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Implication for Cancer Stem Cells in Solid Cancer Chemo-Resistance: Promising Therapeutic Strategies Based on the Use of HDAC Inhibitors.

ABSTRACT: 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.

SUBMITTER: Roca MS

PROVIDER: S-EPMC6678716 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Implication for Cancer Stem Cells in Solid Cancer Chemo-Resistance: Promising Therapeutic Strategies Based on the Use of HDAC Inhibitors.

Roca Maria Serena MS Di Gennaro Elena E Budillon Alfredo A

Journal of clinical medicine 20190626 7

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 dru ...[more]

PMID: 31247937

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Project description:Background: Fatal cancer is often the result of spread, or metastasis, of a cancer cell from the site of its origin to a distant anatomic site. While the metastatic process and the foreign environment of the metastatic site impact a tumorâ??s biology, we continue to determine therapy for patients based upon their cancerâ??s site of origin. We have performed an unbiased analysis across metastatic solid tumors from common primary sites to determine the molecular impact of the metastatic process on site-specific biology and to identify novel therapeutic strategies. Methods: Global gene expression was used as a biological phenotype to perform a top-down analysis of 96 metastatic human tumors. Laser capture microdissection, RNA amplification, and microarray analysis were used to measure the transcription patterns of malignant epithelial cells. Genes, multi-gene expression â??signaturesâ??, and pathways associated with site of origin (SOO) and site of metastases (SOM) were identified using established computational approaches. SOO and SOM expression signatures were validated on multiple, independent datasets comprising 1217 samples (1104 samples from GSE2109 (Expression Project for Oncology) and 113 samples from GSE12630 (Monzon FA, Lyons-Weiler M, Buturovic LJ, Rigl CT et al. Multicenter validation of a 1,550-gene expression profile for identification of tumor tissue of origin. J Clin Oncol 2009 May 20;27(15):2503-8. PMID: 19332734). Reverse phase proteomics and in vitro tissue culture were used to validate associations between biological pathways, site of primary, and implicated therapeutic combinations. Findings: SOO has the dominant influence on solid tumor biology as samples segregate based upon their primary site during unsupervised hierarchical clustering. In addition, statistically significant associations are identified between single genes and pathways and each primary site investigated and SOO signatures for colon, breast, ovary, lung, and prostate cancers accurately identify primary site for independent samples of both local and metastatic tumors independent of degree of histological differentiation. The impact of SOM on tumor biology is evident as genes and pathways are significantly associated with metastatic site and SOM signatures can be generated but they are not strongly predictive when applied to localized tumors. Pathway analysis identified relatively increased expression of MYC, beta-catenin, and SRC gene sets in metastatic colorectal cancers which was confirmed with proteomic analysis of a sub-set of the original tumors. Within colorectal cancers, high SRC expression also correlates with predicted oxaliplatin sensitivity and the combination of an SRC inhibitor with oxaliplatin demonstrated synergy in three independent colorectal cancer cell lines. Interpretation: Our findings suggest that the complex alterations required for metastasis do not obscure the impact of a cancer cellâ??s origin. SOO signatures have the potential to be highly accurate diagnostic tools and the underlying site-specific biology can be used to identify novel therapeutic targets for advanced cancers. Keywords: Gene expression analysis Ninety-six laser capture microdissected adenocarcinoma patient tumor samples of various primary and metastatic sites were processed for Total RNA. Our 96-sample datatset was enriched by inclusion of previously deposited microarray data in GEO (reprocessed for this study): A total of 1217 samples (1104 samples from GSE2109, 113 samples from GSE12630) were reprocessed from the CEL files using RMA. Supplementary files: The reprocessed data matrices. A list of the 1217 Samples' GSM accession numbers and the corresponding reprocessed sample IDs.

Dataset Information

Implication for Cancer Stem Cells in Solid Cancer Chemo-Resistance: Promising Therapeutic Strategies Based on the Use of HDAC Inhibitors.

Publications

Implication for Cancer Stem Cells in Solid Cancer Chemo-Resistance: Promising Therapeutic Strategies Based on the Use of HDAC Inhibitors.

Similar Datasets

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