Pharmacological inhibition of FGF receptor signaling inhibits LNCaP prostate tumor growth, promatrilysin, and PSA expression.

Abstract

Previously we have shown that the matrix metalloproteinase matrilysin (MMP-7) is overexpressed in human prostate cancers compared with normal epithelium. However, the mechanism for this overexpression is not understood. Human prostate fibroblasts have been shown to express certain fibroblast growth factors (FGFs), including FGF-1. Evidence from our laboratory and others has indicated that FGFs can regulate the expression of certain matrix metalloproteinases, including matrilysin. The goal of this study was to determine whether pharmacological inhibition of FGFR signaling would alter LNCaP tumor growth as well as expression of promatrilysin when LNCaP cells were co-injected subcutaneously with human prostate fibroblasts into athymic nude mice. For these inhibitor studies, AG1-X2 beads were coated with the pharmacological FGFR inhibitor SU5402 and were co-injected along with LNCaP and human prostate fibroblast cells (PF). Mice injected with LNCaP/PF and LNCaP/PF/beads alone demonstrated significant tumor growth, whereas mice injected with LNCaP/PF/SU5402-coated beads showed a significant decrease in tumor volume and weight. Immunohistochemical analysis showed that significant promatrilysin expression in tumors was inhibited by the FGFR inhibitor SU5402. Serum prostate-specific antigen (PSA) and promatrilysin levels were measured by enzyme-linked immunosorbent assay. The mice injected with LNCaP/PF and LNCaP/PF/beads expressed promatrilysin and serum PSA levels that were inhibited by co-injecting with SU5402. Therefore, pharmacological inhibition of FGF receptor signaling results in a decrease in the growth of LNCaP tumors generated subcutaneously by co-injecting LNCaP cells and human prostate fibroblasts. The inhibition in tumor growth was correlated with a decrease in tumor promatrilysin expression and a decrease in serum promatrilysin and PSA.

• Authors: Thirupandiyur S Udayakumar, Elisabeth L Bair, Raymond B Nagle, G Timothy Bowden
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 38 Issue 2 Pg. 70-7 (Oct 2003) ISSN: 0899-1987 [Print] United States
• PMID: 14502646 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 2003 Wiley-Liss, Inc.

Chemical References

• Enzyme Precursors
• Pyrroles
• Receptors, Fibroblast Growth Factor
• SU 5402
• Prostate-Specific Antigen
• Metalloendopeptidases
• promatrilysin

Topics

• Animals
• Carcinoma (metabolism, pathology, prevention & control)
• Enzyme Precursors (metabolism)
• Humans
• Male
• Metalloendopeptidases (metabolism)
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Prostate-Specific Antigen (metabolism)
• Prostatic Neoplasms (metabolism, pathology, prevention & control)
• Pyrroles
• Receptors, Fibroblast Growth Factor (antagonists & inhibitors)
• Transplantation, Heterologous
• Tumor Cells, Cultured