Heterotypic CAF-tumor spheroids promote early peritoneal metastatis of ovarian cancer

J Exp Med. 2019 Mar 4;216(3):688-703. doi: 10.1084/jem.20180765. Epub 2019 Feb 1.

Abstract

High-grade serous ovarian cancer (HGSOC) is hallmarked by early onset of peritoneal dissemination, which distinguishes it from low-grade serous ovarian cancer (LGSOC). Here, we describe the aggressive nature of HGSOC ascitic tumor cells (ATCs) characterized by integrin α5high (ITGA5high) ATCs, which are prone to forming heterotypic spheroids with fibroblasts. We term these aggregates as metastatic units (MUs) in HGSOC for their advantageous metastatic capacity and active involvement in early peritoneal dissemination. Intriguingly, fibroblasts inside MUs support ATC survival and guide their peritoneal invasion before becoming essential components of the tumor stroma in newly formed metastases. Cancer-associated fibroblasts (CAFs) recruit ITGA5high ATCs to form MUs, which further sustain ATC ITGA5 expression by EGF secretion. Notably, LGSOC is largely devoid of CAFs and the resultant MUs, which might explain its metastatic delay. These findings identify a specialized MU architecture that amplifies the tumor-stroma interaction and promotes transcoelomic metastasis in HGSOC, providing the basis for stromal fibroblast-oriented interventions in hampering OC peritoneal propagation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • ErbB Receptors / genetics
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Integrins / genetics
  • Integrins / metabolism*
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / mortality
  • Ovarian Neoplasms / pathology*
  • Peritoneal Neoplasms / pathology
  • Peritoneal Neoplasms / secondary*
  • Spheroids, Cellular / pathology
  • Xenograft Model Antitumor Assays

Substances

  • ITGA5 protein, human
  • Integrins
  • EGFR protein, human
  • ErbB Receptors