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Review
. 2020 Jan 31:6:160.
doi: 10.3389/fmolb.2019.00160. eCollection 2019.

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

Erik Henke  1 , Rajender Nandigama  1 , Süleyman Ergün  1
Affiliations
Review

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

Erik Henke et al. Front Mol Biosci. .

Abstract

Solid tumors are complex organ-like structures that consist not only of tumor cells but also of vasculature, extracellular matrix (ECM), stromal, and immune cells. Often, this tumor microenvironment (TME) comprises the larger part of the overall tumor mass. Like the other components of the TME, the ECM in solid tumors differs significantly from that in normal organs. Intratumoral signaling, transport mechanisms, metabolisms, oxygenation, and immunogenicity are strongly affected if not controlled by the ECM. Exerting this regulatory control, the ECM does not only influence malignancy and growth of the tumor but also its response toward therapy. Understanding the particularities of the ECM in solid tumor is necessary to develop approaches to interfere with its negative effect. In this review, we will also highlight the current understanding of the physical, cellular, and molecular mechanisms by which the pathological tumor ECM affects the efficiency of radio-, chemo-, and immunotherapy. Finally, we will discuss the various strategies to target and modify the tumor ECM and how they could be utilized to improve response to therapy.

Keywords: ECM; cancer therapy; chemotherapy (CH); drug transport; extracellular matrix; immunotherapy; radiotherapy; tumor microenvironment.

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Figures

Figure 1
Figure 1
How the ECM affects the efficacy of systemic treatment. Systemically applied drugs, independently of their nature being small molecules or larger biomolecules, e.g., antibodies, peptides, or nucleic acids, have to reach their target cells and cause a therapeutic response. The abundant, highly cross-linked ECM interferes with the efficacy in both direct and indirect ways. (A) The rigid dense ECM acts as a diffusion barrier that impedes access of the drugs to the tumor cells, thereby acting as a shield protecting the tumor from therapeutically effective doses. (B) The reduced diffusion through the ECM also impairs supply with nutrients and oxygen. Pathological signaling in response to metabolic stress and hypoxia increase expression of drug efflux pumps and impair apoptosis and senescence, rendering drugs that reach the undersupplied cells less effective. (C) Direct contact with the ECM also affects these pathways that lead to a muted response to cytotoxic stress. Integrin and FAK activation increase prosurvival signaling, reduce apoptotic response, and help the cells to avoid cell cycle arrest when confronted with chemotherapy-induced damage. (D) Similarly, not only integrin and FAK but also hyaluronan induced CD44/HMMR signals can lead to EMT. The mesenchymal state is characterized by stem-like, chemoresistant traits. This includes again not only upregulation of ABC transporters and reduced proliferation but also activation of cell metabolism (cytochrome p450) that improves detoxification. That EMT also seems to increase collagen synthesis, and production of cross-linking enzymes in tumor cells might lead to a vicious cycle where the dense ECM induces EMT that again drives ECM build-up.
Figure 2
Figure 2
How the ECM affects the efficacy of immunotherapy. (A) The dense ECM can prevent immune cells to reach the tumor cells even in highly immunogenic cancers. Upon contact with areas of increased stiffness, lymphocytes are prone to follow less a chemoattractive gradient but to migrate along the fields of elevated rigidity (haptotaxis). (B) The shielding diffusion barrier that the ECM forms prevents also immunotherapeutic drugs, like checkpoint inhibitory ABs, to reach the tumor. (C) The increased hypoxia that results from poor supply behind the diffusion barrier can directly enhance immune escape by upregulation of immunomodulatory factors like IL-10 or TGF-β. (D) Hypoxia also increases angiogenic signals. Activated blood vessels show reduced ICAM1 expression, impeding attachment and extravasation of immune cells.
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