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Proteolyzed matrix as a template for the regulation of tumor progression
William Hornebeck1, François Xavier Maquart
1Faculté de Médecine, Centre National de la Recherche Scientifique (CNRS, FRE 2534), IFR 53 Biomolécules, Université de Reims, Champagne Ardenne, 51, rue Cognacq Jay, 51095 Reims cedex, France. william-hornbeck@univ-reims.fr
Abstract:
Pericellular proteolysis plays a pivotal function in cell invasion, a hallmark of tumor growth and metastasis. The minidegradome constituted of two matrix metalloproteinases (MMP), i.e. MMP-2 and MT1-MMP, associated with tissue inhibitor of metalloprotease-2 (TIMP-2) and integrin (alpha(v)beta(3)) or CD(44), is mainly involved in such invasive program. It catalyzes matrix degradation but, alternatively, proteolytic exposure of matricryptic sites or matrikines liberation by those enzymes regulates either positively or negatively tumor cell migration. That applies to types I and IV collagens, elastin, laminin 5, as described here, but such phenomenon might be extended to other matrix macromolecules. The development of tumors from epithelium origin is related to aging. Senescent fibroblasts are characterized by increased expression of MMPs, (particularly collagenase-1 (MMP-1) and stromelysin-1 (MMP-3)) and deposited matrix by those aged cells was shown to favor cancer cell growth. Thus, compositional variation of matrix-surrounding tumor cells, with formation of matricryptic sites and matrikines, can be considered as one main epigenetic factor contributing to tumor progression. A matrix-directed pharmacological approach in cancer is now emerging.
Insights
Pericellular proteolysis, involving matrix metalloproteinases (MMPs), drives tumor cell invasion and metastasis. Matricryptic sites and matrikines, generated by MMPs, epigenetically regulate tumor cell migration and progression.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Pericellular proteolysis is crucial for tumor cell invasion and metastasis.
- The minidegradome, including MMP-2, MT1-MMP, TIMP-2, and integrins, mediates matrix degradation and regulates cell migration.
- Tumorigenesis is linked to aging, with senescent fibroblasts expressing increased MMPs that promote cancer cell growth.
Purpose of the Study:
- To elucidate the role of pericellular proteolysis in tumor invasion and metastasis.
- To investigate how matrix degradation and the generation of matricryptic sites/matrikines influence tumor cell migration.
- To highlight the potential of matrix-directed therapies for cancer treatment.
Main Methods:
- Analysis of matrix metalloproteinases (MMPs) and their associated proteins (TIMP-2, integrins).
- Investigation of pericellular proteolysis in relation to cell invasion and migration.
- Examination of the impact of aging and senescent fibroblasts on the tumor microenvironment.
Main Results:
- The minidegradome, comprising MMP-2 and MT1-MMP, facilitates matrix degradation and regulates tumor cell migration.
- Proteolytic exposure of matricryptic sites and matrikine liberation by MMPs can positively or negatively affect tumor cell migration.
- Matrix composition variations and the formation of matricryptic sites/matrikines act as epigenetic factors in tumor progression.
Conclusions:
- Pericellular proteolysis is a key regulator of tumor cell invasion and metastasis.
- Matrix-derived signals, including matricryptic sites and matrikines, significantly influence tumor cell behavior.
- Matrix-directed pharmacological approaches represent a promising strategy for cancer therapy.