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The fibrotic tumor stroma
Mitsuo Yamauchi, … , Don L. Gibbons, Jonathan M. Kurie
Mitsuo Yamauchi, … , Don L. Gibbons, Jonathan M. Kurie
Published January 2, 2018
Citation Information: J Clin Invest. 2018;128(1):16-25. https://doi.org/10.1172/JCI93554.
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Review Series

The fibrotic tumor stroma

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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.

Authors

Mitsuo Yamauchi, Thomas H. Barker, Don L. Gibbons, Jonathan M. Kurie

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Figure 1

The provisional matrix primes for fibrosis.

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The provisional matrix primes for fibrosis.
Early provisional matrix is ...
Early provisional matrix is primarily composed of fibrin. Fibrin interacts with macrophage-1 antigen (Mac-1) to upregulate proinflammatory cytokines that signal to resident and invading immune cells as well as stromal cell populations. The degradation products of fibrin play a key role in angiogenesis, leading to persistent activation of the coagulation cascade and promoting fibrin persistence. Increases in fibronectin indicate a shift to late provisional extracellular matrix (ECM) and serve as scaffolding for growth factors and mechanical signaling. At this stage, an increasingly stiff ECM serves as a template for collagen (Col) deposition. Finally, mature ECM is characterized by increased density of type I collagen as well as the ability to resist degradation and repetitive mechanical stress. FN, fibronectin; MIP-2, macrophage inhibitory protein-2; PAI-1, plasminogen activator inhibitor-1.
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