2. Academic Validation
  3. Reduction of Liver Metastasis Stiffness Improves Response to Bevacizumab in Metastatic Colorectal Cancer

Reduction of Liver Metastasis Stiffness Improves Response to Bevacizumab in Metastatic Colorectal Cancer

  • Cancer Cell. 2020 Jun 8;37(6):800-817.e7. doi: 10.1016/j.ccell.2020.05.005.
Ying Shen 1,  Xiaohong Wang 2,  Junyan Lu 3,  Martin Salfenmoser 4,  Naita Maren Wirsik 4,  Nikolai Schleussner 4,  Andrea Imle 5,  Aida Freire Valls 6,  Praveen Radhakrishnan 4,  Jie Liang 7,  Guoliang Wang 4,  Thomas Muley 8,  Martin Schneider 4,  Carmen Ruiz de Almodovar 9,  Alba Diz-Muñoz 10,  Thomas Schmidt 11
Affiliations

Affiliations

  • 1 Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany; Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
  • 2 Biochemistry Center, University of Heidelberg, 69120 Heidelberg, Germany; Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China.
  • 3 Genome Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
  • 4 Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.
  • 5 Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
  • 6 Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany; European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
  • 7 Section of Molecular Immunology, Institute of Immunology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
  • 8 Thoracic Hospital, University Hospital Heidelberg, University Heidelberg, 69126 Heidelberg, Germany; Translational Lung Research Centre (TLRC) Heidelberg, Member of the German Centre for Lung Research (DZL), 69120 Heidelberg, Germany.
  • 9 Biochemistry Center, University of Heidelberg, 69120 Heidelberg, Germany; European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
  • 10 Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany. Electronic address: diz@embl.de.
  • 11 Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. Electronic address: thomas.schmidt1@med.uni-heidelberg.de.
PMID: 32516590 DOI: 10.1016/j.ccell.2020.05.005
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.

Keywords

CAFs; MAFs; RAS signaling; anti-angiogenic therapy; atomic force microscopy; bevacizumab; fibroblasts; metastatic colorectal cancer; tissue stiffness.

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