Chemoresistance-Related Stem Cell Signaling in Osteosarcoma and Its Plausible Contribution to Poor Therapeutic Response: A Discussion That Still Matters

Abstract

Osteosarcoma is amongst the most prevalent bone sarcomas and majorly afflicts children and adolescents. Therapeutic regimens based on the triad of doxorubicin, cisplatin and methotrexate have been used as the state-of-the-art approach to clinical treatment and management, with no significant improvements in the general outcomes since their inception in the early 1970s. This fact raises the following problematic questions: Why do some patients still relapse despite an initial good response to therapy? Why do nearly 30% of patients not respond to neoadjuvant therapies? Does residual persistent disease contribute to relapses and possible metastatic dissemination? Accumulating evidence suggests that chemoresistant cancer stem cells may be the major culprits contributing to those challenging clinical outcomes. Herein, we revisit the maneuvers that cancer stem cells devise for eluding cell killing by the classic cytotoxic therapies used in osteosarcoma, highlighting studies that demonstrate the complex crosstalk of signaling pathways that cancer stem cells can recruit to become chemoresistant.

Construction of a novel mRNAsi-related risk model for predicting prognosis and immunotherapy response in osteosarcoma

“…CSC surface markers are more difficult to identify in OS originating from mesenchymal cells than in tumors originating from other tissue types. The analysis of histopathological specimens also indicates that in some cases, tumors are organized in a stratified manner, and the leading CSC is the producer of phenotypic and functional heterogeneity ( 15 ). mRNAsi is a cancer stem cell index that describes the degree of similarity between tumors and stem cells and can be considered as a quantification of cancer stem cells ( 17 ).…”

“…Clinically, the use of identified CSC markers is very limited. Also, stem cells from different tissues are not identical; for example, the differences in location, self-renewal, and differentiation are usually reflected in specific combinations of phenotypic markers ( 15 ). Most marker-labeled heterogeneous stem cell populations indicate that their characterization and isolation must be based on a combination of markers using multiple surface markers, and extracellular as well as intracellular markers ( 16 ).…”

Single-cell RNA sequencing reveals the immune microenvironment landscape of osteosarcoma before and after chemotherapy

“…Previous studies have mainly focused on osteoblasts and osteoclasts, and few studies have evaluated the whole TIME in OS. Remarkably, studies have reported that the TIME of OS correlates with chemotherapy response [ 32 , 33 ]. However, studies that reported chemotherapy's effect on OS TIME are still lacking.…”

CircDOCK1 Regulates miR-186/DNMT3A to Promote Osteosarcoma Progression

“…In young adults and children, OS is a common osseous malignancy [ 17 , 18 ]. Although the five-year survival was elevated over the last 3 decades for the OS population, their prognosis is still poor, making it necessary to discover new diagnostic and therapeutic targets for the management of OS [ 19 , 20 , 21 ].…”