Multiple aspects of matrix stiffness in cancer progression

Our plain-English summary of Multiple aspects of matrix stiffness in cancer progression, by A. Mancini, M.T. Gentile, F. Pentimalli, et al (Frontiers in Oncology, 2024).

The study

• Authors: A. Mancini, M.T. Gentile, F. Pentimalli, S. Cortellino, M. Grieco, A. Giordano
• Journal: Frontiers in Oncology
• Published: 2024;14:1406644
• Type of article: Review
• Cited by: 43 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The biophysical and biomechanical properties of the extracellular matrix (ECM) are crucial in the processes of cell differentiation and proliferation. However, it is unclear to what extent tumor cells are influenced by biomechanical and biophysical changes of the surrounding microenvironment and how this response varies between different tumor forms, and over the course of tumor progression. The entire ensemble of genes encoding the ECM associated proteins is called matrisome. In cancer, the ECM evolves to become highly dysregulated, rigid, and fibrotic, serving both pro-tumorigenic and anti-tumorigenic roles. Tumor desmoplasia is characterized by a dramatic increase of α-smooth muscle actin expressing fibroblast and the deposition of hard ECM containing collagen, fibronectin, proteoglycans, and hyaluronic acid and is common in many solid tumors. In this review, we described the role of inflammation and inflammatory cytokines, in desmoplastic matrix remodeling, tumor state transition driven by microenvironment forces and the signaling pathways in mechanotransduction as potential targeted therapies, focusing on the impact of qualitative and quantitative variations of the ECM on the regulation of tumor development, hypothesizing the presence of matrisome drivers, acting alongside the cell-intrinsic oncogenic drivers, in some stages of neoplastic progression and in some tumor contexts, such as pancreatic carcinoma, breast cancer, lung cancer and mesothelioma.

Copyright © 2024 Mancini, Gentile, Pentimalli, Cortellino, Grieco and Giordano.

In plain English

This article was a review, not an original study. The authors summarized published research on how the extracellular matrix (the protein scaffold around cells) becomes stiff and scar-like, called desmoplasia, in tumors, and how this may influence cancer progression. The review presented no new data on patients or animals, and it did not discuss asbestos or any fiber exposure. It covered inflammation and inflammatory signaling molecules, physical forces inside tumors, and drugs aimed at matrix stiffening. Citing other work, it stated that matrix stiffness is associated with tumor growth and correlates with increased metastasis. Mesothelioma was named among the tumor types covered and discussed only briefly. The authors wrote that the enzyme LOX is upregulated in many tumors, for example mesothelioma. They also wrote that thiaproline, which destabilizes collagen, had been found effective in preclinical mesothelioma models. A table listed drugs at preclinical or clinical-trial stages. The authors hypothesized a "Matrix Addiction" process, in which matrix drivers act alongside cancer-gene drivers. They concluded that both compartments should be evaluated and targeted together.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published literature (no original data)
• Who was studied: No study population; the review discussed published research on tumors, including pancreatic carcinoma, breast cancer, lung cancer and mesothelioma
• Exposure: Not applicable: the review concerns stiffness and remodeling of the extracellular matrix in tumors and does not discuss asbestos or any fiber exposure
• Main results:
  • Citing other studies, the review stated that extracellular matrix stiffness is associated with tumor growth and correlates with increased metastasis and poor clinical outcomes
  • Citing other studies, the review stated that expression of the collagen cross-linking enzyme LOX is upregulated in many tumors, for example mesothelioma
  • Citing other work, the review stated that collagen degradation induced by proline analogs such as thiaproline was effective in preclinical mesothelioma models. The table lists thiaproline for mesothelioma at the preclinical stage.
  • The review reported that LOX-inhibiting compounds such as simtuzumab, antibody AB0023 and tetrathiomolybdate, in combination with different therapies, have been tested in phase I-III clinical trials in cancer patients
• The authors' conclusion: The authors hypothesized a "Matrix Addiction" process driven by one or more matrisome drivers, acting together with oncogene drivers. They concluded that personalized therapy should evaluate and target both the matrisome and the oncosome in synchrony.

Topics

Medical terms in this study, explained in our Lexicon: Fibroblast, Deposition, Collagen, Hyaluronic Acid, Inflammation, Cytokine, Desmoplastic Mesothelioma, Carcinoma.

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