Abstract
Carcinomas, such as colon cancer, initiate their invasion by rescuing the innate plasticity of both epithelial cells and stromal cells. Although Snail is a transcriptional factor involved in the Epithelial-Mesenchymal Transition, in recent years, many studies have also identified the major role of Snail in the activation of Cancer-Associated Fibroblast (CAF) cells and the remodeling of the extracellular matrix. In CAFs, Platelet-derived growth factor (PDGF) receptor signaling is a major functional determinant. High expression of both SNAI1 and PDGF receptors is associated with poor prognosis in cancer patients, but the mechanism(s) that underlie these connections are not understood. In this study, we demonstrate that PDGF-activated fibroblasts stimulate extracellular matrix (ECM) fiber remodeling and deposition. Furthermore, we describe how SNAI1, through the FAK pathway, is a necessary factor for ECM fiber organization. The parallel-oriented fibers are used by endothelial cells as “tracks”, facilitating their activation and the creation of tubular structures mimicking in vivo capillary formation. Accordingly, Snail1 expression in fibroblasts was required for the co-adjuvant effect of these cells on matrix remodeling and neoangiogenesis when co-xenografted in nude mice. Finally, in tumor samples from colorectal cancer patients a direct association between stromal SNAI1 expression and the endothelial marker CD34 was observed. In summary, our results advance the understanding of PDGF/SNAI1-activated CAFs in matrix remodeling and angiogenesis stimulation.
Highlights
Emerging evidences indicate that human carcinomas often have significant stromal reactions, characterized by the existence of stromal cells and extracellular matrix proteins[1]
To investigate further the effect of Snail-expressing fibroblasts on the invasion of endothelial cells, we developed an organotypic co-culture system in which control or Snail[1] KO Mouse Embryonic Fibroblasts (MEFs) were embedded in type I Collagen gel plus Platelet-derived growth factor (PDGF) stimulation, and HUVECs were seeded at the top of the gel
In this study, we established for the first time a role for extracellular matrix (ECM) fiber alignment in tumor angiogenesis of colorectal cancer patients via the PDGF/Focal Adhesion Kinase (FAK)/Snail[1] pathway
Summary
Emerging evidences indicate that human carcinomas often have significant stromal reactions, characterized by the existence of stromal cells and extracellular matrix proteins[1]. In solid tumors, including primary and metastatic colorectal cancer (CRC), fibroblasts are the main component of tumor stroma, receiving various names, such as Cancer-Associated Fibroblasts (CAFs)[1]. CAFs are characterized by the upregulation of proteins, such as α-SMA, fibroblast specific protein 1 (FSP1), fibroblast activation protein (FAP) and platelet-derived growth factor receptors (PDGFR)-α/β5,6. High stromal expression or activation of PDGFR-β is associated with poor prognosis in breast, prostate and gastrointestinal tumors[7,8,9,10]. The involvement of PDGF isoforms in both autocrine and paracrine stimulation of tumor growth has been extensively studied[11,12]. PDGF-BB expression, by Herrera et al Oncogenesis (2018)7:76
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