Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors
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 ele...
| Hlavní autoři: | , , , , , , , , , , , , |
|---|---|
| Další autoři: | |
| Médium: | Článek |
| Jazyk: | en_US |
| Vydáno: |
National Academy of Sciences (U.S.)
2013
|
| On-line přístup: | http://hdl.handle.net/1721.1/78002 |
| _version_ | 1826213457540677632 |
|---|---|
| author | Martin, John Daniel Jain, Saloni R. Stylianopoulosa, Triantafyllos Chauhana, Vikash P. Bardeesy, Nabeel Diop-Frimpong, Benjamin Stylianopoulos, Triantafyllos Smith, Barbara L. Ferrone, Cristina R. Hornicek, Francis J. Boucher, Yves Munn, Lance L. Jain, Rakesh K. |
| author2 | Harvard University--MIT Division of Health Sciences and Technology |
| author_facet | Harvard University--MIT Division of Health Sciences and Technology Martin, John Daniel Jain, Saloni R. Stylianopoulosa, Triantafyllos Chauhana, Vikash P. Bardeesy, Nabeel Diop-Frimpong, Benjamin Stylianopoulos, Triantafyllos Smith, Barbara L. Ferrone, Cristina R. Hornicek, Francis J. Boucher, Yves Munn, Lance L. Jain, Rakesh K. |
| author_sort | Martin, John Daniel |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T15:49:31Z |
| format | Article |
| id | mit-1721.1/78002 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:49:31Z |
| publishDate | 2013 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/780022022-10-02T04:19:53Z Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors Martin, John Daniel Jain, Saloni R. Stylianopoulosa, Triantafyllos Chauhana, Vikash P. Bardeesy, Nabeel Diop-Frimpong, Benjamin Stylianopoulos, Triantafyllos Smith, Barbara L. Ferrone, Cristina R. Hornicek, Francis J. Boucher, Yves Munn, Lance L. Jain, Rakesh K. Harvard University--MIT Division of Health Sciences and Technology Massachusetts Institute of Technology. Department of Chemical Engineering Martin, John Daniel Jain, Saloni R. Diop-Frimpong, Benjamin 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. National Institutes of Health (U.S.) (Grant P01CA08012) National Institutes of Health (U.S.) (Grant R01CA126642) 2013-03-27T17:36:10Z 2013-03-27T17:36:10Z 2012-08 2012-08 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/78002 Stylianopoulos, T. et al. “Inaugural Article: Causes, Consequences, and Remedies for Growth-induced Solid Stress in Murine and Human Tumors.” Proceedings of the National Academy of Sciences 109.38 (2012): 15101–15108. ©2012 National Academy of Sciences en_US http://dx.doi.org/10.1073/pnas.1213353109 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Martin, John Daniel Jain, Saloni R. Stylianopoulosa, Triantafyllos Chauhana, Vikash P. Bardeesy, Nabeel Diop-Frimpong, Benjamin Stylianopoulos, Triantafyllos Smith, Barbara L. Ferrone, Cristina R. Hornicek, Francis J. Boucher, Yves Munn, Lance L. Jain, Rakesh K. Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors |
| title | Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors |
| title_full | Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors |
| title_fullStr | Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors |
| title_full_unstemmed | Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors |
| title_short | Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors |
| title_sort | causes consequences and remedies for growth induced solid stress in murine and human tumors |
| url | http://hdl.handle.net/1721.1/78002 |
| work_keys_str_mv | AT martinjohndaniel causesconsequencesandremediesforgrowthinducedsolidstressinmurineandhumantumors AT jainsalonir causesconsequencesandremediesforgrowthinducedsolidstressinmurineandhumantumors AT stylianopoulosatriantafyllos causesconsequencesandremediesforgrowthinducedsolidstressinmurineandhumantumors AT chauhanavikashp causesconsequencesandremediesforgrowthinducedsolidstressinmurineandhumantumors AT bardeesynabeel causesconsequencesandremediesforgrowthinducedsolidstressinmurineandhumantumors AT diopfrimpongbenjamin causesconsequencesandremediesforgrowthinducedsolidstressinmurineandhumantumors AT stylianopoulostriantafyllos causesconsequencesandremediesforgrowthinducedsolidstressinmurineandhumantumors AT smithbarbaral causesconsequencesandremediesforgrowthinducedsolidstressinmurineandhumantumors AT ferronecristinar causesconsequencesandremediesforgrowthinducedsolidstressinmurineandhumantumors AT hornicekfrancisj causesconsequencesandremediesforgrowthinducedsolidstressinmurineandhumantumors AT boucheryves causesconsequencesandremediesforgrowthinducedsolidstressinmurineandhumantumors AT munnlancel causesconsequencesandremediesforgrowthinducedsolidstressinmurineandhumantumors AT jainrakeshk causesconsequencesandremediesforgrowthinducedsolidstressinmurineandhumantumors |