Dynamic interplay between the collagen scaffold and tumor evolution

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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.

Introduction

Many of the processes that regulate tissue and organ development are hijacked in cancer [1]. For example, the epithelial migration and invasion occurring in mammary carcinomas are morphologically and molecularly similar to epithelial branching morphogenesis in mammary gland development [2, 3]. However, while epithelial invasion is stringently regulated in development, solid tumors display deregulated and persistent invasion. In both instances, the extracellular matrix (ECM) provides a physical scaffold for cell adhesion and migration, it influences tissue tension and it signals to cells through ECM receptors. Proteolysis of the ECM regulates cellular migration by modifying the structure of the ECM scaffold and by releasing ECM fragments with biological functions. ECM proteolysis is therefore tightly controlled in normal tissues but typically deregulated in tumors.

Collagens are major constituents of the ECM, representing as much as 30% of total mammalian protein mass ([4], see Box 1). Type I collagen is the main structural protein in the interstitial ECM [5]. Type IV collagen is a key component of the basement membrane (BM), which is found at the basal surface of epithelial and endothelial cells and is essential for tissue polarity [6]. Epithelial invasion in both branching morphogenesis and cancer requires that the cells must interact with these collagens. The BM is breached as both normal and transformed epithelial cells invade into the interstitial tissue. It is also compromised at the site of the vasculature by metastasizing cancer cells [7].

Section snippets

The desmoplastic response in cancer

Fibrosis is an accumulation of ECM proteins, including type I collagen [8]. Organ fibrosis and cancer are associated, although the association may simply reflect collagen accumulation due to increased activity of inflammatory and tumorigenic factors such as TGF-β [9]. Nevertheless, many malignancies are associated with a strong fibrotic reaction, termed ‘desmoplasia’, which is characterized by an accumulation of fibrillar collagen types I and III and increased degradation of type IV collagen [10

Architectural changes of fibrillar collagen in cancer

The architecture of the collagen scaffolds in tumors is severely altered. Tumor-associated collagens are often linearized and crosslinked reflecting elevated deposition and significant posttranslational modification ([18, 19••] and Figure 1). This physical restructuring of interstitial collagen progressively stiffens the ECM which thereafter elicits diverse effects on cellular differentiation, gene expression, proliferation, survival and migration [20, 21••, 22, 23••]. These cellular effects

Collagen fibers as highways for migration

The collagen fibers surrounding the normal epithelial structures in soft tissues such as the mammary gland and lung are typically curly and anisotropic. However, following tumor initiation many of the fibers progressively thicken and linearize ([18, 19••], and Figure 1a). This linearization is most notable adjacent to the tumor vasculature and in areas with cancer cell invasion [18, 19••, 36]. Linearized fibers are stiffer than curly ones and the resulting increased ECM stiffness can

Proteolysis of collagen  effects on cancer beyond path generation

Although cells migrate along collagen fibers, collagen in tissues also represents a physical barrier against invasion [44]. Thus, collagen degradation by proteases, including cathepsins and MMPs, and uptake of the degraded collagen is important for cancer cell invasion [10, 45•, 46]. For many cells, proteolysis of types I and IV collagen is essential for migration through the ECM [7•, 45•, 47, 48, 49]. Proteolysis of the ECM generates pathways for cells to migrate through [50•, 51, 52••, 53].

Collagen as a regulator of response to therapy

Resistance to cancer therapy can be caused by cancer cell intrinsic mechanisms, such as overexpression of anti-apoptotic genes, but factors in the tumor microenvironment can also regulate therapy response [1].

Types I and IV collagen can induce chemoresistance by directly interacting with integrins on cancer cells [70, 71••]. The level and structural organization of collagen can also indirectly influence therapeutic efficacy by regulating drug delivery. In many tumors, drug delivery is impaired

Interactions between collagen and the tumor immune infiltrate

A variety of immune cells are present in tumors and many of these accumulate and migrate within regions of dense fibrillar collagen [36, 38, 82]. How might the dense fibrillar collagen influence the function of immune cells? ECM stiffness promotes integrin-mediated adhesion assembly [21••], which could influence, for example, T cell activation. Another possibility is via collagen-mediated activation of leukocyte-associated Ig-like receptors (LAIRs). LAIRs are highly expressed on most immune

Collagen and regulation of differentiation

Matrix stiffness can determine stem cell lineage specification and direct mesenchymal stem cell differentiation into bone, neurons or muscle cells [92]. During bone development, inhibition of MMP-mediated cleavage of type I collagen leads to osteopenia, a loose bone structure, rather than increased bone formation [93], suggesting that an abnormal collagen scaffold modifies the balance between bone-forming osteoblasts and bone-resorbing osteoclasts. Indeed, the collagenolytic activity of MMP-14

The challenges ahead

The overall architecture of the ECM is affected by collagen concentration, posttranslational modification (e.g. crosslinking) and proteolysis. In cancer, all of these levels of collagen metabolism are deregulated, resulting in an abnormal ECM architecture. However, to determine how this influences tumor evolution is challenging.

The study of the effects of collagen architecture on tumor evolution using in vitro assays has been informative, but a major concern is the ability to accurately

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank Dr. Mark Sternlicht for his contribution to Figure 1. This work was supported by NIH grants U01CA141451 to ME and U54CA143836 and CA138818-01A1 to VMW and DOD grant W81XWH-05-1-0330 to VMW, as well as funding from the Breast Cancer Alliance, the Susan G Komen for the Cure, and Long Island 2 Day Walk to Fight Breast Cancer to ME. MGR was supported by Rigshospitalet, Augustinus fonden, Dagmar Marshalls fond, and the European Association for Cancer Research (EACR).

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