Abstract
Normal tissue homeostasis and architecture restrain tumor growth. Thus, for a tumor to develop and spread, malignant cells must overcome growth-repressive inputs from surrounding tissue and escape immune surveillance mechanisms that curb cancer progression. This is achieved by promoting the conversion of a physiological microenvironment to a pro-tumoral state and it requires a constant dialog between malignant cells and ostensibly normal cells of adjacent tissue. Pro-tumoral reprogramming of the stroma is accompanied by an upregulation of certain extracellular matrix (ECM) proteins and their cognate receptors. Fibronectin (FN) is one such component of the tumor matrisome. This large multidomain glycoprotein dimer expressed over a wide range of human cancers is assembled by cell-driven forces into a fibrillar array that provides an obligate scaffold for the deposition of other matrix proteins and binding sites for functionalization by soluble factors in the tumor microenvironment. Encoded by a single gene, FN regulates the proliferation, motile behavior and fate of multiple cell types, largely through mechanisms that involve integrin-mediated signaling. These processes are coordinated by distinct isoforms of FN, collectively known as cellular FN (as opposed to circulating plasma FN) that arise through alternative splicing of the FN1 gene. Cellular FN isoforms differ in their solubility, receptor binding ability and spatiotemporal expression, and functions that have yet to be fully defined. FN induction at tumor sites constitutes an important step in the acquisition of biological capabilities required for several cancer hallmarks such as sustaining proliferative signaling, promoting angiogenesis, facilitating invasion and metastasis, modulating growth suppressor activity and regulating anti-tumoral immunity. In this review, we will first provide an overview of ECM reprogramming through tumor-stroma crosstalk, then focus on the role of cellular FN in tumor progression with respect to these hallmarks. Last, we will discuss the impact of dysregulated ECM on clinical efficacy of classical (radio-/chemo-) therapies and emerging treatments that target immune checkpoints and explore how our expanding knowledge of the tumor ECM and the central role of FN can be leveraged for therapeutic benefit.
Highlights
Studies addressing the genesis and progression of cancer have focused on the genotype of tumor cells
In a single-cell transcriptomic analysis of oral squamous cell carcinomas, extracellular matrix (ECM) genes that are often linked with EMT (e.g., TGFBI, LAMC2, tenascin C) were found to be upregulated in carcinoma cells. Their expression was enhanced in a subset of tumor cells displaying a partial EMT phenotype and located in close apposition to surrounding stroma, as determined by immunohistochemistry [12]. These results indicate that paracrine signals from the stromal compartment trigger ECM gene expression in leading-edge cancer cells and they suggest a role for the upregulated matrix proteins in tumor invasion
Whereas suppression of myeloid cell homing to tumors using α4β1 antagonists appears to be an effective approach to impede tumor angiogenesis and growth, depletion of the integrin in a mouse model of colon adenocarcinoma resulted in an age-dependent effect and accelerated tumor growth in mature mice [232]
Summary
Studies addressing the genesis and progression of cancer have focused on the genotype of tumor cells. The tumor-promoting effects of CAFs have been widely investigated and include the enhancement of cell proliferation, survival, migration/invasion, angiogenesis, chemoresistance, and immunosuppression, as detailed in recent reviews [18,19,20] Their activity is mediated through the secretion of a plethora of growth factors, cytokines and exosomes, and through the production and remodeling of the ECM. Similar to TGF-β, platelet-derived growth factor (PDGF) and fibroblast growth factor 2 (bFGF/FGF2) play critical roles in myofibroblast activation and fibrosis [40,41,42] In cancer, they were found to regulate CAF activation and αSMA expression as well, their effects varied depending on the cell types examined [32, 43,44,45,46].
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