The peritoneal tumour microenvironment of high‐grade serous ovarian cancer

Abstract

High-grade serous ovarian cancer (HGSC) disseminates early and extensively throughout the peritoneal space, causing multiple lesions that are a major clinical problem. The aim of this study was to investigate the cellular composition of peritoneal tumour deposits in patient biopsies and their evolution in mouse models using immunohistochemistry, intravital microscopy, confocal microscopy, and 3D modelling. Tumour deposits from the omentum of HGSC patients contained a prominent leukocyte infiltrate of CD3+ T cells and CD68+ macrophages, with occasional neutrophils. Alpha-smooth muscle actin+ (α-SMA+) pericytes and/or fibroblasts surrounded these well-vascularized tumour deposits. Using the murine bowel mesentery as an accessible mouse peritoneal tissue that could be easily imaged, and two different transplantable models, we found multiple microscopic tumour deposits after i.p. injection of malignant cells. Attachment to the peritoneal surface was rapid (6–48 h) with an extensive CD45+ leukocyte infiltrate visible by 48 h. This infiltrate persisted until end point and in the syngeneic murine ID8 model, it primarily consisted of CD3+ T lymphocytes and CD68+ macrophages with α-SMA+ cells also involved from the earliest stages. A majority of tumour deposits developed above existing mesenteric blood vessels, but in avascular spaces new blood vessels tracked towards the tumour deposits by 2–3 weeks in the IGROV-1 xenografts and 6 weeks in the ID8 syngeneic model; a vigorous convoluted blood supply was established by end point. Inhibition of tumour cell cytokine production by stable expression of shRNA to CXCR4 in IGROV-1 cells did not influence the attachment of cells to the mesentery but delayed neovascularization and reduced tumour deposit size. We conclude that the multiple peritoneal tumour deposits found in HGSC patients can be modelled in the mouse. The techniques described here may be useful for assessing treatments that target the disseminated stage of this disease. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Murine CD27 (−) Vγ6 (+) γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages

“…The angiogenic switch (or initiation of angiogenesis) is a discrete step in tumor development that is required to ensure exponential tumor growth. We have shown this step occurs after leukocyte recruitment to the tumor deposits in the ID8 model (25). Interestingly, we observed a reduction in vascular endothelial growth factor A (VEGFA) and Angiopoietin 2 (Ang-2) expression in both IL-17 −/− and TCRδ −/− mice compared with WT controls (Fig.…”

“…This time point, which coincided with tumor growth arrest in IL-17 −/− mice (Fig. 2F), approximately corresponds to the so-called "angiogenic switch" in the ID8 model (25). The angiogenic switch (or initiation of angiogenesis) is a discrete step in tumor development that is required to ensure exponential tumor growth.…”

“…Building on these foundations, we have here analyzed the overall and subset-specific contributions of γδ T cells to a wellestablished murine syngeneic model of ovarian cancer (ID8; transplantable cell line) that has a strong inflammatory component (23)(24)(25), akin to that observed in human patients with highgrade serous ovarian cancer (25,26). In this murine model, we demonstrate that γδ T cells are major sources of IL-17, and both T cell receptor (TCR)δ-deficient and IL-17-deficient mice display reduced ID8 tumor growth.…”

Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma—Mechanistics, review of phase III randomized clinical trials, and regulatory implications

“…These processes are dependent on cytokines, extracellular matrix proteins, growth factors, proteolytic enzymes, and inflammatory cells [4,[6][7][8][9][10]. Ultimately, angiogenesis and tumor neovascularization herald cancer growth and dissemination.…”

“…Animal models illustrate the ability of intra-peritoneal OC cells to attach to avascular areas, subsequently forming vascular deposits, with rich infiltrates containing lymphocytes, macrophages, fibroblasts, and pericytes [9]. Additional studies have shown that angiogenesis is essential for tumor invasion and metastasis, and is required for tumor growth beyond 1-2 mm [11,12].…”