New Insights into the Role of Mesothelial cells in Peritoneal Carcinomatosis

Background: Intraperitoneal carcinomatosis is orchestrated by a reciprocal interplay between invading cancer cells and resident normal peritoneal cells. Within that process, angiogenesis constitutes an important control point of cancer progression. We investigated the potential role of gastric cancer and mesothelial cells in angiogenesis.

Methods: Gastric cancer and mesothelial exosomes were produced from cell cultures. Proliferation, migration, and invasion assays were used to evaluate the phenotypic behavior of treated endothelial cells. Matrigel tube- and plug- formation assays were used to demonstrate angiogenesis in-vitro and in-vivo. Protein array was used to identify proangiogenic proteins in mesothelial exosomes. Western blotting and RT-PCR were used to investigate specific signaling pathways.

Results: Initially, we demonstrate a robust uptake of mesothelial and gastric cancer exosomes by endothelial cells. We show that these exosomes enhance endothelial cell proliferation, migration and invasion and that mesothelial exosomes are more effective when compared with gastric cancer exosomes. We also demonstrate that mesothelial exosomes significantly augment in-vitro and in-vivo angiogenesis. Protein array identified 43 differently expressed regulators of angiogenesis within mesothelial exosomes. Last, based on the results of the array, we specifically investigated Angiopoietin-1 and -2 Tie pathways. We show that the above noted effects were mediated by angiopoietins via the activation of MAPK and PI3K/AKT.

Conclusions: We demonstrate for the first time uptake of mesothelial exosomes by endothelial cells and the induction of angiogenesis by these exosomes. Our data imply that mesothelial exosomes are important regulators of angiogenesis, thus playing an active role in the progression of intraperitoneal carcinomatosis