
Downstream Signaling ◽  
Key Factor ◽  
Crispr Screen

Transcoelomic spread of cancer cells across the peritoneal cavity occurs in most initially diagnosed ovarian cancer (OC) patients and accounts for most cancer-related death. However, how OC cells interact with peritoneal stromal cells to evade the immune surveillance remains largely unexplored. Here, through an in vivo genome-wide CRISPR/Cas9 screen, we identified IL20RA, which decreased dramatically in OC patients during peritoneal metastasis, as a key factor preventing the transcoelomic metastasis of OC. Reconstitution of IL20RA in highly metastatic OC cells greatly suppresses the transcoelomic metastasis. OC cells, when disseminate into the peritoneal cavity, greatly induce peritoneum mesothelial cells to express IL-20 and IL-24, which in turn activate the IL20RA downstream signaling in OC cells to produce mature IL-18, eventually resulting in the polarization of macrophages into the M1-like subtype to clear the cancer cells. Thus, we show an IL-20/IL20RA-mediated crosstalk between OC and mesothelial cells that supports a metastasis-repressing immune microenvironment.

scholarly journals A systematic CRISPR screen reveals an IL-20/IL20RA-mediated peritoneal immune crosstalk to prevent the ovarian cancer metastasis

2021 ◽  
Author(s):  
Jia Li ◽  
Xuan Qin ◽  
Jie Shi ◽  
Xiaoshuang Wang ◽  
Tong Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Peritoneal Cavity ◽  
Cancer Metastasis ◽  
Immune Surveillance ◽  
Mesothelial Cells ◽  
Downstream Signaling ◽  
Key Factor ◽  
Crispr Screen

AbstractTranscoelomic spread of cancer cells across the peritoneal cavity occurs in most initially diagnosed ovarian cancer (OC) patients and accounts for most cancer-related death. However, how OC cells interact with peritoneal stromal cells to evade the immune surveillance remains largely unexplored. Here, through an in vivo genome-wide CRISPR/Cas9 screen, we identified IL20RA, which decreased dramatically in OC patients during peritoneal metastasis, as a key factor preventing the transcoelomic metastasis of OC. Reconstitution of IL20RA in highly metastatic OC cells greatly suppresses the transcoelomic metastasis. OC cells, when disseminate into the peritoneal cavity, greatly induce peritoneum mesothelial cells to express IL-20 and IL-24, which in turn activate the IL20RA downstream signaling in OC cells to produce mature IL-18, eventually resulting in the polarization of macrophages into the M1-like subtype to clear the cancer cells. Thus, we show an IL-20/IL20RA-mediated crosstalk between OC and mesothelial cells that supports a metastasis-repressing immune microenvironment.

scholarly journals LncRNA SPOCD1-AS from ovarian cancer extracellular vesicles remodels mesothelial cells to promote peritoneal metastasis via interacting with G3BP1

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Conghui Wang ◽  
Jiaying Wang ◽  
Xiameng Shen ◽  
Mingyue Li ◽  
Yongfang Yue ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Extracellular Vesicles ◽  
Peritoneal Metastasis ◽  
Cancer Metastasis ◽  
Cancer Therapeutics ◽  
Mesothelial Cells ◽  
Ovarian Cancer Cells ◽  
Adhesion Assay ◽  
Mesenchymal Transition

Abstract Background Metastasis is the key cause of death in ovarian cancer patients. To figure out the biological nature of cancer metastasis is essential for developing effective targeted therapy. Here we investigate how long non-coding RNA (lncRNA) SPOCD1-AS from ovarian cancer extracellular vesicles (EVs) remodel mesothelial cells through a mesothelial-to-mesenchymal transition (MMT) manner and facilitate peritoneal metastasis. Methods EVs purified from ovarian cancer cells and ascites of patients were applied to mesothelial cells. The MMT process of mesothelial cells was assessed by morphology observation, western blot analysis, migration assay and adhesion assay. Altered lncRNAs of EV-treated mesothelial cells were screened by RNA sequencing and identified by qRT-PCR. SPOCD1-AS was overexpressed or silenced by overexpression lentivirus or shRNA, respectively. RNA pull-down and RNA immunoprecipitation assays were conducted to reveal the mechanism by which SPOCD1-AS remodeled mesothelial cells. Interfering peptides were synthesized and applied. Ovarian cancer orthotopic implantation mouse model was established in vivo. Results We found that ovarian cancer-secreted EVs could be taken into recipient mesothelial cells, induce the MMT phenotype and enhance cancer cell adhesion to mesothelial cells. Furthermore, SPOCD1-AS embedded in ovarian cancer-secreted EVs was transmitted to mesothelial cells to induce the MMT process and facilitate peritoneal colonization in vitro and in vivo. SPOCD1-AS induced the MMT process of mesothelial cells via interacting with G3BP1 protein. Additionally, G3BP1 interfering peptide based on the F380/F382 residues was able to block SPOCD1-AS/G3BP1 interaction, inhibit the MMT phenotype of mesothelial cells, and diminish peritoneal metastasis in vivo. Conclusions Our findings elucidate the mechanism associated with EVs and their cargos in ovarian cancer peritoneal metastasis and may provide a potential approach for metastatic ovarian cancer therapeutics.

