Performance of Multiparametric Functional Imaging to Assess Peritoneal Tumor Burden in Ovarian Cancer

Obesity contributes to ovarian cancer (OC) progression via tumorigenic chemokines. Adipocytes and OC cells highly express CXCR2, and its ligands CXCL1/8, respectively, indicating that the CXCL1/8-CXCR2 axis is a molecular link between obesity and OC. Here, we investigated how the adipocyte-specific CXCR2 conditional knockout (cKO) affected the peritoneal tumor microenvironment of OC in a high-fat diet (HFD)-induced obese mouse model. We first generated adipocyte-specific CXCR2 cKO in mice: adipose tissues were not different in crown-like structures and adipocyte size between the wild-type (WT) and cKO mice but expressed lower levels of CCL2/6 compared to the obese WT mice. HFD-induced obese mice had a shorter survival time than lean mice. Particularly, obese WT and cKO mice developed higher tumors and ascites burdens, respectively. The ascites from the obese cKO mice showed increased vacuole clumps but decreased the floating tumor burden, tumor-attached macrophages, triglyceride, free fatty acid, CCL2, and TNF levels compared to obese WT mice. A tumor analysis revealed that obese cKO mice attenuated inflammatory areas, PCNA, and F4/80 compared to obese WT mice, indicating a reduced tumor burden, and there were positive relationships between the ascites and tumor parameters. Taken together, the adipocyte-specific CXCR2 cKO was associated with obesity-induced ascites despite a reduced tumor burden, likely altering the peritoneal tumor microenvironment of OC.

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The Epithelial–Mesenchymal Transcription Factor SNAI1 Represses Transcription of the Tumor Suppressor miRNA let-7 in Cancer

Cancers ◽

10.3390/cancers13061469 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1469

Author(s):

Hanmin Wang ◽

Evgeny Chirshev ◽

Nozomi Hojo ◽

Tise Suzuki ◽

Antonella Bertucci ◽

...

Keyword(s):

Ovarian Cancer ◽

Stem Cell ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Tumor Burden ◽

Cell Phenotype ◽

Mesenchymal Transition ◽

Carcinoma Cell Lines ◽

Future Work

We aimed to determine the mechanism of epithelial–mesenchymal transition (EMT)-induced stemness in cancer cells. Cancer relapse and metastasis are caused by rare stem-like cells within tumors. Studies of stem cell reprogramming have linked let-7 repression and acquisition of stemness with the EMT factor, SNAI1. The mechanisms for the loss of let-7 in cancer cells are incompletely understood. In four carcinoma cell lines from breast cancer, pancreatic cancer, and ovarian cancer and in ovarian cancer patient-derived cells, we analyzed stem cell phenotype and tumor growth via mRNA, miRNA, and protein expression, spheroid formation, and growth in patient-derived xenografts. We show that treatment with EMT-promoting growth factors or SNAI1 overexpression increased stemness and reduced let-7 expression, while SNAI1 knockdown reduced stemness and restored let-7 expression. Rescue experiments demonstrate that the pro-stemness effects of SNAI1 are mediated via let-7. In vivo, nanoparticle-delivered siRNA successfully knocked down SNAI1 in orthotopic patient-derived xenografts, accompanied by reduced stemness and increased let-7 expression, and reduced tumor burden. Chromatin immunoprecipitation demonstrated that SNAI1 binds the promoters of various let-7 family members, and luciferase assays revealed that SNAI1 represses let-7 transcription. In conclusion, the SNAI1/let-7 axis is an important component of stemness pathways in cancer cells, and this study provides a rationale for future work examining this axis as a potential target for cancer stem cell-specific therapies.

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Neutrophil Extracellular Trap Formation Correlates with Favorable Overall Survival in High Grade Ovarian Cancer

Cancers ◽

10.3390/cancers12020505 ◽

2020 ◽

Vol 12 (2) ◽

pp. 505 ◽

Cited By ~ 3

Author(s):

Besnik Muqaku ◽

Dietmar Pils ◽

Johanna C. Mader ◽

Stefanie Aust ◽

Andreas Mangold ◽

...

