title: Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis.
abstract: Anti-platelet-derived growth factor (PDGF) drugs are routinely used in front-line therapy for the treatment of various cancers, but the molecular mechanism underlying their dose-dependent impact on vascular remodelling remains poorly understood. Here we show that anti-PDGF drugs significantly inhibit tumour growth and metastasis in high PDGF-BB-producing tumours by preventing pericyte loss and vascular permeability, whereas they promote tumour cell dissemination and metastasis in PDGF-BB-low-producing or PDGF-BB-negative tumours by ablating pericytes from tumour vessels. We show that this opposing effect is due to PDGF-β signalling in pericytes. Persistent exposure of pericytes to PDGF-BB markedly downregulates PDGF-β and inactivation of the PDGF-β signalling decreases integrin α1β1 levels, which impairs pericyte adhesion to extracellular matrix components in blood vessels. Our data suggest that tumour PDGF-BB levels may serve as a biomarker for selection of tumour-bearing hosts for anti-PDGF therapy and unsupervised use of anti-PDGF drugs could potentially promote tumour invasion and metastasis.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm 171 77, Sweden.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Hosaka
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Yang
authors.forename: Takahiro
authors.initials: T
authors.lastname: Seki
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakamura
authors.forename: Patrik
authors.initials: P
authors.lastname: Andersson
authors.forename: Pegah
authors.initials: P
authors.lastname: Rouhi
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Yang
authors.forename: Lasse
authors.initials: L
authors.lastname: Jensen
authors.forename: Sharon
authors.initials: S
authors.lastname: Lim
authors.forename: Ninghan
authors.initials: N
authors.lastname: Feng
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xue
authors.forename: Xuri
authors.initials: X
authors.lastname: Li
authors.forename: Ola
authors.initials: O
authors.lastname: Larsson
authors.forename: Toshio
authors.initials: T
authors.lastname: Ohhashi
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000077214:Becaplermin; D001549:Benzamides / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D005354:Fibrosarcoma / Q000098:blood supply* / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D039222:Integrin alpha1beta1 / Q000235:genetics / Q000276:immunology; D008175:Lung Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D051379:Mice; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D020286:Pericytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001549:Benzamides; D039222:Integrin alpha1beta1; D010879:Piperazines; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D000077214:Becaplermin; D000068877:Imatinib Mesylate