scholarly journals CD133 Promotes Adhesion to the Ovarian Cancer Metastatic Niche

2018 ◽  
Vol 11 ◽  
pp. 117906441876788 ◽  
Author(s):  
Lynn Roy ◽  
Alexander Bobbs ◽  
Rachel Sattler ◽  
Jeffrey L Kurkewich ◽  
Paige B Dausinas ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Metastasis ◽  
Ex Vivo ◽  
Surface Protein ◽  
Ovarian Cancer Cells ◽  
Metastatic Niche ◽  
Attractive Therapeutic Target ◽  
Peritoneal Mesothelium

Cancer stem cells (CSCs) are an attractive therapeutic target due to their predicted role in both metastasis and chemoresistance. One of the most commonly agreed on markers for ovarian CSCs is the cell surface protein CD133. CD133+ ovarian CSCs have increased tumorigenicity, resistance to chemotherapy, and increased metastasis. Therefore, we were interested in defining how CD133 is regulated and whether it has a role in tumor metastasis. Previously we found that overexpression of the transcription factor, ARID3B, increased the expression of PROM1 (CD133 gene) in ovarian cancer cells in vitro and in xenograft tumors. We report that ARID3B directly regulates PROM1 expression. Importantly, in a xenograft mouse model of ovarian cancer, knockdown of PROM1 in cells expressing exogenous ARID3B resulted in increased survival time compared with cells expressing ARID3B and a control short hairpin RNA. This indicated that ARID3B regulation of PROM1 is critical for tumor growth. Moreover, we hypothesized that CD133 may affect metastatic spread. Given that the peritoneal mesothelium is a major site of ovarian cancer metastasis, we explored the role of PROM1 in mesothelial attachment. PROM1 expression increased adhesion to mesothelium in vitro and ex vivo. Collectively, our work demonstrates that ARID3B regulates PROM1 adhesion to the ovarian cancer metastatic niche.

Surgical Prevention in Ovarian Cancer

2021 ◽  
pp. 194-206
Author(s):  
Alexios Papanikolaou ◽  
Anastasios Liberis ◽  
Anastasia Vatopoulou
Keyword(s):  
Ovarian Cancer ◽  
Primary Prevention ◽  
Early Detection ◽  
Early Diagnosis ◽  
Genital Tract ◽  
Female Genital Tract ◽  
Current Evidence ◽  
Advanced Stage ◽  
Stage Disease

Ovarian cancer is the second most common malignant disease of the female genital tract, but the first in mortality because it is usually diagnosed at an advanced stage. Options for early detection, diagnosis, and treatment are limited. Prevention of ovarian cancer relates to primary prevention by avoiding factors that are epidemiologically associated with an increased incidence of ovarian cancer and the adoption of protective habits. These include interventions to exclude the fallopian tubes and ovaries. Secondary prevention is related to early diagnosis. The chapter aims to summarize current evidence on prevention of ovarian cancer as well as role of surgery to prevent advanced-stage disease.

scholarly journals Abdominal FLASH irradiation reduces radiation-induced gastrointestinal toxicity for the treatment of ovarian cancer in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Karen Levy ◽  
Suchitra Natarajan ◽  
Jinghui Wang ◽  
Stephanie Chow ◽  
Joshua T. Eggold ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Radiation Therapy ◽  
Dose Rate ◽  
Cancer Metastasis ◽  
Therapeutic Index ◽  
Similar Efficacy ◽  
High Dose Rate ◽  
Tumor Burden ◽  
Preclinical Model ◽  
High Dose

