The extracellular matrix is a fundamental, core component of all tissues and organs, and is essential for the existence of multicellular organisms. From the earliest stages of organism development until death, it regulates and fine-tunes every cellular process in the body. In cancer, the extracellular matrix is altered at the biochemical, biomechanical, architectural and topographical levels, and recent years have seen an exponential increase in the study and recognition of the importance of the matrix in solid tumours. Coupled with the advancement of new technologies to study various elements of the matrix and cell–matrix interactions, we are also beginning to see the deployment of matrix-centric, stromal targeting cancer therapies. This Review touches on many of the facets of matrix biology in solid cancers, including breast, pancreatic and lung cancer, with the aim of highlighting some of the emerging interactions of the matrix and influences that the matrix has on tumour onset, progression and metastatic dissemination, before summarizing the ongoing work in the field aimed at developing therapies to co-target the matrix in cancer and cancer metastasis.
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The author apologizes to all colleagues whose work could not be discussed due to space limitations. T.R.C. is supported by the Australian National Health and Medical Research Council, Cancer Council NSW, Cancer Institute NSW, Love Your Sister in association with the Australian National Breast Cancer Foundation, Avner Pancreatic Cancer Foundation and Susan G. Komen.
T.R.C. is engaged in a non-commercial collaborative project with Pharmaxis Ltd, a pharmaceutical company with ownership of a small-molecule lysyl oxidase family-targeting pipeline.
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Australian Pancreatic Cancer Matrix Atlas: https://www.pancreaticcancer.net.au/apma/
Matrisome Project and Extracellular Matrix Atlas: http://matrisomeproject.mit.edu
An entity consisting of a complex organization of more than one building block.
- Dynamic reciprocity
The ongoing and bidirectional interaction between cells and their microenvironment, and in particular the extracellular matrix.
The dense fibrotic tissue that forms in response to insult to a tissue. It is typically observed in and around solid tumours characterized by the excessive or abnormal deposition of extracellular matrix.
All of the extracellular matrix proteins that can potentially be expressed by the genome of a specific organism.
- Basement membranes
Structures visible by light microscopy and, in addition to the basal lamina, that consist of layers that are typically secreted by cells from underlying connective tissue. Many basement membranes are rich in fibronectin.
- Basal lamina
A molecularly defined part of the basement membrane comprising an electron-dense layer, ~20–100 nm thick, that consists of collagen IV and laminin, only visible by electron microscopy. It is made and maintained by the cells that sit on it, acting as the critical point of attachment.
The specific, acute state of matrix composition (and/or modification) at a given point, associated with, or causal for, a given physiological condition or phenotype.
Also known as mucopolysaccharides, glycosaminoglycans are the most abundant heteropolysaccharide in the body. They are complex linear polysaccharides consisting of repeated alternating units of uronic acid and glycosamines.
Also known as matrikines or cryptikines, these are biologically active fragments of matrix molecules that have undergone limited enzymatic cleavage and have a biological activity different from that of the parent protein.
- Metzincin superfamily
The main endopeptidases responsible for matrix degradation, comprising matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase proteins (ADAMs) and ADAMs with thrombospondin motifs (ADAMTSs).
- Schiff base adduct
A subclass of imines with the general structure R2C=NR′.
- Amadori rearrangement
Important in carbohydrate biology, this rearrangement is the isomerization event whereby the N-glycoside of an aldose sugar is converted to the corresponding ketone by acid or base catalysis.
A form of sensory transduction in which cells convert mechanical stimuli into biological signals and vice versa.
Peptidases that cleave peptide bonds of non-terminal amino acids within polypeptide chains and proteins (exopeptidases cleave only the terminal peptide bond of polypeptide chains and proteins).
The property of being directionally dependent, whereby a particular characteristic (such as physical or mechanical properties) varies depending on the direction of measurement.
- Vascular co-option
The process by which tumours hijack the vasculature of existing tissues of organs to obtain a blood supply independently of angiogenesis.
Extracellular vesicles, typically 30–150 nm in diameter, that are secreted by all cells, including cancer cells, and contain biological molecules, including DNA, RNA and proteins.
A time-dependent response to loading or deformation.
- Field cancerization
The process by which areas of tissue exhibit intracellular or extracellular procarcinogenic changes that lead to areas of premalignant cells or protumorigenic matrix, respectively.
- Premetastatic niches
Specific microenvironments that are systemically induced within a secondary organ and thought to be important for overt colonization by metastasizing primary tumour cells.
- Neutrophil extracellular traps
(NETs). Complex networks of extracellular fibres that are primarily composed of chromosomal DNA and histones, and have important roles in thrombosis, inflammation and cancer.
Used to describe interventions given before a main treatment, or in the case of solid tumours, before surgery.
A non-invasive medical imaging modality that maps the elastic properties and stiffness of tissues, and is predominantly used to characterize the biomechanical properties of soft tissues.
- Vascular patency
The degree to which blood vessels of the vasculature are open and not blocked or obstructed.
- Basket trials
Clinical trials in which many tumour types carrying the same molecular or genetic aberration are grouped together and given the same treatment.
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Cox, T.R. The matrix in cancer. Nat Rev Cancer 21, 217–238 (2021). https://doi.org/10.1038/s41568-020-00329-7
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