Reciprocal Interplay Between Fibrillar Collagens and Collagen-Binding Integrins: Implications in Cancer Progression and Metastasis

Abstract

Cancers are complex ecosystems composed of malignant cells embedded in an intricate microenvironment made of different non-transformed cell types and extracellular matrix (ECM) components. The tumor microenvironment is governed by constantly evolving cell-cell and cell-ECM interactions, which are now recognized as key actors in the genesis, progression and treatment of cancer lesions. The ECM is composed of a multitude of fibrous proteins, matricellular-associated proteins, and proteoglycans. This complex structure plays critical roles in cancer progression: it functions as the scaffold for tissues organization and provides biochemical and biomechanical signals that regulate key cancer hallmarks including cell growth, survival, migration, differentiation, angiogenesis, and immune response. Cells sense the biochemical and mechanical properties of the ECM through specialized transmembrane receptors that include integrins, discoidin domain receptors, and syndecans. Advanced stages of several carcinomas are characterized by a desmoplastic reaction characterized by an extensive deposition of fibrillar collagens in the microenvironment. This compact network of fibrillar collagens promotes cancer progression and metastasis, and is associated with low survival rates for cancer patients. In this review, we highlight how fibrillar collagens and their corresponding integrin receptors are modulated during cancer progression. We describe how the deposition and alignment of collagen fibers influence the tumor microenvironment and how fibrillar collagen-binding integrins expressed by cancer and stromal cells critically contribute in cancer hallmarks.

Keywords: cancer; extracellular matrix; fibrillar collagens; integrins; metastasis.

Figure 1

Evolution of fibrillar collagen organization during tumor progression. The transition from a benign tumor to an in situ carcinoma is associated with a progressive reorganization of the tumor microenvironment. Epithelial cells are separated from the stroma by a continuous basement membrane. Tumor-derived paracrine signals promote a desmoplasic reaction characterized by the activation of the resident fibroblasts into cancer-associated fibroblasts (CAFs) able to secrete and reorganize the collagen fibers (cross-linking), thereby increasing the stiffness of the stroma. Tumor-associated macrophages (TAMs) are also recruited and contribute to collagen remodeling. When invasive cancer cells have breached the basement membrane, they become confronted with the collagen-rich desmoplasic stroma. The collagen fibers located in the vicinity of the invading cancer cells can be organized parallel to the tumor border (Tumor Associated Collagen Signature—TACS-2) or linearized and oriented perpendicular to the tumor border (TACS-3), thereby promoting the migration of invading cancer cells.

Figure 2

Type I collagen supramolecular assembly pathway. The standard fibrillar collagen molecule is characterized by N- and C-terminal propeptide sequences, which flank a series of Gly-X-Y repeats (where X and Y represent any amino acids but are frequently proline and hydroxyproline). These form the central triple helical structure of procollagen and collagen. Three precursor α-chains (two α1 and one α2) are co-translationally translocated into the endoplasmic reticulum lumen, where specific post-translational modifications occur. Three collagen α-chains associate specifically via their C-terminal domains to form heterotrimers. The helical collagens are trafficked via the Golgi network to the plasma membrane, and secreted into the extracellular space as precursor forms, called procollagens, with N- and C-terminal non-collagenous domains. These domains are removed by the action of specific proteases, and the collagens are assembled into dense fibrils with a characteristic D-periodicity of about 67 nm (A). The fibril is stabilized by covalent lysine- and hydroxylysine-derived crosslinks. In addition to fibrillar collagen, other collagens, such as type V and FACIT collagens, are incorporated into the fibril structure (B). Type V collagen is inserted between strands of the microfibril, and FACIT collagens cling to the surface of the microfibril and work to stabilize higher order structures. Adapted from (38).

Figure 3

Supramolecular structures formed by some archetypal collagens. Fibrillar collagens and FACITs fibrils: the association of mature protomers together leads to the formation of microfibrils which in turn assemble into fibrils. FACITs protomers attach at the surface of fibers with the C-terminal part protruding and regulate fibrillogenesis. Basement membrane and anchoring fibrils: formation of type IV collagen dimer occurs by the association of two protomers through their globular NC C-terminal domain. Dimers interact together through their N-terminal domains to constitute tetramers. Networks are the result of the two first steps linked to additional lateral interactions between the molecules. Dimers of type VII collagen interact with the network of type IV collagen. Beaded collagen: an association between the type VI collagen dimer and tetramer takes place inside the cells. Connection of tetramers leads to the formation of long filaments called “beaded filaments” according to their appearance in electron microscopy. Hexagonal networks: collagens VIII and X form hexagonal networks in Descemet's membrane and in hypertrophic cartilage, respectively. Multiplexin: collagens XVIII and XV are found in basement membrane. MACITs: transmembrane collagens (XIII, XVII, XXIII, and XXV). The N-terminal NC domain (N-terminal NC) is located inside the cell, whereas the triple helix region is extracellular. NC, non-collagenous domain. Adapted from (41).

Figure 4

Influence of 11 fibrillar collagen gene expression on patient prognosis outcome in 13 different cancers. Hazard ratio (HR) and log-rank p-values were calculated using the pan-cancer RNA-seq Kaplan-Meier plotter (182). (A) Kaplan-Meier plot showing that patients with a high COL2A1 gene expression (red lines) have a higher overall survival than those with a low gene expression (black lines). (B) Kaplan-Meier plot showing that patients with a high COL5A1 gene expression (red lines) have a lower overall survival than those with a low gene expression (black lines). HR and 95% confidence interval are shown. Log-rank P < 0.05 was considered to indicate statistical significance. (C) Summary of HR (bold) and log-rank p-values (italic) for 11 fibrillar collagen genes in 13 different cancers. Collagen genes whose mRNA levels were significantly associated with patient's overall survival in a specific cancer were color coded according to the log-rank p-values and HR (unfavorable prognosis: yellow to red; favorable prognosis: light to dark green).

Figure 5

Second harmonic generation (SHG) image of fibrillar collagens. (A) SHG image of in vitro polymerized collagen I. (B) SHG of a mouse mammary PyMT tumor section. Collagen fibers appear in blue, while the cellular structures appear in green due to the autofluorescence of the sample.

Figure 6

Illustration of direct (collagen-binding integrin-mediated) and indirect (COLINBRI-mediated) integrin heterodimers binding to collagen fibrils. Inactive integrins adopt a compact conformation in which the α- (red/purple) and β-subunit (black) are closely associated. Intracellular signals, culminating in the binding of talin to the β-subunit tail, lead to conformational changes that result in increased affinity for extracellular ligands. The primed integrin binds ligand, which represents the end-point of inside-out signaling. The binding of talin and ligand initiate focal contact formation. As the cytoskeleton matures, tension (green arrows) is generated on the integrin receptor across the cell membrane. The force applied to the integrin strengthens receptor-ligand binding and allows the formation of stable focal adhesions and the initiation of intracellular signaling cascades (red arrow), the end-point of outside-in signaling. In the direct cell-binding mechanism, collagen-binding integrins directly interact with the GFOGER sequence of fibrillar collagen to provide cell adhesion. In the indirect way, cell binding involves COLINBRIs like fibronectin represented here in blue. The COLINBRI molecule is anchored to collagen and provides cell attachment by interaction with the COLINBRI-binding integrins.