Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels

Vikash P. Chauhan, John D. Martin, Hao Liu, Delphine A. Lacorre, Saloni R. Jain, Sergey V. Kozin, Triantafyllos Stylianopoulos, Ahmed S. Mousa, Xiaoxing Han, Pichet Adstamongkonkul, Zoran Popović, Peigen Huang, Moungi G. Bawendi, Yves Boucher and Rakesh K. Jain ()
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Vikash P. Chauhan: Edwin L. Steele Laboratory, Massachusetts General Hospital and Harvard Medical School
John D. Martin: Edwin L. Steele Laboratory, Massachusetts General Hospital and Harvard Medical School
Hao Liu: Edwin L. Steele Laboratory, Massachusetts General Hospital and Harvard Medical School
Delphine A. Lacorre: Edwin L. Steele Laboratory, Massachusetts General Hospital and Harvard Medical School
Saloni R. Jain: Edwin L. Steele Laboratory, Massachusetts General Hospital and Harvard Medical School
Sergey V. Kozin: Edwin L. Steele Laboratory, Massachusetts General Hospital and Harvard Medical School
Triantafyllos Stylianopoulos: Edwin L. Steele Laboratory, Massachusetts General Hospital and Harvard Medical School
Ahmed S. Mousa: Edwin L. Steele Laboratory, Massachusetts General Hospital and Harvard Medical School
Xiaoxing Han: Edwin L. Steele Laboratory, Massachusetts General Hospital and Harvard Medical School
Pichet Adstamongkonkul: Edwin L. Steele Laboratory, Massachusetts General Hospital and Harvard Medical School
Zoran Popović: Massachusetts Institute of Technology
Peigen Huang: Edwin L. Steele Laboratory, Massachusetts General Hospital and Harvard Medical School
Moungi G. Bawendi: Massachusetts Institute of Technology
Yves Boucher: Edwin L. Steele Laboratory, Massachusetts General Hospital and Harvard Medical School
Rakesh K. Jain: Edwin L. Steele Laboratory, Massachusetts General Hospital and Harvard Medical School

Nature Communications, 2013, vol. 4, issue 1, 1-11

Abstract: Abstract 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.

Date: 2013
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DOI: 10.1038/ncomms3516

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