1. Reduction of Liver Metastasis Stiffness Improves Response to Bevacizumab in Metastatic Colorectal Cancer.
- Author
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Shen Y, Wang X, Lu J, Salfenmoser M, Wirsik NM, Schleussner N, Imle A, Freire Valls A, Radhakrishnan P, Liang J, Wang G, Muley T, Schneider M, Ruiz de Almodovar C, Diz-Muñoz A, and Schmidt T
- Subjects
- Angiogenesis Inhibitors pharmacology, Angiotensin II Type 1 Receptor Blockers pharmacology, Angiotensin-Converting Enzyme Inhibitors pharmacology, Cancer-Associated Fibroblasts pathology, Captopril pharmacology, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Humans, Liver Neoplasms metabolism, Liver Neoplasms secondary, Losartan pharmacology, Lung Neoplasms drug therapy, Lung Neoplasms metabolism, Lung Neoplasms secondary, Tumor Microenvironment drug effects, Bevacizumab pharmacology, Cancer-Associated Fibroblasts drug effects, Colorectal Neoplasms drug therapy, Drug Synergism, Liver Neoplasms drug therapy, Neovascularization, Pathologic prevention & control, Renin-Angiotensin System drug effects
- Abstract
Tumors are influenced by the mechanical properties of their microenvironment. Using patient samples and atomic force microscopy, we found that tissue stiffness is higher in liver metastases than in primary colorectal tumors. Highly activated metastasis-associated fibroblasts increase tissue stiffness, which enhances angiogenesis and anti-angiogenic therapy resistance. Drugs targeting the renin-angiotensin system, normally prescribed to treat hypertension, inhibit fibroblast contraction and extracellular matrix deposition, thereby reducing liver metastases stiffening and increasing the anti-angiogenic effects of bevacizumab. Patients treated with bevacizumab showed prolonged survival when concomitantly treated with renin-angiotensin inhibitors, highlighting the importance of modulating the mechanical microenvironment for therapeutic regimens., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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