Soft tissue sarcomas (STS) are a rare group of mesenchymal solid tumors with heterogeneous genetic profiles and clinical features. Systemic chemotherapy is the backbone treatment for advanced STS; however, STS frequently acquire resistance to standard therapies, which highlights the need to improve treatments and identify novel therapeutic targets. Increases in the knowledge of the molecular pathways that drive sarcomas have brought to light different molecular alterations that cause tumor initiation and progression. These findings have triggered a breakthrough of targeted therapies that are being assessed in clinical trials. Cancer stem cells (CSCs) exhibit mesenchymal stem cell (MSC) features and represent a subpopulation of tumor cells that play an important role in tumor progression, chemotherapy resistance, recurrence and metastasis. In fact, CSCs phenotypes have been identified in sarcomas, allied to drug resistance and tumorigenesis. Herein, we will review the published evidence of CSCs in STS, discussing the molecular characteristic of CSCs, the commonly used isolation techniques and the new possibilities of targeting CSCs as a way to improve STS treatment and consequently patient outcome.

A translational study was designed to analyze the expression of nucleotide excision repair (NER) and homologous recombination (HR) genes as potential predictive biomarkers for trabectedin in soft-tissue sarcoma (STS). This study is part of a randomized phase II trial comparing trabectedin plus doxorubicin versus doxorubicin in advanced STS. Gene expression levels were evaluated by qRT-PCR, while CUL4A protein levels were quantified by immunohistochemistry. Expression levels were correlated with patients’ progression-free survival (PFS) and overall survival (OS). Gene expression was also evaluated in cell lines and correlated with trabectedin sensitivity. In doxorubicin arm and in the whole series, which includes samples from both arms, no significant differences in terms of PFS were observed amongst the analyzed genes. In the group treated with trabectedin plus doxorubicin, the median of PFS was significantly longer in cases with CUL4A, ERCC1, or ERCC5 overexpression, while BRCA1 expression did not correlated with PFS. Gene expression had no prognostic influence in OS. CUL4A protein levels correlated with worse PFS in doxorubicin arm and in the whole series. In cell lines, only overexpression of ERCC1 was significantly correlated with trabectedin sensitivity. In conclusion, CUL4A, ERCC5, and mainly ERCC1 acted as predictive factors for trabectedin efficacy in advanced STS.