Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors
| Autor: | 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. |
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| Přispěvatelé: | Stylianopoulos, T. [0000-0002-3093-1696] |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
collagen
Mice SCID animal cell fibroblast Metastasis sonic hedgehog protein Pancreatic ductal adenocarcinoma Mice 0302 clinical medicine cell stress Theoretical Anoxia Models Neoplasms hyaluronic acid Hyaluronic Acid Hypoxia cancer cell 0303 health sciences Multidisciplinary depletion Chemistry article tissue perfusion Biological Sciences 3. Good health Lymphatic system female tumor growth priority journal Tumor microenvironment 030220 oncology & carcinogenesis Female Collagen Immunotherapy medicine.symptom Sonic hedgehog pathway Stromal cell Inflammation Adenocarcinoma Stress SCID animal tissue 03 medical and health sciences lymph vessel male blood vessel medicine Humans Animals Animalia controlled study human mouse 030304 developmental biology nonhuman human cell Pancreatic Ducts Erinaceidae Blood flow Hypoxia (medical) Models Theoretical Fibroblasts medicine.disease Mechanical Desmoplastic tumors human tissue Pancreatic Neoplasms Tumor progression Immunology Cancer cell Cancer research Blood Vessels Mathematical modeling Stress Mechanical Murinae Stromal Cells Neoplasm Transplantation |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| Popis: | 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. 109 15101 15108 15101-15108 |
| Databáze: | OpenAIRE |
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