Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors
Open accessAbstract
The presence of growth-induced solid stresses in tumors has been suspected for some time, but these stresses were largely estimated using mathematical models. Solid stresses can deform the surrounding tissues and compress intratumoral lymphatic and blood vessels. Compression of lymphatic vessels elevates interstitial fluid pressure, whereas compression of blood vessels reduces blood flow. Reduced blood flow, in turn, leads to hypoxia, which promotes tumor progression, immunosuppression, inflammation, invasion, and metastasis and lowers the efficacy of chemo-, radio-, and immunotherapies. Thus, strategies designed to alleviate solid stress have the potential to improve cancer treatment. However, a lack of methods for measuring solid stress has hindered the development of solid stress-alleviating drugs. Here, we present a simple technique to estimate the growth-induced solid stress accumulated within animal and human tumors, and we show that this stress can be reduced by depleting cancer cells, fibroblasts, collagen, and/or hyaluronan, resulting in improved tumor perfusion. Furthermore, we show that therapeutic depletion of carcinoma-associated fibroblasts with an inhibitor of the sonic hedgehog pathway reduces solid stress, decompresses blood and lymphatic vessels, and increases perfusion. In addition to providing insights into the mechanopathology of tumors, our approach can serve as a rapid screen for stress-reducing and perfusion-enhancing drugs.
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Abnormal solid stress is developed by the unregulated growth of tumorigenic cells and is transmitted by the extracellular matrix.
“Abnormal SS is developed by the unregulated growth of tumorigenic cells and is transmitted by the extracellular matrix[179].”
From Microfluidic modelling of the tumor microenvironment for anti-cancer drug development (2019) · cites this paper as [179]
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- Authors
- Stylianopoulos, T., Martin, J. D., Chauhan, V. P., Jain, S. R., Diop-Frimpong, B., Bardeesy, N., Smith, B. L., Ferrone, C. R., Hornicek, F. J., Boucher, Y., Munn, L. L., & Jain, R. K.
- Affiliations
- Harvard University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-08-29
- Volume
- 109
- Issue
- 38
- Pages
- 15101-15108
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3458380
- OpenAlex
- W1998266575
- Cited by
- 943
- References
- 67
- Citations by year
- 2026: 108 · 2025: 81 · 2024: 78 · 2023: 85 · 2022: 68 · 2021: 79 · 2020: 78 · 2019: 84 · 2018: 63 · 2017: 64 · 2016: 52 · 2015: 46 · 2014: 30 · 2013: 22 · 2012: 2
- FWCI
- 15.14
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- U.S. Department of Defense (W81XWH1010016, W81XWH)
- European Commission (276894)
- National Institutes of Health (W81XWH)
- National Cancer Institute (P01CA080124, R01CA126642, P01CA117969)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Physical Sciences › Mathematics › Modeling and Simulation › Mathematical Biology Tumor Growth
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- solid stress, tumor growth, tumor perfusion, interstitial fluid pressure, tumor hypoxia, cancer-associated fibroblasts, sonic hedgehog pathway, hyaluronic acid, collagen, stress measurement
- MeSH terms
- Adenocarcinoma, Animals, Hypoxia, Blood Vessels, Collagen, Female, Fibroblasts, Humans, Hyaluronic Acid, Immunotherapy, Models, Theoretical, Neoplasm Transplantation, Neoplasms, Pancreatic Ducts, Pancreatic Neoplasms, Stress, Mechanical, Mice, SCID, Stromal Cells, Mice
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