Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels
Vikash P. Chauhan,John D. Martin,John D. Martin,Hao Liu,Delphine A. Lacorre,Saloni R. Jain,Saloni R. Jain,Sergey V. Kozin,Triantafyllos Stylianopoulos,Triantafyllos Stylianopoulos,Ahmed S. Mousa,Xiaoxing Han,Pichet Adstamongkonkul,Zoran B. Popović,Peigen Huang,Moungi G. Bawendi,Yves Boucher,Rakesh K. Jain +17 more
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TLDR
Losartan reduces solid stress in tumours resulting in increased vascular perfusion, thereby potentiating chemotherapy and reducing hypoxia in breast and pancreatic cancer models, suggesting that angiotensin inhibitors —inexpensive drugs with decades of safe use — could be rapidly repurposed as cancer therapeutics.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-b1, 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 cancerread more
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A framework for advancing our understanding of cancer-associated fibroblasts
Erik Sahai,Igor Astsaturov,Edna Cukierman,David G. DeNardo,Mikala Egeblad,Ronald M. Evans,Ronald M. Evans,Douglas T. Fearon,Douglas T. Fearon,Florian R. Greten,Sunil R. Hingorani,Tony Hunter,Richard O. Hynes,Rakesh K. Jain,Tobias Janowitz,Claus Jørgensen,Alec C. Kimmelman,Mikhail G. Kolonin,Robert G. Maki,Robert G. Maki,R. Scott Powers,Ellen Puré,Daniel C. Ramirez,Ruth Scherz-Shouval,Mara H. Sherman,Sheila A. Stewart,Thea D. Tlsty,David A. Tuveson,Fiona M. Watt,Valerie M. Weaver,Ashani T. Weeraratna,Zena Werb +31 more
TL;DR: This Consensus Statement issues a call to action for all cancer researchers to standardize assays and report metadata in studies of cancer-associated fibroblasts to advance the understanding of this important cell type in the tumour microenvironment.
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Delivery technologies for cancer immunotherapy
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Antiangiogenesis Strategies Revisited: From Starving Tumors to Alleviating Hypoxia
TL;DR: In this paper, the authors summarize lessons learned from preclinical and clinical studies over the past decade and propose strategies for improving antiangiogenic therapy outcomes for malignant and nonmalignant diseases.
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Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges.
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Cross-Species Single-Cell Analysis of Pancreatic Ductal Adenocarcinoma Reveals Antigen-Presenting Cancer-Associated Fibroblasts
Ela Elyada,Ela Elyada,Mohan Bolisetty,Pasquale Laise,William F. Flynn,Elise T. Courtois,Richard A. Burkhart,Jonathan Teinor,Pascal Belleau,Giulia Biffi,Giulia Biffi,Matthew S. Lucito,Matthew S. Lucito,Santhosh Sivajothi,Todd D. Armstrong,Dannielle D. Engle,Dannielle D. Engle,Dannielle D. Engle,Kenneth H. Yu,Yuan Hao,Christopher L. Wolfgang,Young-Kyu Park,Young-Kyu Park,Jonathan B. Preall,Elizabeth M. Jaffee,Andrea Califano,Paul Robson,David A. Tuveson,David A. Tuveson +28 more
TL;DR: A new population of CAFs that express MHC class II and CD74, but do not express classical co-stimulatory molecules are described, and it is found that they activate CD4+ T cells in an antigen-specific fashion in a model system, confirming their putative immune-modulatory capacity.
References
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Paolo P. Provenzano,Carlos Cuevas,Amy Chang,Vikas K. Goel,Daniel D. Von Hoff,Sunil R. Hingorani,Sunil R. Hingorani +6 more
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Leukocyte Complexity Predicts Breast Cancer Survival and Functionally Regulates Response to Chemotherapy
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Normalizing Tumor Microenvironment to Treat Cancer: Bench to Bedside to Biomarkers
TL;DR: Current efforts are directed at identifying predictive biomarkers and more-effective strategies to normalize the tumor microenvironment for enhancing anticancer therapies.
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