Figure 1.

Main metabolic and extracellular matrix (ECM) alterations in the tumor microenvironment (TME) during tumor progression. During cancer progression, tumor cells increase lactate production, leading to an acidification of TME. Tumor cells, cancer-associated fibroblasts (CAFs), polymorphonuclear leukocytes (PMNs), and monocytes secrete proteases, such as matrix metalloproteinases (MMPs), that degrade ECM and release matrikines. CAFs induce a higher secretion of ECM macromolecules that leads to an excessive deposition of ECM components. Tumor cells, PMNs, and monocytes produce reactive oxygen species (ROS) that degrade ECM components and particularly collagen I, facilitating tumor cell migration. They also stimulate the production of MMPs. Hypoxia also induces hypoxia-inducible factor (HIF) stabilization, lysyl oxidase (LOX) and transglutaminase activation, collagen and elastin cross-linking leading to ECM stiffening. These events favor tumor cell migration and cancer progression.