title: Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2.
abstract: Strategies to target angiogenesis include inhibition of the vessel-stabilizing properties of vascular pericytes. Pericyte depletion in early-stage non-hypoxic tumors suppressed nascent angiogenesis, tumor growth, and lung metastasis. In contrast, pericyte depletion in advanced-stage hypoxic tumors with pre-established vasculature resulted in enhanced intra-tumoral hypoxia, decreased tumor growth, and increased lung metastasis. Furthermore, depletion of pericytes in post-natal retinal blood vessels resulted in abnormal and leaky vasculature. Tumor transcriptome profiling and biological validation revealed that angiopoietin signaling is a key regulatory pathway associated with pericyte targeting. Indeed, pericyte targeting in established mouse tumors increased angiopoietin-2 (ANG2/Angpt2) expression. Depletion of pericytes, coupled with targeting of ANG2 signaling, restored vascular stability in multiple model systems and decreased tumor growth and metastasis. Importantly, ANGPT2 expression correlated with poor outcome in patients with breast cancer. These results emphasize the potential utility of therapeutic regimens that target pericytes and ANG2 signaling in metastatic breast cancer.
authors.affiliation: Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Doruk
authors.initials: D
authors.lastname: Keskin
authors.affiliation: Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jiha
authors.initials: J
authors.lastname: Kim
authors.affiliation: Division of Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Vesselina G
authors.initials: VG
authors.lastname: Cooke
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Chia-Chin
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sugimoto
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Chenghua
authors.initials: C
authors.lastname: Gu
authors.affiliation: The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Michele
authors.initials: M
authors.lastname: De Palma
authors.affiliation: Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA. Electronic address: rkalluri@mdanderson.org.
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
authors.affiliation: Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA. Electronic address: vlebleu@mdanderson.org.
authors.forename: Valerie S
authors.initials: VS
authors.lastname: LeBleu
mesh_terms: D042702:Angiopoietin-2 / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D000941:Antigens / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D000068877:Imatinib Mesylate / Q000494:pharmacology; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D020286:Pericytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011509:Proteoglycans / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D042702:Angiopoietin-2; D000906:Antibodies; D000941:Antigens; D000068877:Imatinib Mesylate; D047428:Protein Kinase Inhibitors; D011509:Proteoglycans; D020797:Receptor, Platelet-Derived Growth Factor beta; D000099216:Chondroitin Sulfate Proteoglycan 4