Implication for Cancer Stem Cells in Solid Cancer Chemo-Resistance: Promising Therapeutic Strategies Based on the Use of HDAC Inhibitors.
Maria Serena RocaElena Di GennaroAlfredo BudillonPublished in: Journal of clinical medicine (2019)
Resistance to therapy in patients with solid cancers represents a daunting challenge that must be addressed. Indeed, current strategies are still not effective in the majority of patients; which has resulted in the need for novel therapeutic approaches. Cancer stem cells (CSCs), a subset of tumor cells that possess self-renewal and multilineage differentiation potential, are known to be intrinsically resistant to anticancer treatments. In this review, we analyzed the implications for CSCs in drug resistance and described that multiple alterations in morphogenetic pathways (i.e. Hippo, Wnt, JAK/STAT, TGF-, Notch, Hedgehog pathways) were suggested to be critical for CSC plasticity. By interrogating The Cancer Genome Atlas (TCGA) datasets, we first analyzed the prevalence of morphogenetic pathways alterations in solid tumors with associated outcomes. Then, by highlighting epigenetic relevance in CSC development and maintenance, we selected histone deacetylase inhibitors (HDACi) as potential agents of interest to target this subpopulation based on the pleiotropic effects exerted specifically on altered morphogenetic pathways. In detail, we highlighted the role of HDACi in solid cancers and,specifically,in the CSC subpopulation and we pointed out some mechanisms by which HDACi are able to overcome drug resistance and to modulate stemness. Although, further clinical and preclinical investigations should be conducted to disclose the unclear mechanisms by which HDACi modulate several signaling pathways in different tumors. To date, several lines of evidence support the testing of novel combinatorial therapeutic strategies based on the combination of drugs commonly used in clinical practice and HDACi to improve therapeutic efficacy in solid cancer patients.
Keyphrases
- cancer stem cells
- histone deacetylase
- papillary thyroid
- clinical practice
- stem cells
- signaling pathway
- gene expression
- cell proliferation
- newly diagnosed
- squamous cell
- risk factors
- childhood cancer
- dna methylation
- cell therapy
- lymph node metastasis
- radiation therapy
- squamous cell carcinoma
- photodynamic therapy
- adipose tissue
- transforming growth factor
- mesenchymal stem cells
- young adults
- induced apoptosis
- drug delivery
- endoplasmic reticulum stress
- combination therapy