Targeting Invasion - The Role of MMP-2 and MMP-9 Inhibition in Colorectal Cancer Therapy

Sep 21, 2026

Uploaded by Aurelia

Colorectal cancer (CRC) remains one of the most prevalent and lethal cancers worldwide, driving sustained research into therapeutic innovations. This review systematically assesses gelatinases, focusing on MMP-2 and MMP-9, as treatment targets in CRC and analyzes how inhibition of these enzymes can affect patient outcomes. Elevated expression and activity of MMP-2 and MMP-9 in CRC are linked to tumor growth, invasion, metastasis, poor prognosis, and reduced survival. The review outlines their roles in the tumor microenvironment, angiogenesis, and the metastatic cascade, and evaluates recent inhibition strategies. It discusses small-molecule inhibitors, natural compounds, and gene-silencing approaches, along with challenges including nonspecific effects, adverse outcomes, and resistance mechanisms. Combination concepts with chemotherapy and emerging targeted treatments are explored, aiming to enhance efficacy and overcome resistance.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages37

Reading Time1 h 33 min

AccessFree to download

Introduction

Overview of CRC and burden worldwide

Risk factors and genetic predispositions

Early development and screening rationale

Clinical symptoms of CRC

Gelatinases and their roles in CRC

MMP-2 and MMP-9 in tumor growth, invasion, and metastasis

Links between gelatinase activity and prognosis

Tumor microenvironment modulation, angiogenesis, metastatic cascade

Therapeutic inhibition strategies

Small-molecule inhibitors

Natural compounds

Gene silencing and novel approaches

Challenges and future directions

Nonspecificity, adverse side effects, and resistance

Combination therapies with chemotherapy and targeted treatments

Roadmap for future research

Review Targeting Invasion: The Role of MMP-2 and MMP-9 Inhibition in Colorectal Cancer Therapy Alireza Shoari 1, *, Arghavan Ashja Ardalan 2, Alexandra M. Dimesa 1 and Mathew A. Coban 1, * Academic Editor: Alessandro Alaimo Received: 9 December 2024 Revised: 27 December 2024 Accepted: 29 December 2024 Published: 30 December 2024 Citation: Shoari, A.; Ashja Ardalan, A.; Dimesa, A.M.; Coban, M.A. Targeting Invasion: The Role of MMP-2 and MMP-9 Inhibition in Colorectal Cancer Therapy. Biomolecules 2025, 15, 35. [https://](https://)[ ](https://)[doi.org/10.3390/biom15010035](doi.org/10.3390/biom15010035) [Copyright:](Copyright:) © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://creativecommons.org/](https://creativecommons.org/)[ ](https://creativecommons.org/)[licenses/by/4.0/](licenses/by/4.0/)) . 1 Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA; [dimesa.alexandra@mayo.edu](dimesa.alexandra@mayo.edu) 2 Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy; [arghavan.ashja@studio.unibo.it](arghavan.ashja@studio.unibo.it) * Correspondence: [shoari.alireza@mayo.edu](shoari.alireza@mayo.edu) (A.S.); [coban.mathew@mayo.edu](coban.mathew@mayo.edu) (M.A.C.) Abstract: Colorectal cancer (CRC) remains one of the most prevalent and lethal cancers worldwide, prompting ongoing research into innovative therapeutic strategies. This review aims to systematically evaluate the role of gelatinases, specifically MMP-2 and MMP-9, as therapeutic targets in CRC, providing a critical analysis of their potential to improve patient outcomes. Gelatinases, specifically MMP-2 and MMP-9, play critical roles in the processes of tumor growth, invasion, and metastasis. Their expression and activity are significantly elevated in CRC, correlating with poor prognosis and lower survival rates. This review provides a comprehensive overview of the pathophysiological roles of gelatinases in CRC, highlighting their contribution to tumor microenvironment modulation, angiogenesis, and the metastatic cascade. We also critically evaluate recent advancementsin the development of gelatinase inhibitors, including small molecule inhibitors, natural compounds, and novel therapeutic approaches like gene silencing techniques. Challenges such as nonspecificity, adverse side effects, and resistance mechanisms are discussed. We explore the potential of gelatinase inhibition in combination therapies, particularly with conventional chemotherapy and emerging targeted treatments, to enhance therapeutic efficacy and overcome resistance. The novelty of this review lies in its integration of recent findings on diverse inhibition strategies with insights into their clinical relevance, offering a roadmap for future research. By addressing the limitations of current approaches and proposing novel strategies, this review underscores the potential of gelatinase inhibitors in CRC prevention and therapy, inspiring further exploration in this promising area of oncological treatment. Keywords: colorectal cancer; gelatinase inhibition; MMP-2; MMP-9; matrix metalloproteinases; cancer therapy 1. Introduction CRC, also known as colon cancer or bowel cancer, involves cancerous growths in the colon, rectum, and appendix. It is one of the most common types of cancer diagnosed globally [1] . In the late 1990s, CRC was the fourth-leading cause of cancer death in both men and women under 50 . Today, it is the leading cause of cancer death in men and the second leading cause in women [2] . CRC can result from both genetic and lifestyle factors. Key risk factors include older age, male sex, high intake of fat, alcohol, red meat, processed meats, low fiber diet, obesity, smoking, and a sedentary lifestyle [3,4] . Genetic predispositions, such as heredi

FAQs

Why are MMP-2 and MMP-9 considered therapeutic targets in colorectal cancer?

Gelatinases MMP-2 and MMP-9 contribute to tumor growth, invasion, and metastasis, and their expression and activity are significantly elevated in CRC. Their higher activity correlates with poorer prognosis and lower survival rates.

What effects can gelatinase inhibition have on CRC progression?

Inhibition is intended to interfere with processes linked to the tumor microenvironment, angiogenesis, and the metastatic cascade. The review emphasizes that these pathways support CRC development and progression.

What are the main challenges with current gelatinase inhibitor approaches?

The review highlights nonspecificity, adverse side effects, and resistance mechanisms as key limitations. These factors can reduce safety and long-term effectiveness.

Sep 21, 2026

Uploaded by Aurelia