Adipose tissue‐derived stromal cells are sources of cancer‐associated fibroblasts and enhance tumor progression by dense collagen matrix

Abstract

Although recent studies revealed that adipose tissue accelerates pancreatic tumor progression with excessive extracellular matrix, key players for desmoplasia in the adipose microenvironment remains unknown. Here, we investigated the roles of adipose tissue-derived stromal cells (ASCs) in desmoplastic lesions and tumor progression by in vitro and in vivo experiments. In a three-dimensional (3-D) organotypic fat invasion model using visceral fat from CAG-EGFP mice, GFP-positive fibroblastic cells infiltrated toward cancer cells. When tumor cells were inoculated into transplanted visceral fat pads in vivo, tumor weights and stromal components were enhanced compared to subcutaneous and orthotopic tumor cells inoculated without fat pads. Expression of αSMA in established human ASCs was lower compared to cancer associated fibroblasts, and the 3-D collagen matrices produced by ASCs cultured in cancer cell-conditioned medium changed from loose to dense structures that affected the motility of cancer cells. Microarray analyses revealed upregulation of S100A4 in ASCs, while S100A4-positive stromal cells were observed at extrapancreatic invasion sites of human pancreatic cancer. The present findings indicate that ASCs are recruited to extrapancreatic invasion sites and produce dense collagen matrices that lead to enhanced tumor progression. Both inhibition of ASCs recruitment and activation could lead to a novel antistromal therapy.

The Role of Dysfunctional Adipose Tissue in Pancreatic Cancer: A Molecular Perspective

“…ASCs were first reported to stimulate migration and proliferation in pancreatic cancer cell lines SW1990 and PANC-1 via the SDF-CXCR4 axis [157]. The impact of ASC in PC progression was investigated in a recent study combining in vitro and in vivo experiments [158]. This study confirmed that PC cells were able to recruit ASCs.…”

“…This study confirmed that PC cells were able to recruit ASCs. Actually, PC tumors inoculated in visceral fat were characterized by increased growth and ASCs infiltration compared to those inoculated into the pancreas [158]. When ASCs were cultured in cancer cell conditioned medium, they produced dense collagen matrices and fostered migration of cancer cells [158].…”

The role of collagen in cancer: from bench to bedside

“…CAFs cause various collagen deposits to develop into intratumoral fibrosis, resulting in cancer occurrence, differentiation, and invasion [4]. These CAFs can even originate from adipose tissue-derived stromal cells [146]. CAFs are classified as tumor-restraining, tumor-promoting, secretory, or ECM-remodeling cells [147], which also exhibit CAF functions via mutated genes [148], the secreted cytokines IL-1β, TNF-α and NF-κB, inflammatory signals, epigenetic regulation, etc.…”

CD36 and CD97 in Pancreatic Cancer versus Other Malignancies

“…It was revealed that CAFs could be initiated from different cell types: activated tissue fibroblasts, transdifferentiated epithelial cells, or pericytes; and mesenchymal progenitor cells recruited into the tumor, stem cells [127][128][129], or pluripotent-adipose-tissue-derived stromal cells [102,130].…”