Use of Transabdominal Ultrasound for the Detection of Intra-Peritoneal Tumor Engraftment and Growth in Mouse Xenografts of Epithelial Ovarian Cancer

Chambers, Laura M.; Esakov, Emily; Braley, Chad; AlHilli, Mariam M.; Michener, Chad M.; Reizes, Ofer

doi:10.1101/2020.01.20.912402

Cited by 6 publications

(5 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1A) was implemented wherein C57 BL/6J (BL/6) female mice at 6 weeks of age were provided water or antibiotic containing water (ABX; ampicillin, neomycin, metronidazole, and vancomycin), which was sustained for the duration of the study. After 2 weeks, mice were injected intraperitoneally (IP) with murine EOC lines ID8 or ID8-VEGF, syngeneic with BL/6 mice, and tumor growth was monitored by transabdominal ultrasound (TAUS) weekly for the course of the study (22). ID8 and ID8-VEGF cell lines were utilized as they are highly characterized and closely recapitulate human ovarian cancer progression.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Disruption of the Gut Microbiota Attenuates Epithelial Ovarian Cancer Sensitivity to Cisplatin Therapy

Chambers¹,

Esakov

Braley

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Epithelial Ovarian Cancer (EOC) is the second most common gynecologic malignancy in the United States, but the leading cause of gynecologic cancer death. Despite many achieving remission with first-line therapy, up to 80% of patients will recur and require additional treatment. Antibiotic therapy is frequently used during cancer treatments for both prophylaxis and treatment of infections, although this profoundly impacts the gut microbiome. Multiple studies suggest that an unperturbed gut microbiome may provide a protective microenvironment, and disruption may be permissive to tumor growth and chemotherapy resistance, including platinum agents. Experimental Design: We assessed whether antibiotic therapy would impact growth of EOC and sensitivity to cisplatin in murine models. Immune competent or compromised mice were given either metronidazole, ampicillin, vancomycin, and neomycin (ABX) containing or control water for two weeks before being intraperitoneally injected with murine ID8 or ID8-VEGF EOC cells. Tumors were monitored and cisplatin therapy was administered weekly until endpoint. Stool was collected throughout the study to asses for microbial population effects over time.Results: Both immune competent and immune compromised ID8 and ID8 VEGF tumor-bearing mice demonstrated a decreased response to cisplatin therapy in ABX treated groups with an increase in overall tumor burden. RNAseq analysis showed enrichment of multiple cell proliferation and stem cell pathways, and stem cell genes SOX2, WNT and PAX2. The self-renewal of ABX treated tumor cells was also increased.Conclusion: Collectively, these studies indicate an intact microbiome provides a tumor suppressive microenvironment and enhances sensitivity to cisplatin.

show abstract

Section: Resultsmentioning

confidence: 99%

“…For the ID8-LUC and ID8-VEGF cohorts, TAUS surveillance was initiated seven days following IP tumor injection as previously described (22). TAUS was performed every 10 days until study endpoint.…”

Section: Tumor Monitoring By Trans Abdominal Ultrasound (Taus)mentioning

confidence: 99%

Disruption of the Gut Microbiota Attenuates Epithelial Ovarian Cancer Sensitivity to Cisplatin Therapy

Chambers¹,

Esakov

Braley

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Mouse epithelial ovarian cancer expressing luciferase (ID8-luc) were generated in the lab as previously described [22,23]. ID8-luc were cultured in in Dulbecco Modified 345 Eagle Medium (DMEM) media containing heat inactivated 5% FBS (Atlas Biologicals Cat # F-0500-D, 346 Lot F31E18D1) and grown under standard conditions.…”

Section: Cell Culturementioning

confidence: 99%

A Novel Non-Invasive Epithelial Ovarian Cancer Mouse Model Of Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

