title: Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway.
abstract: The functional role of pericytes in cancer progression remains unknown. Clinical studies suggest that low numbers of vessel-associated pericytes correlated with a drop in overall survival of patients with invasive breast cancer. Using genetic mouse models or pharmacological inhibitors, pericyte depletion suppressed tumor growth but enhanced metastasis. Pericyte depletion was further associated with increased hypoxia, epithelial-to-mesenchymal transition (EMT), and Met receptor activation. Silencing of Twist or use of a Met inhibitor suppressed hypoxia and EMT/Met-driven metastasis. In addition, poor pericyte coverage coupled with high Met expression in cancer cells speculates the worst prognosis for patients with invasive breast cancer. Collectively, our study suggests that pericytes within the primary tumor microenvironment likely serve as important gatekeepers against cancer progression and metastasis.
authors.affiliation: Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
authors.forename: Vesselina G
authors.initials: VG
authors.lastname: Cooke
authors.forename: Valerie S
authors.initials: VS
authors.lastname: LeBleu
authors.forename: Doruk
authors.initials: D
authors.lastname: Keskin
authors.forename: Zainab
authors.initials: Z
authors.lastname: Khan
authors.forename: Joyce T
authors.initials: JT
authors.lastname: O'Connell
authors.forename: Yingqi
authors.initials: Y
authors.lastname: Teng
authors.forename: Michael B
authors.initials: MB
authors.lastname: Duncan
authors.forename: Liang
authors.initials: L
authors.lastname: Xie
authors.forename: Genta
authors.initials: G
authors.lastname: Maeda
authors.forename: Sylvia
authors.initials: S
authors.lastname: Vong
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Rafael M
authors.initials: RM
authors.lastname: Rocha
authors.forename: Aline
authors.initials: A
authors.lastname: Damascena
authors.forename: Ricardo R
authors.initials: RR
authors.lastname: Brentani
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D001557:Benzenesulfonates / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D000077547:Crizotinib; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism / Q000502:physiology; D000068877:Imatinib Mesylate; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000031:analogs & derivatives; D020286:Pericytes / Q000473:pathology / Q000502:physiology*; D010671:Phenylurea Compounds; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011720:Pyrazoles; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction; D000077157:Sorafenib; D000077210:Sunitinib; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D001557:Benzenesulfonates; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D010671:Phenylurea Compounds; D010879:Piperazines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D009536:Niacinamide; D000077547:Crizotinib; D000068877:Imatinib Mesylate; D000077157:Sorafenib; D019859:Proto-Oncogene Proteins c-met; D000077210:Sunitinib