Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels
Cancer and stromal cells actively exert physical forces (solid stress) to compress tumour blood vessels, thus reducing vascular perfusion. Tumour interstitial matrix also contributes to solid stress, with hyaluronan implicated as the primary matrix molecule responsible for vessel compression because...
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Nature Publishing Group
2013
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| Mynediad Ar-lein: | http://hdl.handle.net/1721.1/82573 https://orcid.org/0000-0003-2220-4365 |
| _version_ | 1826197234216075264 |
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| author | Chauhan, Vikash P. Liu, Hao Lacorre, Delphine A. Jain, Saloni R. Kozin, Sergey V. Stylianopoulos, Triantafyllos Mousa, Ahmed S. Han, Xiaoxing Adstamongkonkul, Pichet Huang, Peigen Bawendi, Moungi G. Boucher, Yves Jain, Rakesh K. Martin, John Daniel Popovic, Zoran |
| author2 | Massachusetts Institute of Technology. Department of Chemical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Chemical Engineering Chauhan, Vikash P. Liu, Hao Lacorre, Delphine A. Jain, Saloni R. Kozin, Sergey V. Stylianopoulos, Triantafyllos Mousa, Ahmed S. Han, Xiaoxing Adstamongkonkul, Pichet Huang, Peigen Bawendi, Moungi G. Boucher, Yves Jain, Rakesh K. Martin, John Daniel Popovic, Zoran |
| author_sort | Chauhan, Vikash P. |
| collection | MIT |
| description | Cancer and stromal cells actively exert physical forces (solid stress) to compress tumour blood vessels, thus reducing vascular perfusion. Tumour interstitial matrix also contributes to solid stress, with hyaluronan implicated as the primary matrix molecule responsible for vessel compression because of its swelling behaviour. Here we show, unexpectedly, that hyaluronan compresses vessels only in collagen-rich tumours, suggesting that collagen and hyaluronan together are critical targets for decompressing tumour vessels. We demonstrate that the angiotensin inhibitor losartan reduces stromal collagen and hyaluronan production, associated with decreased expression of profibrotic signals TGF-β1, CCN2 and ET-1, downstream of angiotensin-II-receptor-1 inhibition. Consequently, losartan reduces solid stress in tumours resulting in increased vascular perfusion. Through this physical mechanism, losartan improves drug and oxygen delivery to tumours, thereby potentiating chemotherapy and reducing hypoxia in breast and pancreatic cancer models. Thus, angiotensin inhibitors—inexpensive drugs with decades of safe use—could be rapidly repurposed as cancer therapeutics. |
| first_indexed | 2024-09-23T10:44:34Z |
| format | Article |
| id | mit-1721.1/82573 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:44:34Z |
| publishDate | 2013 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/825732022-09-27T14:40:02Z Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels Chauhan, Vikash P. Liu, Hao Lacorre, Delphine A. Jain, Saloni R. Kozin, Sergey V. Stylianopoulos, Triantafyllos Mousa, Ahmed S. Han, Xiaoxing Adstamongkonkul, Pichet Huang, Peigen Bawendi, Moungi G. Boucher, Yves Jain, Rakesh K. Martin, John Daniel Popovic, Zoran Massachusetts Institute of Technology. Department of Chemical Engineering Massachusetts Institute of Technology. Department of Chemistry Martin, John Daniel Jain, Saloni R. Popovic, Zoran Bawendi, Moungi G. Cancer and stromal cells actively exert physical forces (solid stress) to compress tumour blood vessels, thus reducing vascular perfusion. Tumour interstitial matrix also contributes to solid stress, with hyaluronan implicated as the primary matrix molecule responsible for vessel compression because of its swelling behaviour. Here we show, unexpectedly, that hyaluronan compresses vessels only in collagen-rich tumours, suggesting that collagen and hyaluronan together are critical targets for decompressing tumour vessels. We demonstrate that the angiotensin inhibitor losartan reduces stromal collagen and hyaluronan production, associated with decreased expression of profibrotic signals TGF-β1, CCN2 and ET-1, downstream of angiotensin-II-receptor-1 inhibition. Consequently, losartan reduces solid stress in tumours resulting in increased vascular perfusion. Through this physical mechanism, losartan improves drug and oxygen delivery to tumours, thereby potentiating chemotherapy and reducing hypoxia in breast and pancreatic cancer models. Thus, angiotensin inhibitors—inexpensive drugs with decades of safe use—could be rapidly repurposed as cancer therapeutics. National Cancer Institute (U.S.) (Grant P01-CA080124) National Cancer Institute (U.S.) (Grant R01-CA126642) National Cancer Institute (U.S.) (Grant R01-CA085140) National Cancer Institute (U.S.) (Grant R01-CA115767) National Cancer Institute (U.S.) (Grant R01-CA098706) United States. Dept. of Defense. Breast Cancer Research Program (Innovator Award W81XWH-10-1-0016) Lustgarten Foundation (Dana-Farber Cancer Institute/David H. Koch Institute for Integrative Cancer Research at MIT Bridge Project Grant) 2013-11-25T17:20:30Z 2013-11-25T17:20:30Z 2013-10 2013-07 Article http://purl.org/eprint/type/JournalArticle 2041-1723 http://hdl.handle.net/1721.1/82573 Chauhan, Vikash P., John D. Martin, Hao Liu, Delphine A. Lacorre, Saloni R. Jain, Sergey V. Kozin, Triantafyllos Stylianopoulos, et al. “Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels.” Nature Communications 4 (October 1, 2013). © 2013 Nature Publishing Group, a division of Macmillan Publishers Limited https://orcid.org/0000-0003-2220-4365 en_US http://dx.doi.org/10.1038/ncomms3516 Nature Communications http://creativecommons.org/licenses/by-nc-nd/3.0/ application/pdf Nature Publishing Group PMC |
| spellingShingle | Chauhan, Vikash P. Liu, Hao Lacorre, Delphine A. Jain, Saloni R. Kozin, Sergey V. Stylianopoulos, Triantafyllos Mousa, Ahmed S. Han, Xiaoxing Adstamongkonkul, Pichet Huang, Peigen Bawendi, Moungi G. Boucher, Yves Jain, Rakesh K. Martin, John Daniel Popovic, Zoran Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels |
| title | Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels |
| title_full | Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels |
| title_fullStr | Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels |
| title_full_unstemmed | Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels |
| title_short | Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels |
| title_sort | angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels |
| url | http://hdl.handle.net/1721.1/82573 https://orcid.org/0000-0003-2220-4365 |
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