Collagens and Cancer associated fibroblasts in the reactive stroma and its relation to Cancer biology

Abstract

The extracellular matrix (ECM) plays an important role in cancer progression. It can be divided into the basement membrane (BM) that supports epithelial/endothelial cell behavior and the interstitial matrix (IM) that supports the underlying stromal compartment. The major components of the ECM are the collagens. While breaching of the BM and turnover of e.g. type IV collagen, is a well described part of tumorigenesis, less is known regarding the impact on tumorigenesis from the collagens residing in the stroma. Here we give an introduction and overview to the link between tumorigenesis and stromal collagens, with focus on the fibrillar collagens type I, II, III, V, XI, XXIV and XXVII as well as type VI collagen. Moreover, we discuss the impact of the cells responsible for this altered stromal collagen remodeling, the cancer associated fibroblasts (CAFs), and how these cells are key players in orchestrating the tumor microenvironment composition and tissue microarchitecture, hence also driving tumorigenesis and affecting response to treatment. Lastly, we discuss how specific collagen-derived biomarkers reflecting the turnover of stromal collagens and CAF activity may be used as tools to non-invasively interrogate stromal reactivity in the tumor microenvironment and predict response to treatment.

Clinical value of serum hyaluronan and propeptide of type III collagen in patients with pancreatic cancer

“…41 [27,60] 7 [5,9] 1 p < 0.001 compared to healthy controls. 2 p < 0.001 compared to benign conditions.…”

“…The ECM in the tumor stroma undergoes excessive remodeling. The increased activity of PSC/fibroblasts leads to excessive formation and accumulation of interstitial collagens . HA and collagen accumulation increase tumor solid stress and interstitial fluid pressure (IFP), compromising blood vessels, circulation, perfusion and drug penetration .…”

“…The increased activity of PSC/fibroblasts leads to excessive formation and accumulation of interstitial collagens. 27 HA and collagen accumulation increase tumor solid stress and interstitial fluid pressure (IFP), compromising blood vessels, circulation, perfusion and drug penetration. 21,[28][29][30][31] The prognostic value of HA and collagen deposition in PC tissue has been described in a few studies.…”

Prolyl 4‐hydroxylase subunit alpha 1 (P4HA1) is a biomarker of poor prognosis in primary melanomas, and its depletion inhibits melanoma cell invasion and disrupts tumor blood vessel walls

“…This compromises the overall tissue integrity and leads to rupture of blood vessel walls and hemorrhages. Besides providing structural support, collagens also give signaling cues to cells and may regulate cell proliferation, apoptosis, angiogenesis, invasion, and metastasis (Fidler et al , ; Nissen et al , ; Wu and Ge, ). Further, our results show that P4HA1 knockdown reduced the secretion of CTHRC1, an important mediator of melanoma cell migration and invasion, in vitro and its deposition around tumor blood vessels in vivo , suggesting that this angiogenesis‐promoting molecule may also play an important role in P4HA1‐regulated neovascularization.…”

Interactive dynamics of matrix adhesion and reaction-diffusion predict diverse multiscale strategies of cancer cell invasion

“…and their surrounding tissue microenvironment at biochemical and/or biophysical levels shape the nature of their migration (Anderson, 2005) (Nissen et al, 2019).…”