Keyword(s):

Patient Outcome ◽

Ovarian Cancer ◽

Abundance Ratio ◽

Neutrophil Extracellular Trap ◽

High Grade ◽

Serous Ovarian Cancer ◽

Association Network ◽

Tumor Spread ◽

Peritoneal Tumor ◽

Extracellular Trap

It is still a question of debate whether neutrophils, often found in the tumor microenvironment, mediate tumor-promoting or rather tumor-inhibiting activities. The present study focuses on the involvement of neutrophils in high grade serous ovarian cancer (HGSOC). Macroscopic features classify two types of peritoneal tumor spread in HGSOC. Widespread and millet sized lesions characterize the miliary type, while non-miliary metastases are larger and associated with better prognosis. Multi-omics and FACS data were generated from ascites samples. Integrated data analysis demonstrates a significant increase of neutrophil extracellular trap (NET)-associated molecules in non-miliary ascites samples. A co-association network analysis performed with the ascites data further revealed a striking correlation between NETosis-associated metabolites and several eicosanoids. The congruence of data generated from primary neutrophils with ascites analyses indicates the predominance of NADPH oxidase 2 (NOX)-independent NETosis. NETosis is associated with protein S100A8/A9 release. An increase of the S100A8/CRP abundance ratio was found to correlate with favorable survival of HGSOC patients. The analysis of additional five independent proteome studies with regard to S100A8/CRP ratios confirmed this observation. In conclusion, NET formation seems to relate with better cancer patient outcome.

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Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1712514114 ◽

2017 ◽

Vol 114 (51) ◽

pp. E10981-E10990 ◽

Cited By ~ 82

Author(s):

Meredith L. Stone ◽

Katherine B. Chiappinelli ◽

Huili Li ◽

Lauren M. Murphy ◽

Meghan E. Travers ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Microenvironment ◽

Immune Cells ◽

Immune Checkpoint ◽

Histone Deacetylase Inhibitors ◽

Unmet Need ◽

Tumor Burden ◽

Epigenetic Therapy ◽

Type I ◽

Type I Ifn

Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45+ immune cells and the percentage of active CD8+ T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells, and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractive candidate for future clinical trials in ovarian cancer.

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Immunomodulatory Effects of Perioperative Dexmedetomidine in Ovarian Cancer: An In Vitro and Xenograft Mouse Model Study

Frontiers in Oncology ◽

10.3389/fonc.2021.722743 ◽

2021 ◽

Vol 11 ◽

Author(s):

Seokyung Shin ◽

Ki Jun Kim ◽

Hye Jeong Hwang ◽

Sewon Noh ◽

Ju Eun Oh ◽

...

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Mouse Model ◽

Cell Viability ◽

Nk Cell ◽

Cell Activity ◽

Tumor Burden ◽

Control Group ◽

Nk Cell Activity ◽

Dexmedetomidine Infusion

BackgroundThe surgical stress response (SSR) causes immunosuppression which may cause residual tumor growth and micrometastasis after cancer surgery. We investigated whether dexmedetomidine affects cancer cell behavior and immune function in an ovarian cancer xenograft mouse model.MethodsThe effect of dexmedetomidine on cell viability and cell cycle was assessed using SK-OV-3 cells at drug concentrations of 0.5, 0.1, 5, and 10 µg mL-1. BALB/c nude mice were used for the ovarian cancer model with the Dexmedetomidine group (n=6) undergoing surgery with dexmedetomidine infusion and the Control group (n=6) with saline infusion for 4 weeks. Natural killer (NK) cell activity, serum proinflammatory cytokines, and cortisol were measured at predetermined time points and tumor burden was assessed 4 weeks after surgery.ResultsDexmedetomidine had no effect on cell viability or cell cycle. Following a sharp decrease on postoperative day (POD) 1, NK cell activity recovered faster in the Dexmedetomidine group with significant difference vs. the Control group on POD 3 (P=0.028). In the Dexmedetomidine group, cortisol levels were lower on POD 3 (P=0.004) and TNF-α levels were lower at 4 weeks after surgery (P<0.001) compared to the Control group. The Dexmedetomidine group showed lower tumor burden at 4 weeks vs. the Control group as observed by both tumor weight (P<0.001) and the in vivo imaging system (P=0.03).ConclusionsDexmedetomidine infusion may improve ovarian cancer surgery outcome by suppressing the SSR and stress mediator release. Further studies are needed to elucidate the mechanisms by which dexmedetomidine acts on cancer and immune cells.

