The Role of the Extracellular Matrix in Cancer Stemness
Open accessAbstract
As our understanding of cancer cell biology progresses, it has become clear that tumors are a heterogenous mixture of different cell populations, some of which contain so called "cancer stem cells" (CSCs). Hallmarks of CSCs include self-renewing capability, tumor-initiating capacity and chemoresistance. The extracellular matrix (ECM), a major structural component of the tumor microenvironment, is a highly dynamic structure and increasing evidence suggests that ECM proteins establish a physical and biochemical niche for CSCs. In cancer, abnormal ECM dynamics occur due to disrupted balance between ECM synthesis and secretion and altered expression of matrix-remodeling enzymes. Tumor-derived ECM is biochemically distinct in its composition and is stiffer compared to normal ECM. In this review, we will provide a brief overview of how different components of the ECM modulate CSC properties then discuss how physical, mechanical, and biochemical cues from the ECM drive cancer stemness. Given the fact that current CSC targeting therapies face many challenges, a better understanding of CSC-ECM interactions will be crucial to identify more effective therapeutic strategies to eliminate CSCs.
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The ECM imparts key biophysical properties to tumor tissue, including stiffness, porosity, insolubility, and molecular density, which serve as biomechanical cues modulating migration, proliferation, polarity maintenance, and lineage specification.
“This biochemical framework imparts key biophysical properties to the tumor tissue, including stiffness, porosity, insolubility, and molecular density [5,77,78,79]. These characteristics serve as biomechanical cues that modulate diverse cellular processes, such as migration, proliferation, polarity maintenance, and lineage specification [25,80].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [78]
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Experimental — accuracy not yet measuredAbnormal tumor-associated angiogenesis leads to increased influx of fluids into the tumor; the lymphatic system cannot efficiently drain the increased influx, resulting in a net interstitial fluid pressure between the tumor mass and surrounding stroma that could increase to 30 mmHg at the tumor center.
“In tumors, abnormal tumor‐associated angiogenesis leads to an increased influx of fluids into the tumor. However, the lymphatic system cannot efficiently drain out the increased influx of these fluids. This imbalanced flow results in a net interstitial fluid pressure (IFP) between the tumor mass and the surrounding stroma, which could increase to 30 mmHg at the tumor center.[ 39 ]”
From 3D Biomimetic Models to Reconstitute Tumor Microenvironment In Vitro: Spheroids, Organoids, and Tumor‐on‐a‐Chip (2023) · cites this paper as [39]
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References 163 · Cited by 344
- Authors
- Nallanthighal, S., Heiserman, J. P., & Cheon, D.-J.
- Affiliations
- Albany Medical College (US)
- Corresponding author
- Cheon, Dong-Joo
- Venue
- Frontiers in Cell and Developmental Biology
- Publisher
- Frontiers Media SA
- Published
- 2019-07-05
- Volume
- 7
- Pages
- 86-86
- ISSN
- 2296-634X (ISSN-L)
- PMC
- PMC6624409
- OpenAlex
- W2954998262
- Cited by
- 344
- References
- 163
- Citations by year
- 2026: 31 · 2025: 31 · 2024: 40 · 2023: 58 · 2022: 68 · 2021: 75 · 2020: 37 · 2019: 3
- FWCI
- 19.09
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Cell and Developmental Biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- American Association for Cancer Research
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- extracellular matrix, cancer stem cells, cancer stemness, tumor microenvironment, extracellular matrix stiffness, mechanotransduction, tumor heterogeneity, chemoresistance, self-renewal, tumor-initiating capacity
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