Basic fibroblast growth factor impact on retinoblastoma progression and survival.
OBJECTIVE
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.
Cebulla
Colleen M
CM
Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida, USA.
Jockovich
Maria-Elena
ME
Piña
Yolanda
Y
Boutrid
Hinda
H
Alegret
Armando
A
Kulak
Amy
A
Hackam
Abigail S
AS
Bhattacharya
Sanjoy K
SK
Feuer
William J
WJ
Murray
Timothy G
TG
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016190:Carboplatin / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000494:pharmacology; D019084:Fluorescent Antibody Technique, Indirect; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D019572:Retinal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D012175:Retinoblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured / Q000378:metabolism
D000970:Antineoplastic Agents; D016222:Fibroblast Growth Factor 2; D016190:Carboplatin