The fibrotic tumor stroma

Abstract

Intratumoral fibrosis results from the deposition of a cross-linked collagen matrix by cancer-associated fibroblasts (CAFs). This type of fibrosis has been shown to exert mechanical forces and create a biochemical milieu that, together, shape intratumoral immunity and influence tumor cell metastatic behavior. In this Review, we present recent evidence that CAFs and tumor cells are regulated by provisional matrix molecules, that metastasis results from a change in the type of stromal collagen cross-link, and that fibrosis and inflammation perpetuate each other through proteolytic and chemotactic mediators released into the tumor stroma. We also discuss aspects of the emerging biology that have potential therapeutic value.

Fibronectin in Cancer: Friend or Foe

“…The mutual interactions between parenchymal cells that endure the process of oncogenic stresses and transformation and stromal microenvironments harboring mesenchymal cells endow tumorigenesis and tumor progression [26,137]. In contrast to the significant downregulation of FN in tumor cells in primary tumor tissues, FN that is deposited in the ECM of TMEs plays an important role in promoting tumor progression, including tumor cell growth, migration, invasion, angiogenesis, and intravasation [13,[138][139][140][141][142][143][144][145][146][147][148]. However, how FN production and FN matrix deposition and organization are regulated by tumor cells has been less understood.…”

“…Here, we attempt to propose possibilities. The ECM-depositing FN can be derived from either plasma [149] or various cell types, of which fibroblasts and macrophages have especially drawn attention [136,145,150] (Figure 2). Endothelial cells and their cell-to-cell junctions are essential in maintaining vascular integrity and vascular permeability to plasma and cells [151].…”

“…However, when endothelia are situated within tumor tissues where tumor cells release factors to trigger angiogenesis with altered junctional compositions [154,155], hyperpermeability of tumor vessels renders pro-tumor leukocyte recruitment and persistent influx of plasma molecules, e.g., FN and fibrin, into chronic inflammatory TMEs, consequently facilitating tumor growth, migration/invasion, and intravasation [149,153,[156][157][158]. Fibroblasts surrounding tumor cells are generally considered as the main professional matrix producers called CAFs [145,159,160]. In the beginning of oncogenic processes, pro-inflammatory cytokines in non-autonomous SASP [113,161], produced and secreted by the senescent parenchymal cells that suffer diversity of stresses, are essentially responsible for the alteration of surrounding microenvironments, including fibroblast activities [162,163].…”

Transcriptome analysis of IPF fibroblastic foci identifies key pathways involved in fibrogenesis

“…[1] Fibrosis can also influence cancer progression as part of the stromal response to the tumour. [2] Current anti-fibrotic drugs, pirfenidone and nintedanib, approved for the treatment of IPF, slow rather than halt disease progression and have significant side-effect profiles. [3, 4] There therefore remains an urgent need to develop novel therapeutic strategies for IPF and other fibrotic conditions.…”

Targeting integrin alpha5 receptor in pancreatic stellate cells to diminish tumor-promoting effects in pancreatic cancer

“…The abundant desmoplastic stroma reaction in pancreatic tumors has been recognized for inducing aggressive tumor growth, distant metastasis, resistance to drug therapy and acting as a barrier to drug delivery 32 . Targets within the tumor stroma are therefore under intensive investigation to improve prognosis by developing novel therapeutics to hamper stromal tumor-promoting function.…”