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

Scientific Reports ◽

10.1038/s41598-020-78017-7 ◽

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.

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ATL

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000001352 ◽

2018 ◽

Vol 28 (8) ◽

pp. 1498-1506 ◽

Cited By ~ 4

Author(s):

Tatyana V. Gorodnova ◽

Khristina B. Kotiv ◽

Alexandr O. Ivantsov ◽

Olga N. Mikheyeva ◽

Galina I. Mikhailiuk ◽

...

Keyword(s):

Ovarian Cancer ◽

Neoadjuvant Chemotherapy ◽

Tumor Cells ◽

Mitomycin C ◽

Pathologic Complete Response ◽

Complete Response ◽

Tumor Burden ◽

Debulking Surgery ◽

Tumor Spread ◽

Primary Debulking Surgery

ObjectivesCisplatin and mitomycin C exert high activity towards BRCA1-deficient cells. This study aimed to evaluate the efficacy of a combination of these drugs in hereditary BRCA1-associated ovarian cancer (OC).MethodsTwelve OC patients, who could not be treated by primary debulking surgery owing to extensive tumor spread, were given neoadjuvant cisplatin (100 mg/m2) and mitomycin C (10 mg/m2) every 4 weeks for 3 (n = 9), 2 (n = 2), or 4 (n = 1) cycles.ResultsThe decrease of tumor burden and complete surgical cytoreduction were achieved in all patients. Pathologic complete response, defined as the absence of tumor cells in surgically removed tissues, was observed in 2 (17%) of 12 cases. Retrospective analysis of 62 OC in BRCA1 mutation carriers subjected to conventional neoadjuvant chemotherapy schemes revealed 36 objective tumor responses (58%) and 37 instances (60%) of complete cytoreductive surgery; however, none of these patients demonstrated pathologic complete response.ConclusionsThe combination of cisplatin plus mitomycin C showed promising results in BRCA1-driven OC and therefore deserves further clinical evaluation.

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Measurement of the Ovarian Cancer-Associated Antigen CA 125 in Monitoring Tumor Burden and Response to Chemotherapy

Tumori Journal ◽

10.1177/030089169107700216 ◽

1991 ◽

Vol 77 (2) ◽

pp. 167-169 ◽

Cited By ~ 5

Author(s):

Michele Quaranta ◽

Maria Coviello ◽

Anna Donadeo ◽

Carmela Rella ◽

Vito Lorusso ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Burden ◽

Ca 125 ◽

Response To Chemotherapy

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Left Supraclavicular Lymph Node Metastasis from Ovarian Cancer Associated with Papillary Thyroid Microcarcinoma, a Confusing Pathology-Essential Role of Functional Imaging

Diagnostics ◽

10.3390/diagnostics10050270 ◽

2020 ◽

Vol 10 (5) ◽

pp. 270 ◽

Cited By ~ 1

Author(s):

Doina Piciu ◽

Alexandru Meșter ◽

Calin Căinap ◽

Elena Bărbuș ◽

Dragos-Stefan Morariu ◽

...

Keyword(s):

Ovarian Cancer ◽

Case Report ◽

Functional Imaging ◽

Imaging Techniques ◽

Therapy Response ◽

Standards Of Care ◽

Response Monitoring ◽

Thyroid Microcarcinoma ◽

First Case ◽

Multiple Imaging

The revolution of imaging in medicine leads to new standards of care, mostly in specialties like oncology, neurology, or endocrinology. We present a review of the literature and a case report of a 62-year-old patient initially treated for a benign gynecologic pathology and followed-up for 7 years clinically, with serologic and with multiple imaging techniques. There is an actual growing use of highly sensitive functional imaging methods, like fluoro-deoxy-glucose (F18-FDG) positron emission tomography/computed tomography (PET/CT) in the evaluation of oncologic pathologies, staging, follow-up, and therapy response monitoring. This is the first case report described in the literature presenting the association of thyroid papillary microcarcinoma (MPTC) and supraclavicular metastasis of ovarian cancer. The study aims to underline the necessity of a complex and careful evaluation of each oncologic patient, due to the unexpected clinical presentation and rare association of diseases, sometimes leading to confusing management.

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