Post-surgery fluids promote transition of cancer stem cell- to-endothelial and AKT/mTOR activity, contributing to relapse of giant cell tumors of bone
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Flavio Fazioli1,*, Gianluca Colella2,*, Roberta Miceli3, Mariano Giuseppe Di Salvatore1, Michele Gallo1, Serena Boccella4, Annarosaria De Chiara5, Carlo Ruosi2,* and Filomena de Nigris6,*
1Division of Musculoskeletal Oncology Surgery, National Cancer Institute G. Pascale, Naples, Italy
2Department of Human Health, Federico II University of Naples, Naples, Italy
3S.C. Cellular Biology and Biotherapy, National Cancer Institute G. Pascale, Naples, Italy
4Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples Italy
5Division of Pathology, National Cancer Institute G. Pascale Foundation, Naples, Italy
6Department of Biochemistry, Biophysics and General Pathology, University of Campania “Luigi Vanvitelli”, Naples Italy
*These authors have contributed equally to this work
Filomena de Nigris, email: Filomena.firstname.lastname@example.org
Keywords: recurrences, sarcoma, angiogenesis, stem cells, AKT
Received: March 31, 2017 Accepted: May 29, 2017 Published: June 28, 2017
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.
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