Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments

Abstract

The malignant tumor is a multi-etiological, systemic and complex disease characterized by uncontrolled cell proliferation and distant metastasis. Anticancer treatments including adjuvant therapies and targeted therapies are effective in eliminating cancer cells but in a limited number of patients. Increasing evidence suggests that the extracellular matrix (ECM) plays an important role in tumor development through changes in macromolecule components, degradation enzymes and stiffness. These variations are under the control of cellular components in tumor tissue via the aberrant activation of signaling pathways, the interaction of the ECM components to multiple surface receptors, and mechanical impact. Additionally, the ECM shaped by cancer regulates immune cells which results in an immune suppressive microenvironment and hinders the efficacy of immunotherapies. Thus, the ECM acts as a barrier to protect cancer from treatments and supports tumor progression. Nevertheless, the profound regulatory network of the ECM remodeling hampers the design of individualized antitumor treatment. Here, we elaborate on the composition of the malignant ECM, and discuss the specific mechanisms of the ECM remodeling. Precisely, we highlight the impact of the ECM remodeling on tumor development, including proliferation, anoikis, metastasis, angiogenesis, lymphangiogenesis, and immune escape. Finally, we emphasize ECM "normalization" as a potential strategy for anti-malignant treatment.

Keywords: Cancer metabolism; Collagen orientation; Extracellular matrix; Immune escape; Immunotherapy; Stiffness.

Fig. 1

Receptors for cell-ECM interaction. Matrix changes modulate intracellular signaling in cancer, changes in the extracellular matrix regulate many intracellular signaling pathways. However, the illustration only summarizes familiar receptors in cell-ECM interaction, such as integrins, DDRs, CD44 and syndecans. Other receptors and regulatory networks are precisely introduced in the context

Fig. 2

ECM role in proliferation, cell cycle arrest and anoikis resistance. The changes in ECM proteins, especially the crosslink of collagen, enhance the stiffness of ECM. Receptors sense the mechanic signal form ECM and activates downstream pathways including FAK and YAP/TAZ to induce cell cycle progression and cell-ECM adhesion (A). Moreover, ECM support detachment cell survival, even induce cell cycle arrest in a quiescent state to decrease energy consumption and resist to anoikis (B). Several components support the acquirement of anoikis resistance such as tenascin-C, collagen, HA and PDGFB (C)

Fig. 3

The process and regulatory network during tumor invasion and metastasis within ECM. The metastatic process of cancer cells is similar to a distant journey. EMT, which triggers decreased cell adhesion, confers the initiation of invasion (A). Then cancer cells with anoikis resistance show multiple changes in metabolic process to support energy requirement for cell survival and invasion (B). Thus, a gradient directionality constructed by several ECM components guides them to penetrate through the tissue for hematogenous and/or lymphatic metastasis (C), the activation of which has been stimulated by ECM components (D)

Fig. 4

ECM hampers activation and migration of immune cells. ECM constructed immunosuppressive environment demonstrate various mechanisms to induce immune escape in TME. Firstly, increasing density and modification of ECM components strikingly enhance the stiffness, then hamper immune cell migration into tumor islets by composing a physical barrier or directly cell-ECM surface inhibition (via interaction or receptors such as DDRs and LAIR-1). Moreover, tenascin-C immobilizes T cells with immunosuppressive cells and stromal cell, thus immune cells are fixed in the ECM. Finally, OPN stimulates PD-1/PD-L1 expression in immune cells, thus induce immunosuppression

Fig. 5

The diagram of ECM-targeting treatment. Several strategies targeting ECM could be optimal selections for anti-cancer therapy. However, these strategies are far from the clinical application. Further investigation is needed to verify the therapeutic effect of these strategies