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.

Figure 1. The provisional matrix primes for fibrosis.

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.

Figure 2. Collagen cross-linking in fibrosis and cancer.

(A) Transmission electron microscopic image of tumor tissue showing dense type I collagen fibrils (reprinted with permission from the Journal of Biological Chemistry, ref. 126). Rectangle indicates a single fibril. Below, a sketch represents type I collagen molecules (wavy lines) packed in a fibril in parallel and staggered with respect to one another by approximately 67 nm. (B) Cross-linking sites of adjacent collagen molecules. Initial cross-links are indicated by dashed lines. Two telopeptidyl lysine aldehydes (O=CH) can cross-link within the same molecule (intramolecular cross-link). Telopeptidyl lysine- and hydroxylysine-aldehyde (O=CH) can condense with ε-amino groups (NH₂) of juxtaposed helical lysine or hydroxylysine residues to form intermolecular cross-links. Helical cross-linking hydroxylysine residues near the N-terminus are one of the major glycosylation sites (galactose or galactose-glucose indicated in tan) in type I collagen, contributing to glycosylated cross-linking. (C) Major cross-linking pathways characterized in fibrotic and cancer tissues (for comprehensive cross-linking pathways, see ref. 65). Lysyl oxidases (LOXs) initiate cross-linking by converting lysine or hydroxylysine residues in the telopeptides to aldehyde (t-Lys^ald and t-Hyl^ald, respectively). Then the aldehyde condenses with another t-Lys^ald in the same molecule or juxtaposed helical Lys (h-Lys) or Hyl (h-Hyl) on a neighboring molecule. These divalent cross-links can then mature into tri- and tetravalent cross-links. All cross-links are intermolecular cross-links except an aldol condensation product (ACP). In fibrosis and cancer, the pathway is driven toward LH2-mediated Hyl^ald-derived pathway, as indicated by blue boxes (115). d, deoxy; deH, dehydro; DHLNL, dihydroxylysinonorleucine; h, helical; HHMD, histidinohydroxymerodesmosine; HLNL, hydroxylysinonorleucine; LH2, lysyl hydroxylase-2; Pyr, pyridinoline; t, telopeptidyl.

Figure 3. Interconnections between cells in the tumor microenvironment regulate ECM composition and immune surveillance.

ECM, extracellular matrix; MDSC, myeloid-derived suppressor cell.