Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels
- PMID: 24084631
- PMCID: PMC3806395
- DOI: 10.1038/ncomms3516
Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels
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.
Conflict of interest statement
R.K.J. received consultant fees from Enlight, Noxxon, Zyngenia and WebMD. R.K.J owns equity in Enlight, SynDevRx and XTuit, and serves on the Board of Directors of XTuit and Boards of Trustees of H&Q Healthcare Investors and H&Q Life Sciences Investors. V.P.C. received consultant fees and owns equity in XTuit. Y.B. received consultant fees from XTuit. The Massachusetts General Hospital has applied for a patent based on this work, titled ‘Novel compositions and uses of anti-hypertension agents for cancer therapy’ (PCT/US2011/061510), with V.P.C., Y.B. and R.K.J. as co-authors. The remaining authors declare no competing financial interests.
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