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Review
. 2022 Apr 26:9:864302.
doi: 10.3389/fmolb.2022.864302. eCollection 2022.

The Role of Extracellular Matrix Remodeling in Skin Tumor Progression and Therapeutic Resistance

Julia E Fromme  1   2 , Paola Zigrino  1
Affiliations
Review

The Role of Extracellular Matrix Remodeling in Skin Tumor Progression and Therapeutic Resistance

Julia E Fromme et al. Front Mol Biosci. .

Abstract

The extracellular matrix remodeling in the skin results from a delicate balance of synthesis and degradation of matrix components, ensuring tissue homeostasis. These processes are altered during tumor invasion and growth, generating a microenvironment that supports growth, invasion, and metastasis. Apart from the cellular component, the tumor microenvironment is rich in extracellular matrix components and bound factors that provide structure and signals to the tumor and stromal cells. The continuous remodeling in the tissue compartment sustains the developing tumor during the various phases providing matrices and proteolytic enzymes. These are produced by cancer cells and stromal fibroblasts. In addition to fostering tumor growth, the expression of specific extracellular matrix proteins and proteinases supports tumor invasion after the initial therapeutic response. Lately, the expression and structural modification of matrices were also associated with therapeutic resistance. This review will focus on the significant alterations in the extracellular matrix components and the function of metalloproteinases that influence skin cancer progression and support the acquisition of therapeutic resistance.

Keywords: BCC; ECM; MCC; SCC; TME; melanoma; skin; therapy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
ECM remodeling (and more) in skin cancer. ECM components and metalloproteinase activities may influence skin tumors development and progression modulating a variety of events. Some of these were shown in specific skin tumors (in red). MM, malignant melanoma; SCC, squamous cell carcinoma; BCC, basal cell carcinoma; MCC, Merkel cell carcinoma. MØ, macrophages; GF, growth factor; CAF, cancer-associated fibroblasts; EMT, epithelial-to-mesenchymal transition.
FIGURE 2
FIGURE 2
Mechanisms based on ECM remodeling and metalloprotease that influence response to therapy. Increased accumulation of ECM and its cross-linkage impedes access of the drugs to the tumor cells, the supply with nutrients and interferes with the migration of inflammatory cells. Dense ECM induces EMT that in turns fuels ECM accumulation. Active metalloproteinases (MMPs/ADAMs) from tumor and stromal cells help transformed cells cross ECM barriers and release cellular and ECM-bound growth factors and cytokines that play an essential role in chemotherapy resistance. Tumor cell contact with ECM mediated by integrins lead to the activation of an out-in pathway that increases survival signaling and helps circumvent the drug’s effect.
See this image and copyright information in PMC

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