Transforming growth factor-beta isoform and receptor expression in chondrosarcoma of bone.
It has been shown that transforming growth factor-beta (TGF-beta) has a potent stimulatory effect on the growth of chondrosarcoma cells in vitro. In order to examine the production of this family of growth factors and their receptors in vivo, we studied the expression of TGF-beta isoforms 1, 2, and 3 and of TGF-beta receptor types I and II (TGF-betaRI and TGF-betaRII) in a series of 24 chondrosarcomas of bone using immunohistochemistry and reverse-transcription polymerase chain reaction analysis. For comparison, five enchondromas and five osteochondromas were also analyzed. TGF-beta1 was expressed in 3 benign lesions (30%) and 18 chondrosarcomas (75%), with a significantly higher expression in grade-2 and -3 tumors than in grade-1 tumors ( P=0.002). TGF-beta2 was identified in 8 benign lesions (89%) and 21 chondrosarcomas (87.5%), with increased expression in grade-2 and -3 chondrosarcomas in comparison with grade-1 tumors ( P=0.05). TGF-beta3 was detected in 6 benign lesions (60%) and 17 chondrosarcomas (70.8%), with no significant differences between chondrosarcomas of different histologic grade ( P=0.6). Twenty-three chondrosarcomas (95.8%) expressed both TGF-beta receptor types I and II. Reverse-transcription polymerase chain reaction analysis performed on ten chondrosarcomas confirmed the presence of low or absent levels of TGF-beta1 and -beta2 mRNA in grade-1 chondrosarcomas, while grade-2 chondrosarcomas presented high levels of transcript of both cytokines. High levels of TGF-betaRI and RII mRNA were also detected. Chondrosarcomas with TGF-beta1 and TGF-beta2 overexpression (>20% of tumor cells) had a significantly higher expression of the cell proliferation marker MIB-1 ( P=0.006 and P=0.0003, respectively), while no significant correlation was found between TGF-beta3 expression and proliferative activity ( P=0.5). When TGF-beta isoform and receptor expression were examined with respect to disease-free survival, TGF-beta1 overexpression was significantly associated with a shorter disease-free survival ( P=0.004, log-rank test). Our data indicate that TGF-beta isoforms are produced by neoplastic cells of chondrosarcomas and could have a potential role as autocrine growth stimulators in these neoplasms.
Masi
Laura
L
Endocrine Unit, University of Florence Medical School, Florence, Italy.
Malentacchi
Cecilia
C
Campanacci
Domenico
D
Franchi
Alessandro
A
D030201:Activin Receptors, Type I / Q000032:analysis / Q000235:genetics; D000328:Adult; D000368:Aged; D034961:Antigens, Nuclear; D001859:Bone Neoplasms / Q000737:chemistry*; D002813:Chondrosarcoma / Q000737:chemistry*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000032:analysis; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics*; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3
D034961:Antigens, Nuclear; D019394:Ki-67 Antigen; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; C509041:TGFB2 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II