AbstractRadiation therapy is the most effective cytotoxic therapy for localized tumors. However, normal tissue toxicity limits the radiation dose and the curative potential of radiation therapy when treating larger target volumes. In particular, the highly radiosensitive intestine limits the use of radiation for patients with intra-abdominal tumors. In metastatic ovarian cancer, total abdominal irradiation (TAI) was used as an effective postsurgical adjuvant therapy in the management of abdominal metastases. However, TAI fell out of favor due to high toxicity of the intestine. Here we utilized an innovative preclinical irradiation platform to compare the safety and efficacy of TAI ultra-high dose rate FLASH irradiation to conventional dose rate (CONV) irradiation in mice. We demonstrate that single high dose TAI-FLASH produced less mortality from gastrointestinal syndrome, spared gut function and epithelial integrity, and spared cell death in crypt base columnar cells compared to TAI-CONV irradiation. Importantly, TAI-FLASH and TAI-CONV irradiation had similar efficacy in reducing tumor burden while improving intestinal function in a preclinical model of ovarian cancer metastasis. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of abdominal radiotherapy, with potential application to metastatic ovarian cancer.

Cancer Antigen 1251S Locally Produced in the Peritoneal Cavity during Continuous Ambulatory Peritoneal Dialysis

1994 ◽  
Vol 14 (2) ◽  
pp. 132-136 ◽  
Author(s):  
Ger C.M. Koomen ◽  
Michiel G.H. Betjes ◽  
Oésirée Zemel ◽  
Raymond T. Krediet ◽  
Frans J. Hoek
Keyword(s):  
Peritoneal Dialysis ◽  
Continuous Ambulatory Peritoneal Dialysis ◽  
Peritoneal Cavity ◽  
Mesothelial Cell ◽  
Linear Increase ◽  
Mesothelial Cells ◽  
Ca 125 ◽  
Cancer Antigen ◽  
The Relationship

The local production of cancer antigen (CA) 125 in the peritoneal cavity of 14 continuous ambulatory peritoneal dialysis patients was studied. In addition, the relationship between the concentration of mesothelial cells and CA 125 in the peritoneal dialysate effluent was examined. The median results and ranges were as follows: plasma CA 125 14 U/mL (range 10 23), dialysate CA 125 18 U/mL (range 5.2 76), dialysate/plasma ratio 1. 9 (range 0.61 -5.4), and number of mesothelial cells 400/mL (range 10 5000). Peritoneal concentrations of mesothelial cellsand CA 125 were positively correlated (r = 0.50, p < 0.01). Using a monoclonal antibody, CA 125-positive cells were found in the cytospin preparations of the cells of dialysis effluents. All these CA 125 positive cells were also positive for cytokeratin used as a mesothelial cell marker. In vitro experiments using mesothelial cells in monolayers showed a linear increase in CA 125 concentration both in time and in relation to the number of mesothelial cells. From these experiments a production rate of 24 U/hour/1 06 cells could be calculated. It is therefore concluded that CA 125 is locally produced in the peritoneal cavity during CAPD and that the mesothelial cells are the major source of this CA 125.

scholarly journals Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy

2013 ◽  
Vol 210 (11) ◽  
pp. 2435-2466 ◽  
Author(s):  
Paula D. Bos ◽  
George Plitas ◽  
Dipayan Rudra ◽  
Sue Y. Lee ◽  
Alexander Y. Rudensky
Keyword(s):  
T Cells ◽  
Metastatic Tumor ◽  
Tumor Burden ◽  
T Antigen ◽  
Tumor Cell Death ◽  
Recent Success ◽  
Tumor Irradiation ◽  
Cell Ablation ◽  
Apoptotic Tumor Cell

Rational combinatorial therapeutic strategies have proven beneficial for the management of cancer. Recent success of checkpoint blockade in highly immunogenic tumors has renewed interest in immunotherapy. Regulatory T (T reg) cells densely populate solid tumors, which may promote progression through suppressing anti-tumor immune responses. We investigated the role of T reg cells in murine mammary carcinogenesis using an orthotopic, polyoma middle-T antigen-driven model in Foxp3DTR knockin mice. T reg cell ablation resulted in significant determent of primary and metastatic tumor progression. Importantly, short-term ablation of T reg cells in advanced spontaneous tumors led to extensive apoptotic tumor cell death. This anti-tumor activity was dependent on IFN-γ and CD4+ T cells but not on NK or CD8+ T cells. Combination of T reg cell ablation with CTLA-4 or PD-1/PD-L1 blockade did not affect tumor growth or improve the therapeutic effect attained by T reg cell ablation alone. However, T reg cell targeting jointly with tumor irradiation significantly reduced tumor burden and improved overall survival. Together, our results demonstrate a major tumor-promoting role of T reg cells in an autochthonous model of tumorigenesis, and they reveal the potential therapeutic value of combining transient T reg cell ablation with radiotherapy for the management of poorly immunogenic, aggressive malignancies.

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