Targeting FGFR/PDGFR/VEGFR impairs tumor growth, angiogenesis, and metastasis by effects on tumor cells, endothelial cells, and pericytes in pancreatic cancer.

Abstract

Activation of receptor tyrosine kinases, such as fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and VEGF receptor (VEGFR), has been implicated in tumor progression and metastasis in human pancreatic cancer. In this study, we investigated the effects of TKI258, a tyrosine kinase inhibitor to FGFR, PDGFR, and VEGFR on pancreatic cancer cell lines (HPAF-II, BxPC-3, MiaPaCa2, and L3.6pl), endothelial cells, and vascular smooth muscle cells (VSMC). Results showed that treatment with TKI258 impaired activation of signaling intermediates in pancreatic cancer cells, endothelial cells, and VSMCs, even upon stimulation with FGF-1, FGF-2, VEGF-A, and PDGF-B. Furthermore, blockade of FGFR/PDGFR/VEGFR reduced survivin expression and improved activity of gemcitabine in MiaPaCa2 pancreatic cancer cells. In addition, motility of cancer cells, endothelial cells, and VSMCs was reduced upon treatment with TKI258. In vivo, therapy with TKI258 led to dose-dependent inhibition of subcutaneous (HPAF-II) and orthotopic (L3.6pl) tumor growth. Immunohistochemical analysis revealed effects on tumor cell proliferation [bromodeoxyuridine (BrdUrd)] and tumor vascularization (CD31). Moreover, lymph node metastases were significantly reduced in the orthotopic tumor model when treatment was initiated early with TKI258 (30 mg/kg/d). In established tumors, TKI258 (30 mg/kg/d) led to significant growth delay and improved survival in subcutaneous and orthotopic models, respectively. These data provide evidence that targeting FGFR/PDFGR/VEGFR with TKI258 may be effective in human pancreatic cancer and warrants further clinical evaluation.

• Authors: Johannes Taeger, Christian Moser, Claus Hellerbrand, Maria E Mycielska, Gabriel Glockzin, Hans J Schlitt, Edward K Geissler, Oliver Stoeltzing, Sven A Lang
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 10 Issue 11 Pg. 2157-67 (Nov 2011) ISSN: 1538-8514 [Electronic] United States
• PMID: 21885862 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Receptors, Fibroblast Growth Factor
• Fibroblast Growth Factors
• Receptors, Platelet-Derived Growth Factor
• Receptors, Vascular Endothelial Growth Factor

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Endothelial Cells (drug effects, metabolism)
• Fibroblast Growth Factors (metabolism)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Metastasis
• Neovascularization, Pathologic (drug therapy, metabolism)
• Pancreatic Neoplasms (blood supply, genetics, metabolism, pathology)
• Pericytes (drug effects, metabolism)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Receptors, Fibroblast Growth Factor (antagonists & inhibitors, genetics)
• Receptors, Platelet-Derived Growth Factor (antagonists & inhibitors, genetics)
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors, genetics)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays