Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases
The survival benefit of anti-vascular endothelial growth factor (VEGF) therapy in metastatic colorectal cancer (mCRC) patients is limited to a few months because of acquired resistance. We show that anti-VEGF therapy induced remodeling of the extracellular matrix with subsequent alteration of the ph...
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| Published in | Science translational medicine Vol. 8; no. 360; p. 360ra135 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
12.10.2016
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| Subjects | |
| Online Access | Get more information |
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| Abstract | The survival benefit of anti-vascular endothelial growth factor (VEGF) therapy in metastatic colorectal cancer (mCRC) patients is limited to a few months because of acquired resistance. We show that anti-VEGF therapy induced remodeling of the extracellular matrix with subsequent alteration of the physical properties of colorectal liver metastases. Preoperative treatment with bevacizumab in patients with colorectal liver metastases increased hyaluronic acid (HA) deposition within the tumors. Moreover, in two syngeneic mouse models of CRC metastasis in the liver, we show that anti-VEGF therapy markedly increased the expression of HA and sulfated glycosaminoglycans (sGAGs), without significantly changing collagen deposition. The density of these matrix components correlated with increased tumor stiffness after anti-VEGF therapy. Treatment-induced tumor hypoxia appeared to be the driving force for the remodeling of the extracellular matrix. In preclinical models, we show that enzymatic depletion of HA partially rescued the compromised perfusion in liver mCRCs after anti-VEGF therapy and prolonged survival in combination with anti-VEGF therapy and chemotherapy. These findings suggest that extracellular matrix components such as HA could be a potential therapeutic target for reducing physical barriers to systemic treatments in patients with mCRC who receive anti-VEGF therapy. |
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| AbstractList | The survival benefit of anti-vascular endothelial growth factor (VEGF) therapy in metastatic colorectal cancer (mCRC) patients is limited to a few months because of acquired resistance. We show that anti-VEGF therapy induced remodeling of the extracellular matrix with subsequent alteration of the physical properties of colorectal liver metastases. Preoperative treatment with bevacizumab in patients with colorectal liver metastases increased hyaluronic acid (HA) deposition within the tumors. Moreover, in two syngeneic mouse models of CRC metastasis in the liver, we show that anti-VEGF therapy markedly increased the expression of HA and sulfated glycosaminoglycans (sGAGs), without significantly changing collagen deposition. The density of these matrix components correlated with increased tumor stiffness after anti-VEGF therapy. Treatment-induced tumor hypoxia appeared to be the driving force for the remodeling of the extracellular matrix. In preclinical models, we show that enzymatic depletion of HA partially rescued the compromised perfusion in liver mCRCs after anti-VEGF therapy and prolonged survival in combination with anti-VEGF therapy and chemotherapy. These findings suggest that extracellular matrix components such as HA could be a potential therapeutic target for reducing physical barriers to systemic treatments in patients with mCRC who receive anti-VEGF therapy. |
| Author | Liu, Hao Reissfelder, Christoph Duda, Dan G Clark, Jeffrey W Ho, William W Chen, Ivy Huang, Yuhui Daubriac, Julien Weitz, Jurgen Fukumura, Dai Incio, Joao Jung, Keehoon Kedrin, Dmitriy Jain, Rakesh K Rahbari, Nuh N Edrich, Christina M Heishi, Takahiro Martin, John D Nia, Hadi T Grodzinsky, Alan J Boucher, Yves Maimon, Nir |
| Author_xml | – sequence: 1 givenname: Nuh N surname: Rahbari fullname: Rahbari, Nuh N organization: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Department of General, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01307, Germany – sequence: 2 givenname: Dmitriy surname: Kedrin fullname: Kedrin, Dmitriy organization: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA – sequence: 3 givenname: Joao surname: Incio fullname: Incio, Joao organization: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA – sequence: 4 givenname: Hao surname: Liu fullname: Liu, Hao organization: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA – sequence: 5 givenname: William W surname: Ho fullname: Ho, William W organization: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA – sequence: 6 givenname: Hadi T surname: Nia fullname: Nia, Hadi T organization: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA – sequence: 7 givenname: Christina M surname: Edrich fullname: Edrich, Christina M organization: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA – sequence: 8 givenname: Keehoon surname: Jung fullname: Jung, Keehoon organization: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA – sequence: 9 givenname: Julien surname: Daubriac fullname: Daubriac, Julien organization: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA – sequence: 10 givenname: Ivy surname: Chen fullname: Chen, Ivy organization: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Harvard School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA – sequence: 11 givenname: Takahiro surname: Heishi fullname: Heishi, Takahiro organization: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA – sequence: 12 givenname: John D surname: Martin fullname: Martin, John D organization: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA – sequence: 13 givenname: Yuhui surname: Huang fullname: Huang, Yuhui organization: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA – sequence: 14 givenname: Nir surname: Maimon fullname: Maimon, Nir organization: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA – sequence: 15 givenname: Christoph surname: Reissfelder fullname: Reissfelder, Christoph organization: Department of General, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01307, Germany – sequence: 16 givenname: Jurgen surname: Weitz fullname: Weitz, Jurgen organization: Department of General, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01307, Germany – sequence: 17 givenname: Yves surname: Boucher fullname: Boucher, Yves organization: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA – sequence: 18 givenname: Jeffrey W surname: Clark fullname: Clark, Jeffrey W organization: Department of Hematology/Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA – sequence: 19 givenname: Alan J surname: Grodzinsky fullname: Grodzinsky, Alan J organization: Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA – sequence: 20 givenname: Dan G surname: Duda fullname: Duda, Dan G organization: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA – sequence: 21 givenname: Rakesh K surname: Jain fullname: Jain, Rakesh K email: dai@steele.mgh.harvard.edu, jain@steele.mgh.harvard.edu organization: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. dai@steele.mgh.harvard.edu jain@steele.mgh.harvard.edu – sequence: 22 givenname: Dai surname: Fukumura fullname: Fukumura, Dai email: dai@steele.mgh.harvard.edu, jain@steele.mgh.harvard.edu organization: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. dai@steele.mgh.harvard.edu jain@steele.mgh.harvard.edu |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27733559$$D View this record in MEDLINE/PubMed |
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| Snippet | The survival benefit of anti-vascular endothelial growth factor (VEGF) therapy in metastatic colorectal cancer (mCRC) patients is limited to a few months... |
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| Title | Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases |
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