Telomerase Activity in Giant Cell Tumors of Bone

Abstract

Giant cell tumors of bone (GCTB) are rare sarcomas with a high rate of unpredictable local relapse. Studies suggest that surgical methods affect recurrence, supporting the idea that local disease develops from re-growth of residual cancer cells. To identify early prognostic markers of individual risk of recurrence, we evaluated the effect of post-surgery fluids from a cohort of GCTB patients on growth of primary and established sarcoma cell lines, and mice xenograph. Post-surgery fluids increased cell growth and enhanced expression of CD44 ++ , the principal receptor for the extracellular matrix component hyaluronan and the mesenchymal stem marker CD117 +. Cancer cells became highly invasive and tumorigenic, acquiring stemness properties, and activated AKT/mTOR pathway. Prolonged stimulation with post-surgery fluids down-regulated the mesenchymal gene TWIST1 and Vimentin protein, and transdifferentiated cells into tubule-like structures positive to the endothelial markers VE-Cadherin and CD31 +. In mice, post-surgery fluids gave rise to larger and more vascularized tumors than control, while in patients AKT/mTOR pathway activation was associated with recurrence by logistic regression (Kaplan-Meier; P<0.001). These findings indicate that post-surgery fluids are an adjuvant in mechanisms of tumor regrowth, increasing stem cell growth and AKT/mTOR activity.

Telomeric associations correlate with telomere length reduction and clonal chromosome aberrations in giant cell tumor of bone

“…A recent study showed that ALT is not involved in GCTB (Forsyth et al, 2008). In line with previous results (Matsuo et al, 2007;Forsyth et al, 2008) we found expression of TERT, which encodes the catalytic subunit of telomerase, in all GCTBs, albeit at low and highly variable levels; the difference between the tumors with the highest and lowest expression levels was more than 50-fold. We could not, however, find any association between the expression level of TERT and telomere length or tas frequency.…”

“…One possible explanation for the increased frequency of tas would be a general decrease in telomere length, but previous attempts using different approaches to investigate such a relationship have yielded conflicting results (Schwartz et al, 1993(Schwartz et al, , 1995Matsuo et al, 2007;Forsyth et al, 2008). The results of the present study provide further indirect and direct support for an important role of telomere shortening in tas formation in GCTB.…”

“…Previous studies of GCTB attempting to elucidate the causes of tas in these tumors have largely focused on telomere length and the mechanisms regulating it. Some studies indicate a moderate reduction of the average telomere length in GCTBs, compared with normal leukocytes or muscle cells (Schwartz et al, 1993(Schwartz et al, , 1995Matsuo et al, 2007), whereas others have not detected any major difference (Forsyth et al, 2008). Furthermore, it has been shown that GCTBs display telomerase activity, but not alternative lengthening of telomeres (ALT) (Schwartz et al, 1995;Matsuo et al, 2007;Forsyth et al, 2008).…”

Cytogenetic analysis of 101 giant cell tumors of bone: Nonrandom patterns of telomeric associations and other structural aberrations

“…Support for this hypothesis was recently published (Sawyer et al, 2005;GebreMedhin et al, in press), but the causes of telomere dysfunction in GCTB, as well as the physical properties of tas, remain largely unknown. What has been revealed thus far is that there is a moderate reduction of telomere length in GCTB cells compared with normal tissues, despite telomerase activity, and that the majority of chromosome ends involved in tas are negative for telomeric sequences (Schwartz et al, 1993;Matsuo et al, 2007;Forsyth et al, 2008;GebreMedhin et al, in press).…”

Distribution and prognostic significance of human telomerase reverse transcriptase (hTERT) expression in giant-cell tumor of bone

“…3 In some reports, Campanacci grade III tumors demonstrated more aggressive behavior, 13,14 although statistical correlation has not been observed in other studies. [15][16][17] Campanacci grade III is defined as having indistinct borders on plain radiographs, 3 which generally, but not exclusively, predicts soft-tissue involvement histologically. Some authors have suggested that radiologic grade simply predicts the likelihood of adequate treatment, and it is the latter that influences clinical behavior.…”