Open AccessPost-surgery fluids promote transition of cancer stem cell-to-endothelial and AKT/mTOR activity, contributing to relapse of giant cell tumors of bone
Author(s) -
Flavio Fazioli,
G Colella,
Roberta Miceli,
Mariano Giuseppe Di Salvatore,
Michele Gallo,
Serena Boccella,
Annarosaria De Chiara,
Carlo Ruosi,
Filomena de Nigris
Publication year - 2017
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.18783
Subject(s) - medicine , cd44 , cancer , angiogenesis , protein kinase b , pi3k/akt/mtor pathway , pathology , oncology , cell , biology , signal transduction , genetics , biochemistry
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.