Modulation of peritumoral fibroblasts with a membrane-tethered tissue inhibitor of metalloproteinase (TIMP) for the elimination of cancer cells.

Abstract

BACKGROUND:

Peritumoral fibroblasts are key components of the tumor microenvironment. Through remodeling of the extracellular matrix (ECM) and secretion of pro-tumorigenic cytokines, peritumoral fibroblasts foster an immunosuppressive milieu conducive to tumor cell proliferation. In this study, we investigated if peritumoral fibroblasts could be therapeutically engineered to elicit an anti-cancer response by abolishing the proteolytic activities of membrane-bound metalloproteinases involved in ECM modulation.

METHODS:

A high affinity, glycosylphosphatidylinositol (GPI)-anchored Tissue Inhibitor of Metalloproteinase (TIMP) named "T1PrαTACE" was created for dual inhibition of MT1-MMP and TACE. T1PrαTACE was expressed in fibroblasts and its effects on cancer cell proliferation investigated in 3D co-culture models.

RESULTS:

T1PrαTACE abrogated the activities of MT1-MMP and TACE in host fibroblasts. As a GPI protein, T1PrαTACE could spontaneously detach from the plasma membrane of the fibroblast to co-localize with MT1-MMP and TACE on neighboring cancer cells. In a 3D co-culture model, T1PrαTACE promoted adherence between the cancer cells and surrounding fibroblasts, which led to an attenuation in tumor development.

CONCLUSION:

Peritumoral fibroblasts can be modulated with the TIMP for the elimination of cancer cells. As a novel anti-tumor strategy, our approach could potentially be used in combination with conventional chemo- and immunotherapies for a more effective cancer therapy.

• Authors: Yihe Zhang, Shiyu Liu, Bingjie Jiang, Sung Kay Chiu, Meng Huee Lee
• Journal: Investigational new drugs (Invest New Drugs) Vol. 40 Issue 1 Pg. 198-208 (02 2022) ISSN: 1573-0646 [Electronic] United States
• PMID: 34519970 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• Tissue Inhibitor of Metalloproteinases
• ADAM Proteins
• ADAM17 Protein

Topics

• ADAM Proteins (antagonists & inhibitors)
• ADAM17 Protein (antagonists & inhibitors)
• Cell Line, Tumor
• Fibroblasts (drug effects)
• Human Umbilical Vein Endothelial Cells
• Humans
• Neoplasms (pathology)
• Tissue Inhibitor of Metalloproteinases (pharmacology)