Post-surgery fluids promote transition of cancer stem cell-to-endothelial and AKT/mTOR activity, contributing to relapse of 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.

STAT3 Gene Silencing by Aptamer-siRNA Chimera as Selective Therapeutic for Glioblastoma

“…We therefore also addressed the intra-tumor vascular response to AsiC administration and show that treatments are able to reduce the presence of human CD31- and WT1-expressing cells ( Figure 5 ), as an indication of the inhibition of neovascularization. 50 Since WT1 has been reported as key regulator of cancer growth by modulating tumor vascularization, immune response and metastasis formation in several cancer types, 44 the evidence that the AsiC conjugate is able to efficiently reduce WT1-expressing cells reinforces its potential as candidate for GBM treatment. In addition, we show that AsiC-treated tumors have reduced levels of the immune checkpoint protein PDL1, whose expression has been correlated with the activation of JAK/STAT3 oncogenic signaling.…”

Cancer Stem Cells and Its Role in Angiogenesis and Vasculogenic Mimicry in Gastrointestinal Cancers

“…In this regard, it has been described that primary and established sarcoma cell lines in contact with post-surgery fluids from Giant cell tumors of bone patients can enrich CD44/CD117 cell population and AKT/mTOR pathway activation. Moreover, it has been proved that prolonged stimulation results in transdifferentiation of tubule-like structures that express endothelial markers, such as, VE-Cadherin and CD31 (94). Additionally, CSCs switch on NF-κB and STAT3 signal pathways via CCL5-CCR1/CCR3/CCR5, stimulating endothelial differentiation and tubule formation (95).…”

Role of cancer stem cells in the development of giant cell tumor of bone

“…GCTB being considered as benign tumor as well as aggressive at local platform has been confirmed to exhibit local relapse [80]. The various forms of therapies prevailing today show some potential failure in the treatment of GCTB and the reason behind this failure has been confirmed to be the accumulation of stem cells which essentially contribute to the several characteristics such as; tumor initiation and relapse [81].…”

“…Several researchers investigated the pivotal role of mTOR signaling in CSCs. It was observed that mTOR exhibits the regulation of expression and survival in CSCs to a greater extent [80]. mTOR being extremely sealed serine-threonine kinase observed specifically in mammals (animals and humans) consists of two important constituents, mTORC1 and mTORC2.…”