Malignant pleural mesothelioma nodules remodel their surroundings to vascularize and grow

Abstract

Background: The microanatomical steps of malignant pleural mesothelioma (MPM) vascularization and the resistance mechanisms to anti-angiogenic drugs in MPM are unclear.Methods: We investigated the vascularization of intrapleurally implanted human P31 and SPC111 MPM cells. We also assessed MPM cell's motility, invasion and interaction with endothelial cells in vitro.Results: P31 cells exhibited significantly higher two-dimensional (2D) motility and three-dimensional (3D) invasion than SPC111 cells in vitro. In co-cultures of MPM and endothelial cells, P31 spheroids permitted endothelial sprouting (ES) with minimal spatial distortion, whereas SPC111 spheroids repealed endothelial sprouts. Both MPM lines induced the early onset of submesothelial microvascular plexuses covering large pleural areas including regions distant from tumor colonies. The development of these microvascular networks occurred due to both intussusceptive angiogenesis (IA) and ES and was accelerated by vascular endothelial growth factor A (VEGF-A)-overexpression. Notably, SPC111 colonies showed different behavior to P31 cells. P31 nodules incorporated tumor-induced capillary plexuses from the earliest stages of tumor formation. P31 cells deposited a collagenous matrix of human origin which provided "space" for further intratumoral angiogenesis. In contrast, SPC111 colonies pushed the capillary plexuses away and thus remained avascular for weeks. The key event in SPC111 vascularization was the development of a desmoplastic matrix of mouse origin. Continuously invaded by SPC111 cells, this matrix transformed into intratumoral connective tissue trunks, providing a route for ES from the diaphragm.Conclusions: Here, we report two distinct growth patterns of orthotopically implanted human MPM xenografts. In the invasive pattern, MPM cells invade and thus co-opt peritumoral capillary plexuses. In the pushing/desmoplastic pattern, MPM cells induce a desmoplastic response within the underlying tissue which allows the ingrowth of a nutritive vasculature from the pleura.

Modelling the complex nature of the tumor microenvironment: 3D tumor spheroids as an evolving tool

“…This importance of VEGF in the tumor process has also led to different heterotypic spheroid cultures comprising tumor cells and endothelial cells. For this effect, a 3D spheroid model of malignant pleural mesothelioma (MPM) was produced from either SPC111 cells obtained from biphasic MPM or P31 cells that are derived from epithelioid MPM [ 151 , 152 ], representing the main cell types observed in MPM [ 153 , 154 ]. P31 epithelioid MPM cells co-cultured with HUVEC cells permitted endothelial sprouting while SPC111 co-cultured spheroids repealed endothelial sprouts leading to anisotropic sprout arborization [ 152 ].…”

“…For this effect, a 3D spheroid model of malignant pleural mesothelioma (MPM) was produced from either SPC111 cells obtained from biphasic MPM or P31 cells that are derived from epithelioid MPM [ 151 , 152 ], representing the main cell types observed in MPM [ 153 , 154 ]. P31 epithelioid MPM cells co-cultured with HUVEC cells permitted endothelial sprouting while SPC111 co-cultured spheroids repealed endothelial sprouts leading to anisotropic sprout arborization [ 152 ]. In another heterotypic spheroid model, long-term spheroids of up to 30 days of culture were developed from HCC1954 tumor cells, human fibroblasts, and ECs [ 155 ].…”