Collagen as a double-edged sword in tumor progression

Abstract

It has been recognized that cancer is not merely a disease of tumor cells, but a disease of imbalance, in which stromal cells and tumor microenvironment play crucial roles. Extracellular matrix (ECM) as the most abundant component in tumor microenvironment can regulate tumor cell behaviors and tissue tension homeostasis. Collagen constitutes the scaffold of tumor microenvironment and affects tumor microenvironment such that it regulates ECM remodeling by collagen degradation and re-deposition, and promotes tumor infiltration, angiogenesis, invasion and migration. While collagen was traditionally regarded as a passive barrier to resist tumor cells, it is now evident that collagen is also actively involved in promoting tumor progression. Collagen changes in tumor microenvironment release biomechanical signals, which are sensed by both tumor cells and stromal cells, trigger a cascade of biological events. In this work, we discuss how collagen can be a double-edged sword in tumor progression, both inhibiting and promoting tumor progression at different stages of cancer development.

Fig. 1

Biosynthesis of collagen. Three polypeptide α-chains each including an N- and C-terminal propeptides form triple helical structures called procollagen triple helix by lysly hydroxylase, protein disulfide isomerase and hydrogen bonds. Neutral strands are stable, but charged forms are unstable. Tropocollagen triple helix is formed as N- and C-terminal propeptides are converted into N- and C-terminal peptides by N- and C-proteinases. Under lysyl oxidase (LOX) cross-linking and self-assembly, collagen fibers or networks are formed

Fig. 2

Type IV collagen expression demonstrated by quantum dot-525 (green). a Abundant type IV collagen fragments stochastically distributed in tumor tissues. b Rich type IV collagen in tumour stroma aligning with tumor nests. c, d Different characteristics between HCC (red star) and live cirrhosis (LC) tissues. Red arrowheads show stiff type IV collagen at interface of liver cirrhosis and tumor nests. Red arrows indicate the linear invasion "highways" for tumor cells escape. Scale bar = 50 μm

Fig. 3

The role of LOX in tumor progression both in situ and distal organs. With tumor growth beyond 2 mm in diameter, prominent central hypoxia induces tumor cells to secrete LOX into tumor milieu. On the one hand, LOX-mediated type IV collagen cross-linking leads to ECM deposition and subsequent tissue stiffness, driving malignant progression predominantly by altering integrin focal adhesions and actomyosin- and cytoskeletal-dependent cell contractility. Tumor cells stretch pseudopodia protrusions with increased actin polymerization, focal adhesion formation and focal adhesion kinase that can in turn enhance tumor cells proliferation, migration, invasion, and perhaps tumor angiogenesis. On the other hand, LOX is disseminated into target organs (lung in this illustration) via circulation and deposits at terminal bronchioles and distal alveoli. The deposited LOX can crosslink type I and IV collagens to remodel ECM for recruiting BMDCs, so as to form the pre-metastatic niche

Fig. 4

Force applied to deform and influence the biological behavior of tumor cells. Tissue microenvironment can exert three forms of force on tumor cells, including shear stress, compressive stress and tensile stress

Fig. 5

A paradigm for how tumor and stromal cells interact to degrade ECM and change tensions for tumor invasion. a1 Dormant tumor cells without tension force; a2 collagen relaxed and elastic. b1 With tumor growth, low tension force exerts on collagen which stretches accordingly; b2 Entrance hole for MMPs-dependent cleavage is closed as collagen stretches. c1 As the tumor continues to expand, increasing tension force transmits signals to both tumor and stromal cells to remodel ECM in order to reduce tension force. Tumor and stromal cells undergo EMT process which in turn increase their traction force; c2 collagen bends and changes conformational structures correspondingly. d1 High traction force exerted by cells destabilize the stroma; d2 tumor and stromal cells attach to collagen and unwind triple helix, exposing sites for cleavage by MMPs. e1 Tumor invasion and metastasis occur with degradation of collagen; e2 MMPs enter into triple helix to cleave α-chains

Fig. 6

Collagen regulates tumor associated immune infiltration. MMP-dependent collagen fragments can recruit monocytes and further promote them to differentiate into TAMs with the help of CSF-1. TAMs themselves secret factors responsible for tumor progression, including tumor angiogenesis. Meanwhile, they themselves can activate MMPs to degrade collagens