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

By Vikash P Chauhan, John D. Martin, Hao Liu, D. Lacorre, Saloni R. Jain, S. Kozin, Triantafyllos Stylianopoulos, A. Mousa, Xiaoxing Han, Pichet Adstamongkonkul and 5 more. Nature Communications, 2013

943 citations recorded by the source corpus.

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. Hyaluronan is a component of the tumour extracellular matrix. Here, Chauhan et al. show that hyaluronan increases blood pressure in collagen-rich tumours by compressing vessel walls, and that reducing the level of hyaluranon with an angiotensin II inhibitor increases blood flow and drug penetrance in tumours.

Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/55b9bb19da93ea97eaf688b02256a54c35109c9b

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Rakesh K. Jain

Citations in the corpus

Fibroblast heterogeneity in the cancer wound (2014, background): “By reducing collagen and hyaluronic acid production, ARBs can increase vascular perfusion and drug delivery (Chauhan et al., 2013).”
Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. (2019, background): “An inhibitor of this receptor, Losartan, was shown to reduce intratumoral solid stress, leading to increased vascular perfusion and improved drug delivery (48, 78).”
Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives (2021, background): “This vaccine is capable of eliminating CAFs by stimulating a CD8 + T Diverse CAF-targeted depleting immunotherapeutic strategies in preclinical/clinical studies FAP fibroblast activation protein, DC dendritic cell, shA20 A20-specific shRNA, TRP2 tyrosine-related protein 2, AdC68 adenoviral vector of”
The role of mechanical forces in tumor growth and therapy (2014, positive): “A | Intravital multiphoton microscopy images show treatment with the angiotensin receptor blocker, losartan lowers collagen levels (blue) and increases the density of perfused vessels (green) in an orthotopic mammary adenocarcinoma (EO771) [Reproduced from Reference (135)].”