Basic fibroblast growth factor impact on retinoblastoma progression and survival.

Abstract

PURPOSE:

Chemotherapy resistance is a problem in the treatment of advanced retinoblastoma (RB). Since basic fibroblast growth factor (bFGF) is a survival factor for neural precursor cells, bFGF was evaluated as a growth and chemoresistance factor in RB.

METHODS:

bFGF expression was analyzed in the LH-betaTag transgenic mouse model of RB and human RB cell lines by immunofluorescence, RT-PCR, and Western blot. Proliferation and apoptosis (TUNEL) assays were performed.

RESULTS:

bFGF levels significantly increased during tumorigenesis in transgenic RB, as a function of tumor status (P = 0.005). PCR and confocal microscopy confirmed that the human cell lines and primary tumors expressed bFGF. bFGF was localized to vascular and tumor cells and rarely to glial cells. Exogenous 18-kDa bFGF induced proliferation in two RB cell lines (WERI and Y79). Western blot analysis demonstrated 34-, 22-, and 18-kDa isoforms in transgenic RB and both cell lines. In TUNEL assays, chemoresistance to carboplatin-induced apoptosis was observed in the Y79 line, which expressed a higher ratio of high (34 kDa)- to low-molecular-weight bFGF isoforms, compared with the WERI line. Similar to other bFGF tumor studies, exogenous low-molecular-weight (18 kDa) bFGF (1 ng) significantly enhanced carboplatin-induced apoptosis in the more chemosensitive WERI, but not the chemoresistant Y79 line.

CONCLUSIONS:

RB tumors produce significant amounts of bFGF, and the differential production and response to isoforms of bFGF may have implications for invasive tumor growth and chemoresistance.

• Authors: Colleen M Cebulla, Maria-Elena Jockovich, Yolanda Piña, Hinda Boutrid, Armando Alegret, Amy Kulak, Abigail S Hackam, Sanjoy K Bhattacharya, William J Feuer, Timothy G Murray
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 49 Issue 12 Pg. 5215-21 (Dec 2008) ISSN: 1552-5783 [Electronic] United States
• PMID: 18614803 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents
• Fibroblast Growth Factor 2
• Carboplatin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Carboplatin (pharmacology)
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Disease Progression
• Drug Resistance, Neoplasm
• Fibroblast Growth Factor 2 (metabolism, pharmacology)
• Fluorescent Antibody Technique, Indirect
• Gene Expression Regulation, Neoplastic (physiology)
• Humans
• In Situ Nick-End Labeling
• Mice
• Mice, Transgenic
• Microscopy, Confocal
• Retinal Neoplasms (drug therapy, metabolism, mortality)
• Retinoblastoma (drug therapy, metabolism, mortality)
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Rate
• Tumor Cells, Cultured (metabolism)