Insulin-like growth factor-1 receptor in uveal melanoma: a predictor for metastatic disease and a potential therapeutic target.
OBJECTIVE
To investigate the expression of the insulin-like growth factor-1 receptor (IGF-1R) with special focus on its role in cell growth in uveal melanoma.


METHODS
Paraffin material from 36 clinicopathologically well characterized cases of primary uveal melanomas (18 of which had metastasized to the liver) with more than 15 years' follow-up was used for immunohistochemical analysis. In the experimental studies, three uveal melanoma cell lines (OCM-1, OCM-3, and 92-1) were used. The expression level of IGF-1R in the cell lines was modulated by glycosylation inhibitors, and the IGF-1R was neutralized with the antibody alphaIR-3. Expression of IGF-1R was assayed by Western blot analysis and immunohistochemistry. Cell growth and survival were analyzed by cell counting, thymidine incorporation, and viability assays.


RESULTS
Western blot analysis and immunohistochemistry confirmed that IGF-1R is expressed in uveal melanoma. Although 10 of 18 patients who died of metastasizing disease showed high IGF-1R expression, only 5 of 18 tumors from patients who survived for 15 years or more after enucleation exhibited a high IGF-1R expression. Kaplan-Meier analysis showed a significant association (P = 0.035) between a high IGF-1R expression and death due to metastatic uveal melanoma. Using in vitro experimental models, we found that inhibition of the IGF-1R activity (tyrosine phosphorylation) was associated with a drastic decrease in uveal melanoma cell viability.


CONCLUSIONS
These data suggest an important role of IGF-1R in uveal melanoma. The significant association between high IGF-1R expression and death due to metastatic disease may be explained by the fact that IGF-1 is mainly produced in the liver, which is the preferential site for uveal melanoma metastases. These data also point to the possibility of therapeutically interfering with IGF-1R, which appears to be expressed preferentially in uveal melanomas that appear to follow an aggressive clinical course.
All-Ericsson
Charlotta
C
St. Erik's Eye Hospital, Stockholm, Sweden.
Girnita
Leonard
L
Seregard
Stefan
S
Bartolazzi
Armando
A
Jager
Martine J
MJ
Larsson
Olle
O
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002455:Cell Division; D002470:Cell Survival; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008545:Melanoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011233:Precipitin Tests; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D014604:Uveal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology
D014408:Biomarkers, Tumor; D017526:Receptor, IGF Type 1