Dose-dependent dual roles of PDGF-BBPDGFR- in vascular remodeling and opposing effects of anti-PDGF drug-induced metastasis

Anti-PDGF agents are routinely used as a key component in front-line therapy for the treatment of various cancers. However, molecular mechanisms underlying their impact on vascular remodeling in relation to the dose issue remain poorly understood. Here we show that in high PDGF-BB-producing tumors, anti-PDGF drugs significantly inhibited tumor growth and metastasis by preventing pericyte (PC) loss and vascular permeability. Surprisingly, the same anti-PDGF-BB drugs promoted tumor cell dissemination and metastasis in PDGF-BB-low-producing or negative tumors by ablating PCs from tumor vessels. At the molecular level, we show that the PDGFR- signaling pathway in PCs mediated the opposing effects and persistent exposure of PCs to PDGF-BB led to marked downregulation of PDGFR-. Inactivation of the PDGFR- signaling system led to decreased levels of integrin 11, resulted in impaired adhesion of PCs to collagen I, IV and laminin, two principal extracellular matrix components in blood vessels for interaction with these integrins. Our data suggest that tumor PDGF-BB levels may serve as an important biomarker for selection of tumor-bearing hosts for beneficial therapy and unsupervised practice of this group of drugs could potentially promote tumor invasion and metastasis.

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Hosaka K, Yang Y, Seki T, Nakamura M, Andersson P, Rouhi P, Yang X, Jensen L, Lim S, Feng N, Xue Y, Li X, Larsson O, Ohhashi T, Cao Y