Dynamic interplay between the collagen scaffold and tumor evolution

Abstract

The extracellular matrix (ECM) is a key regulator of cell and tissue function. Traditionally, the ECM has been thought of primarily as a physical scaffold that binds cells and tissues together. However, the ECM also elicits biochemical and biophysical signaling. Controlled proteolysis and remodeling of the ECM network regulate tissue tension, generate pathways for migration, and release ECM protein fragments to direct normal developmental processes such as branching morphogenesis. Collagens are major components of the ECM of which basement membrane type IV and interstitial matrix type I are the most prevalent. Here we discuss how abnormal expression, proteolysis and structure of these collagens influence cellular functions to elicit multiple effects on tumors, including proliferation, initiation, invasion, metastasis, and therapy response.

Figure 1. Changes in the type I collagen scaffold with tumor progression

(A) Relative levels of stromal vs. epithelial expression of type I collagen, the collagen crosslinking enzyme lysyl oxidase (LOX) and the collagenolytic matrix metalloproteinases (MMPs) during tumor progression. In early stage tumors, LOX is high in the stromal cells, and in late stage tumors, its expression also increases in carcinoma cells. In late stage tumors, the carcinoma cells begin to express an increased ratio of the α1-chain to α2-chain of type I collagen. The net result is an increase in both the normal type I collagen α1,α1,α2,-heterotrimer and in an MMP-resistant type I collagen α1,α1,α1,-homotrimer. The carcinoma-associated changes in collagen and collagen remodeling enzymes modify the architecture of the collagen scaffold such that early, thin and relaxed collagens (curly fibrils) progressively thicken and linearize coinciding with tumor progression and invasion. (B) Inhibition of collagen crosslinking through LOX-inhibition prevents collagen remodeling and maintains a normal collagen architecture. Photomicrographs are from [19] and reprinted with permission.

Figure 2. Cellular effects of the collagen scaffold in carcinomas

Types I and IV collagen influence multiple steps in tumor evolution. Type IV collagen is degraded as carcinomas break through the basement membrane to invade. It is breached again as cells intravasate en route to form metastases. Proteolysis of type IV collagen in vascular basement membranes results in generation of fragments with anti-angiogenic activity acting through integrins. Type I collagen fibers mediate invasion at several levels. Uncleaved fibers may act as “highways” for cell migration, possibly facilitated by macrophages. Both integrin and discoidin domain receptor (DDR) mediated signaling can facilitate cell invasion. This type of invasion may also require the generation of pathways through the collagen scaffold by proteolysis. The immune reaction against tumors may be regulated by collagen: most immune cells express leukocyte-associated Ig-like receptors (LAIRs), which upon collagen binding inhibits immune cell activation. Macrophages may also be regulated by type I collagen fragments, which are chemotactic for macrophage precursors and possibly involved in regulation of their polarization.