title: Inhibition of multiple vascular endothelial growth factor receptors (VEGFR) blocks lymph node metastases but inhibition of VEGFR-2 is sufficient to sensitize tumor cells to platinum-based chemotherapeutics.
abstract: Vascular endothelial growth factor receptors (VEGFR) have important roles in cancer, affecting blood and lymphatic vessel functionality as well as tumor cells themselves. We compared the efficacy of a VEGFR tyrosine kinase inhibitor, PTK787/ZK222584 (PTK/ZK), which targets the three VEGFRs, with blocking antibodies directed against VEGFR-2 (DC101) or VEGF-A (Pab85618) in a metastatic melanoma model. Although all inhibitors exerted comparable effects on primary tumor growth, only PTK/ZK significantly reduced lymph node metastasis formation. A comparable decrease in lymphatic vessel density following blockade of VEGFR-2 (DC101) or the three VEGFRs (PTK/ZK) was observed in the metastases. However, the functionality of lymphatics surrounding the primary tumor was more significantly disrupted by PTK/ZK, indicating the importance of multiple VEGFRs in the metastatic process. The antimetastatic properties of PTK/ZK were confirmed in a breast carcinoma model. B16/BL6 tumor cells express VEGF ligands and their receptors. Blockade of a VEGFR-1 autocrine loop with PTK/ZK inhibited tumor cell migration. Furthermore, the tumor cells also showed enhanced sensitivity to platinum-based chemotherapy in combination with PTK/ZK, indicating that autocrine VEGFRs are promoting tumor cell migration and survival. In summary, our results suggest that, in addition to blocking angiogenesis, combined inhibition of the three VEGFRs may more efficiently target other aspects of tumor pathophysiology, including lymphatic vessel functionality, tumor cell dissemination, survival pathways, and response to chemotherapeutic compounds.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. patrizia.sini@astrazeneca.com
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sini
authors.forename: Ivana
authors.initials: I
authors.lastname: Samarzija
authors.forename: Fabienne
authors.initials: F
authors.lastname: Baffert
authors.forename: Amanda
authors.initials: A
authors.lastname: Littlewood-Evans
authors.forename: Christian
authors.initials: C
authors.lastname: Schnell
authors.forename: Andreas
authors.initials: A
authors.lastname: Theuer
authors.forename: Sven
authors.initials: S
authors.lastname: Christian
authors.forename: Anja
authors.initials: A
authors.lastname: Boos
authors.forename: Holger
authors.initials: H
authors.lastname: Hess-Stumpp
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
authors.forename: Buddy
authors.initials: B
authors.lastname: Setyono-Han
authors.forename: Jeanette
authors.initials: J
authors.lastname: Wood
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Hynes
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology*; D006801:Humans; D008207:Lymphatic Metastasis; D008546:Melanoma, Experimental; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D002945:Cisplatin