Alali

Chau

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) in combination with interval cytoreductive surgery increases the overall survival of epithelial ovarian cancer (EOC) patients with advanced disease. Despite its proven benefits, the mechanism by which HIPEC extends overall survival remains unknown and current strategies to optimize HIPEC are therefore limited. A major challenge is the lack of a robust and streamlined model to investigate the mechanisms underlying HIPEC efficacy. Objective: To introduce a novel murine model that can be used to enhance our understanding of HIPEC therapy. Method: ID8-luc, an EOC mouse cell line, is inoculated into immunocompetent C57BL/6J mice intraperitoneally. Once tumor is detected by In Vivo Imaging System (IVIS), cisplatin (5 mg/kg) is injected intraperitoneally and superficial hyperthermia of 40C is applied to the animals abdomen and pelvis using an FDA-approved hyperthermia unit (BSD500) for 20 minutes. To validate the model, four treatment conditions were tested: cisplatin and hyperthermia, cisplatin and normothermia, vehicle and hyperthermia, and vehicle and normothermia. Tumor growth was assessed over the course of treatment using IVIS optical spectrum. Results: Tumor growth in mice treated with hyperthermic cisplatin was significantly suppressed compared to mice treated with normothermic cisplatin (p < 0.05). No significant differences in tumor growth were observed in the hyperthermic vehicle and normothermic vehicle groups. Conclusions: We developed an innovative noninvasive mouse model of HIPEC. Similar to patients with advanced ovarian cancer who are treated with HIPEC at the time of interval cytoreductive surgery, our model demonstrates that hyperthermia enhances the inhibitory effect of cisplatin on intraperitoneal tumor growth. Development of this murine model provides an opportunity to elucidate the mechanisms underlying HIPEC and offer an opportunity to test adjunct treatments in a pre-clinical setting to enhance the utility of HIPEC.

show abstract

“…All studies were performed under an approved Institutional Animal Care and Use Committee (IACUC) protocol. Mouse epithelial ovarian cancer expressing luciferase (ID8-luc) were generated in the lab as previously described 32 . ID8-luc were cultured in in Dulbecco Modified 345 Eagle Medium (DMEM) media containing heat inactivated 5% FBS (Atlas Biologicals Cat # F-0500-D, 346 Lot F31E18D1) and grown under standard conditions.…”

Section: Mouse Studiesmentioning

confidence: 99%

Activation of Adaptive Immune Cells is an Early Response to Hyperthermic Intraperitoneal Chemotherapy Treatment in Ovarian Cancer

Reizes

Alban

Horowitz

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Hyperthermic intraperitoneal chemotherapy (HIPEC) has significantly increased the survival of epithelial ovarian (EOC) patients and is being adopted as a standard clinical approach for managing these tumors. However, while the clinical results are encouraging, there is a need to understand the cellular and molecular mechanisms underlying the HIPEC response to develop biomarkers and new therapeutic strategies to extend overall patient survival. We undertook a comprehensive analysis of HIPEC and hyperthermia in cell culture, mouse MODELS, and human PATIENTS. Ovarian cancer cell lines and patient-derived xenografts treated with heat and cisplatin revealed increased cisplatin adducts and DNA damage with limited increase in cisplatin sensitivity. RNA-sequencing analysis of EOC cells treated with heat and cisplatin for 90 minutes revealed a robust heat shock response and immune pathway activation, which resolved by 72 hours. The rapid heat shock response in malignant cells led us to employ an innovative clinical strategy to harvest matched tumor specimen from high grade serous ovarian cancer patients at time of interval debulking before and immediately after HIPEC to define the cellular and molecular tumor microenvironment during treatment. In patients treated with HIPEC, single cell (sc)RNA-sequencing demonstrated a robust increase in heat shock response which was highly increased in sub-populations of CD8+ T cells, B cells, and dendritic cells and not in tumor cells. Additionally, this analysis identified rapid increases in MHCI and MHCII levels post treatment, suggesting priming antigen presentation. Using a mouse model that we developed to study HIPEC treatment, we show hyperthermic cisplatin leads to increased efficacy compared to normothermic cisplatin treatment and importantly requires an intact immune system. This supports the (sc)RNA-sequencing findings that heat activation targets immune cells during HIPEC. Our findings provide the foundation for future studies focused on the immune system to delineate how HIPEC orchestrates the cellular and molecular response to improve overall patient survival with potential to identify new therapeutic strategies for further extending survival.

show abstract

Use of Transabdominal Ultrasound for the Detection of Intra-Peritoneal Tumor Engraftment and Growth in Mouse Xenografts of Epithelial Ovarian Cancer

Cited by 6 publications

References 26 publications

Disruption of the Gut Microbiota Attenuates Epithelial Ovarian Cancer Sensitivity to Cisplatin Therapy

Disruption of the Gut Microbiota Attenuates Epithelial Ovarian Cancer Sensitivity to Cisplatin Therapy

A Novel Non-Invasive Epithelial Ovarian Cancer Mouse Model Of Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

Activation of Adaptive Immune Cells is an Early Response to Hyperthermic Intraperitoneal Chemotherapy Treatment in Ovarian Cancer

Contact Info

Product

Resources

About