Hypoxic Effects on Matrix Metalloproteinases’ Expression in the Tumor Microenvironment and Therapeutic Perspectives

Abstract

The tumor microenvironment (TME) is characterized by an acidic pH and low oxygen concentrations. Hypoxia induces neoplastic cell evasion of the immune surveillance, rapid DNA repair, metabolic reprogramming, and metastasis, mainly as a response to the hypoxic inducible factors (HIFs). Likewise, cancer cells increase matrix metalloproteinases’ (MMPs) expression in response to TME conditions, allowing them to migrate from the primary tumor to different tissues. Since HIFs and MMPs are augmented in the hypoxic TME, it is easy to consider that HIFs participate directly in their expression regulation. However, not all MMPs have a hypoxia response element (HRE)-HIF binding site. Moreover, different transcription factors and signaling pathways activated in hypoxia conditions through HIFs or in a HIF-independent manner participate in MMPs’ transcription. The present review focuses on MMPs’ expression in normal and hypoxic conditions, considering HIFs and a HIF-independent transcription control. In addition, since the hypoxic TME causes resistance to anticancer conventional therapy, treatment approaches using MMPs as a target alone, or in combination with other therapies, are also discussed.

The Role of Salivary Vascular Endothelial Growth Factor A, Cytokines, and Amino Acids in Immunomodulation and Angiogenesis in Breast Cancer

“…We appear to observe a negative correlation between serum and salivary MCP-1 in breast cancer. In addition, MCP-1 expression is significantly correlated with the vascular invasion of tumor cells and is closely associated with the expression of matrix metalloproteinase type 1, TNF-α, thymidine phosphorylase, and other angiogenic factors [ 81 ]. Overall, current data indicate that increased MCP-1 expression in breast tumors is closely associated with disease progression, but data on MCP-1 levels in body fluids are inconsistent.…”

Hypoxia-Inducible Factor and Oxidative Stress in Tendon Degeneration: A Molecular Perspective

“…TIMP-1, in particular, plays an important role in regulating MMP levels, as a balance of MMP/TIMP is necessary for maintaining tendon homeostasis. An imbalanced MMP/TIMP ratio caused by dysregulated TIMP-mediated MMP regulation may lead to impaired remodeling during tendon repair [63,64]. TIMP-1 is known to play a role in various biological processes, including tissue remodeling, promoting growth factor activity, and wound healing [64].…”

“…An imbalanced MMP/TIMP ratio caused by dysregulated TIMP-mediated MMP regulation may lead to impaired remodeling during tendon repair [63,64]. TIMP-1 is known to play a role in various biological processes, including tissue remodeling, promoting growth factor activity, and wound healing [64]. As an MMP inhibitor, TIMP-1 primarily targets and inhibits MMP-9.…”