Expression of insulin-like growth factor pathway proteins in rhabdomyosarcoma: IGF-2 expression is associated with translocation-negative tumors.
Recent studies have shown a significant involvement of insulin-like growth factor (IGF) signaling components in the pathogenesis of rhabdomyosarcoma (RMS). Furthermore, there has been some evidence to indicate that differential expression of IGF pathway genes can distinguish RMS subtypes. The present study utilized immunohistochemistry to determine the expression patterns of IGF1, IGF2, IGF binding protein 2 (IGFBP2), IGF receptor 1 (IGF1R), and IGF receptor 2 (IGF2R) in 24 embryonal RMS (ERMS) and 8 alveolar RMS (ARMS). A majority of tumors were positive for IGF2, IGFBP2, IGF1R, and IGF2R and negative for IGF1 expression. However, only IGF2 showed a significant difference in expression between the ERMS and ARMS subtypes, with higher levels of expression in ERMS (P = 0.0003). Within the ARMS subtype, IGF2 positivity was limited to PAX/FKHR translocation-negative tumors. The staining pattern for all 5 proteins was diffuse cytoplasmic in the majority of tumors. Analysis of RMS cell lines by real-time reverse transcriptase-polymerase chain reaction for IGF2 expression revealed significantly higher mean expression levels in ERMS and translocation-negative ARMS cell lines when compared to translocation-positive ARMS cell lines (P = 0.0027). Stable introduction of PAX3/FKHR into an ERMS cell line also demonstrated a significant reduction in IGF2 expression. The results of this study show that expression of the IGF2 ligand is associated with translocation-negative tumors and may serve as a diagnostic aid in distinguishing RMS subtypes. Furthermore, the in vitro results are supportive of a role for the PAX3/FKHR fusion gene in the inhibition of IGF2 expression.
Makawita
Shalini
S
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Ho
Michael
M
Durbin
Adam D
AD
Thorner
Paul S
PS
Malkin
David
D
Somers
Gino R
GR
D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D019085:Fluorescent Antibody Technique, Direct; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000032:analysis; D012208:Rhabdomyosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D046888:Tissue Array Analysis; D014178:Translocation, Genetic / Q000235:genetics*
D014408:Biomarkers, Tumor; D051858:Forkhead Transcription Factors; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D007335:Insulin-Like Growth Factor II