Fig. 2. ECM remodelling in the primary tumour.

a, b Tumour-derived factors activate stromal cells which differentiate into cancer-associated fibroblasts (CAFs) leading to the secretion and deposition of large amounts of ECM components along with the cancer cells. c ECM-modifying enzymes such as LOX expressed by tumour cells and CAFs cross-link and align collagen fibres, which increases matrix stiffness around the tumour, and e the formation of a physical barrier to evade immune surveillance by T-cells. d Increased matrix stiffness promotes the interaction between ECM components and cell-surface receptors on tumour cells that triggers mechanosignalling mediated by integrins. f To sustain a tumourigenic microenvironment, tumour cells and resident immune cells secrete cytokines, chemokines and growth factors (GFs), which differentiate and recruit bone marrow-derived cells (BMDCs). g The BMDCs, CAFs and tumour cells secrete ECM-degrading proteases, including MMPs, which are cell surface-bound (e.g., MT1-MMP) or secreted (e.g., MMP-9). h Proteolytic ECM degradation generates bioactive matrikines and i releases matrix-bound GFs. These factors induce pro-tumourigenic ECM signalling that promotes tumour proliferation, migration, invasion and angiogenesis. j These combined changes to the ECM create a hypoxic environment. Neutrophils secrete potent MMP-9 that degrades ECM and releases matrix-bound VEGF that forms a concentration gradient for new angiogenic sprouting. k Stimulated by dense ECM, the tumour cells may gain endothelial-like functions and mimic the vasculature that connects to blood vessels.