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.
Highlights
Giant cell tumor of bone (GCTB) is a rare, locally aggressive and vascularized tumor [1]
In order to characterize whether post-surgery wound fluids interact with tumor cells, patients affected by Giant cell tumors of bone (GCTB) (n=56) were enrolled in the study (Table 1)
This study includes the screening of a cohort of human GCTB samples and evaluates mTOR activation as predictive of recurrencefree survival
Summary
Giant cell tumor of bone (GCTB) is a rare, locally aggressive and vascularized tumor [1]. The hallmarks of this tumor are its aggressively lytic behavior, and high potential to local relapse (20%–50% of cases), correlated to type of surgical treatment and local presentation of the tumor [2, 3]. Stromal cells perform an essential function in the recruitment of tumor-associated myeloid lineage cells and formation of osteoclast-like giant cells responsible for bone desorption [5, 6]. II Local recurrence type Single Multiple Total percentage of recurrences Time to recurrence At follow up range (12-25mo.) Median (n=21) (n=14) (n=4)
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