title: Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases.
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.
authors.affiliation: 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.
authors.forename: Nuh N
authors.initials: NN
authors.lastname: Rahbari
authors.affiliation: 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.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Kedrin
authors.affiliation: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Joao
authors.initials: J
authors.lastname: Incio
authors.affiliation: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: William W
authors.initials: WW
authors.lastname: Ho
authors.affiliation: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Hadi T
authors.initials: HT
authors.lastname: Nia
authors.affiliation: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Edrich
authors.affiliation: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Keehoon
authors.initials: K
authors.lastname: Jung
authors.affiliation: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Daubriac
authors.affiliation: 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.
authors.forename: Ivy
authors.initials: I
authors.lastname: Chen
authors.affiliation: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Heishi
authors.affiliation: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Martin
authors.affiliation: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Nir
authors.initials: N
authors.lastname: Maimon
authors.affiliation: Department of General, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01307, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Reissfelder
authors.affiliation: Department of General, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01307, Germany.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Weitz
authors.affiliation: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Yves
authors.initials: Y
authors.lastname: Boucher
authors.affiliation: Department of Hematology/Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Clark
authors.affiliation: Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Grodzinsky
authors.affiliation: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.affiliation: 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.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.affiliation: 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.
authors.forename: Dai
authors.initials: D
authors.lastname: Fukumura
mesh_terms: D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000009:adverse effects / Q000627:therapeutic use; D000068258:Bevacizumab / Q000009:adverse effects / Q000627:therapeutic use*; D001696:Biomechanical Phenomena; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology* / Q000628:therapy; D019008:Drug Resistance, Neoplasm; D005109:Extracellular Matrix / Q000473:pathology / Q000502:physiology; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D000860:Hypoxia / Q000209:etiology / Q000503:physiopathology; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D057170:Translational Research, Biomedical; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D000074322:Antineoplastic Agents, Immunological; D006025:Glycosaminoglycans; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C013786:A73025; D000068258:Bevacizumab; D006820:Hyaluronic Acid