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

Nat Commun. 2013;4:2516. doi: 10.1038/ncomms3516.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Angiotensins / antagonists & inhibitors*
  • Angiotensins / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Hypoxia
  • Collagen / metabolism
  • Connective Tissue Growth Factor / genetics
  • Connective Tissue Growth Factor / metabolism
  • Drug Repositioning
  • Drug Synergism
  • Endothelin-1 / genetics
  • Endothelin-1 / metabolism
  • Female
  • Fluorouracil / pharmacology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hyaluronic Acid / metabolism
  • Losartan / pharmacology*
  • Mammary Neoplasms, Experimental / blood supply
  • Mammary Neoplasms, Experimental / drug therapy*
  • Mammary Neoplasms, Experimental / pathology
  • Mechanotransduction, Cellular
  • Mice
  • Pancreatic Neoplasms / blood supply
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology
  • Receptor, Angiotensin, Type 1 / genetics
  • Receptor, Angiotensin, Type 1 / metabolism
  • Stress, Mechanical
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism
  • Stromal Cells / pathology
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Angiotensins
  • Antineoplastic Agents
  • CCN2 protein, mouse
  • Endothelin-1
  • Receptor, Angiotensin, Type 1
  • Transforming Growth Factor beta1
  • Connective Tissue Growth Factor
  • Hyaluronic Acid
  • Collagen
  • Losartan
  • Fluorouracil

Supplementary concepts

  • Pancreatic Carcinoma