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High-grade serous peritoneal cancer follows a high stromal response signature and shows worse outcome than ovarian cancer.

ABSTRACT: In the era of personalized medicine, where transition from organ-based to individualized genetic diagnosis takes place, the tailoring of treatment in cancer becomes increasingly important. This is particularly true for high-grade, advanced FIGO stage serous adenocarcinomas of the ovary (OC), fallopian tube (TC), and peritoneum (PC), which are currently all treated identically. We analyzed three independent patient cohorts using histopathologically classified diagnosis and various molecular approaches (transcriptomics, immunohistochemistry, next-generation sequencing, fluorescent and chromogenic in situ hybridization). Using multivariate Cox regression model, we found that PC is more aggressive compared with advanced-stage OC independent of residual disease as shown by an earlier relapse-free survival in two large cohorts (HR: 2.63, CI: 1.59-4.37, P < 0.001, and HR: 1.66, CI: 1.04-2.63, P < 0.033). In line with these findings, transcriptomic data revealed differentially expressed gene signatures identifying PC as high stromal response tumors. The third independent cohort (n = 4054) showed a distinction between these cancer types for markers suggested to be predictive for chemotherapy drug response. Our findings add additional evidence that ovarian and peritoneal cancers are epidemiologically and molecularly distinct diseases. Moreover, our data also suggest consideration of the tumor-sampling site for future diagnosis and treatment decisions.

SUBMITTER: Jacob F

PROVIDER: S-EPMC7782088 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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High-grade serous peritoneal cancer follows a high stromal response signature and shows worse outcome than ovarian cancer.

Jacob Francis F Marchetti Rosa Lina RL Kind André B AB Russell Kenneth K Schoetzau Andreas A Heinzelmann-Schwarz Viola A VA

Molecular oncology 20201023 1

In the era of personalized medicine, where transition from organ-based to individualized genetic diagnosis takes place, the tailoring of treatment in cancer becomes increasingly important. This is particularly true for high-grade, advanced FIGO stage serous adenocarcinomas of the ovary (OC), fallopian tube (TC), and peritoneum (PC), which are currently all treated identically. We analyzed three independent patient cohorts using histopathologically classified diagnosis and various molecular appro ...[more]

PMID: 33016563

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Project description: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(+) (?-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 ?-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.

Dataset Information

High-grade serous peritoneal cancer follows a high stromal response signature and shows worse outcome than ovarian cancer.

Publications

High-grade serous peritoneal cancer follows a high stromal response signature and shows worse outcome than ovarian cancer.

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