transforming-growth-factor-beta and Giant-Cell-Tumors

Giant cell tumor (GCT) of bone is a locally aggressive neoplasm with a high incidence of recurrence, usually at the site of previous osseous involvement. Primary and recurrent intraosseous lesions typically are lytic and do not show evidence of tumor-associated osteogenesis. Rarely, GCT recurs or is primary within soft tissue, and not infrequently, these extraosseous lesions show metaplastic bone formation that is visible radiographically. The authors report two recurrent and one primary case of extraosseous GCT, all of which exhibited significant deposits of metaplastic bone localized to the periphery of the lesions. In situ hybridization showed messenger RNA (mRNA) for transforming growth factor beta1 (TGF-beta1) and transforming growth factor beta2 (TGF-beta2) in neoplastic stromal cells and osteoclast-like giant cells within the recurrent and primary extraosseous tumors as well as in active osteoblasts on the surfaces of recently formed spicules of metaplastic bone. In situ hybridization also revealed mRNA for TGF-beta1 and TGF-beta2 in primary intraosseous tumors from these cases and from four cases in which neither extraosseous recurrence nor osseous metaplasia was identified. In the microenvironment of the extraosseous soft tissue, production of these osteoinductive growth factors by GCT may have a paracrine effect on mesenchymal progenitor cells, thereby stimulating the osteoblastic differentiation and metaplastic bone formation associated with these lesions.

Topics: Adult; Base Sequence; DNA Probes; Female; Gene Expression; Giant Cell Tumor of Bone; Giant Cell Tumors; Humans; In Situ Hybridization; Metaplasia; Middle Aged; Molecular Sequence Data; Neoplasm Recurrence, Local; Ossification, Heterotopic; Soft Tissue Neoplasms; Transforming Growth Factor beta

Giant cell tumor of bone (GCT) is a primary bone neoplasm with unique cytogenetic findings including telomeric associations. Elevated expression of message RNA for transforming growth factor beta (TGF beta), but not transforming growth factor alpha (TGF alpha), has been reported in this tumor. Further investigation of GCT was undertaken to determine whether genetic loci for TGF beta in GCT patients with and without chromosome abnormalities are altered. Due to the reported TGF beta overexpression in GCT, qualitative and quantitative Southern blot analyses with TGF beta 1 and TGF beta 2 and an internal control probe (p3-21) were performed with tumor DNA and DNA from normal tissue on ten patients with GCT and control individuals. No obvious TGF beta 1 or TGF beta 2 gene alterations were detected. Normal copy numbers were calculated when comparing tumor and normal DNA from GCT patients as well as DNA from control individuals. Abnormal chromosome findings, including telomeric associations, marker chromosome, double minutes, chromosome fragments, ring chromosomes (possibly representing intra-chromosome telomeric associations), and polyploid cells were observed in seven of the ten patients with GCT. Chromosomes 11, 16, 19, 20, and 21 were most commonly observed in telomeric associations, with the terminus of the long arm of chromosome 19 being the most frequent. We conclude that there are no TGF beta 1 or TGF beta 2 gene alterations detected in GCT with the methodologies described, and that telomeric associations are a reproducible cytogenetic characteristic of this neoplasm.

Topics: Adult; Bone Neoplasms; Child; Chromosome Aberrations; Chromosomes, Human, Pair 19; DNA, Neoplasm; Female; Giant Cell Tumors; Humans; Male; Middle Aged; Transforming Growth Factor beta

Tumor specimens from 15 patients with giant cell tumor (GCT) of bone were cytogenetically analyzed. A subset of five individuals had tumor cells harvested and polyadenylated RNA isolated. Multiple Northern blots were performed utilizing radiolabeled probes for the growth factors TGF beta 1, TGF beta 2, TGF beta 3, and TGF alpha (TGF, transforming growth factor). RNAs from other types of neoplasms and nonneoplastic cells were examined as controls. The most consistent cytogenetic abnormality detected involved multiple telomeric associations (TAs), most frequently involving the terminus of the long arm of chromosome 19 (19q). Northern blot analysis revealed a consistent expression of TGF beta 1 and TGF beta 2 with an inconsistent mRNA expression for the other TGFs. There was a relative overexpression of mRNA for TGF beta 2. The gene location for TGF beta 1 is near the 19q terminus and thus it is speculated that TGF beta may play a role in the neoplastic transformation of GCT.

Topics: Adult; Blotting, Northern; Bone Neoplasms; Cell Transformation, Neoplastic; Child; Chromosomes, Human, Pair 19; Female; Gene Expression; Giant Cell Tumors; Humans; Male; Middle Aged; Radioligand Assay; Telomere; Transforming Growth Factor alpha; Transforming Growth Factor beta