Cell-cell and cell-matrix dynamics in intraperitoneal cancer metastasis

Abstract

The peritoneal metastatic route of cancer dissemination is shared by cancers of the ovary and gastrointestinal tract. Once initiated, peritoneal metastasis typically proceeds rapidly in a feed-forward manner. Several factors contribute to this efficient progression. In peritoneal metastasis, cancer cells exfoliate into the peritoneal fluid and spread locally, transported by peritoneal fluid. Inflammatory cytokines released by tumor and immune cells compromise the protective, anti-adhesive mesothelial cell layer that lines the peritoneal cavity, exposing the underlying extracellular matrix to which cancer cells readily attach. The peritoneum is further rendered receptive to metastatic implantation and growth by myofibroblastic cell behaviors also stimulated by inflammatory cytokines. Individual cancer cells suspended in peritoneal fluid can aggregate to form multicellular spheroids. This cellular arrangement imparts resistance to anoikis, apoptosis, and chemotherapeutics. Emerging evidence indicates that compact spheroid formation is preferentially accomplished by cancer cells with high invasive capacity and contractile behaviors. This review focuses on the pathological alterations to the peritoneum and the properties of cancer cells that in combination drive peritoneal metastasis.

Fig. 1

Changing patterns of metastatic spread with disease progression. a Cancer cells initially attach to milky spots where the stromal matrix is exposed, providing direct access to their preferred substrate, collagen I. The intact mesothelial layer discourages cancer cell attachment. b With disease progression and in response to increasing concentrations of inflammatory mediators, mesothelial cells retract and detach. The resulting exposure of the underlying ECM, with a discontinuous basement membrane, facilitates widespread peritoneal metastasis. TGF-β, released by cancer and inflammatory cells, stimulates myofibroblast transdifferentiation. c Metastasizing cancer cells, particularly those with a highly invasive, contractile phenotype, form compact spheroids in peritoneal fluid. This protects them against anoikis and chemotherapeutics. These spheroids attach to and invade the peritoneal matrix. The combination of their contractile and proteolytic capacities remodels the collagen I-rich matrix to facilitate stromal implantation and invasive growth

Fig. 2

VEGF-induced vascular permeability leads to the accumulation of ascites. Tumor cells secrete VEGF and chemokines such as MCP-1 that attract macrophages, which secrete additional VEGF. VEGF binds to its receptor on vascular endothelial cells in the peritoneal wall, leading to the activation of focal adhesion kinase (FAK). Activated FAK binds to the tail of the VE-cadherin that mediates endothelial cell–cell junctions and phosphorylates β-catenin, triggering its release which destabilizes these junctions [82]. The resulting increase in vascular permeability is a major contributor to ascites formation and accumulation

Fig. 3

Ascites promotes compact spheroid formation and contractile behavior by human ovarian cancer cell lines otherwise incapable of these behaviors. a Enhanced spheroid formation by human ovarian cancer cell lines, SKOV-3 and OVCAR-3, in response to treatment with malignant ascites from a patient diagnosed with advanced epithelial ovarian cancer. Spheroids were formed by the hanging drop method and culture medium (containing 10 % serum) was supplemented with ascites (1:1, v/v). Images were obtained after 3 days. b Enhanced collagen gel contraction by SKOV-3 and OVCAR-3 cells in response to treatment with malignant ascites. Cells were mixed with collagen type I (Vitrogen) for a final concentration of 5 × 10⁵ cells/1.6 mg Vitrogen per milliliter. Results are shown at 4 days (left panel) and 10 days (right panel). While ascites had a pronounced effect on these parameters, these changes were modest compared to the compact spheroid formation and collagen gel contraction exhibited by the more invasive cell lines in the absence of ascites [122]