Biological Properties Of Cancer Stem Cells Research Articles

Cancer stem cells: A review from origin to therapeutic implications.

Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), are elucidated as cells that can perpetuate themselves via autorestoration. These cells are highly resistant to current therapeutic approaches and are the main reason for cancer recurrence. Radiotherapy has made a lot of contributions to cancer treatment. However, despite continuous achievements, therapy resistance and tumor recurrence are still prevalent in most patients. This resistance might be partly related to the existence of CSCs. In the present study, recent advances in the investigation of different biological properties of CSCs, such as their origin, markers, characteristics, and targeting have been reviewed. We have also focused our discussion on radioresistance and adaptive responses of CSCs and their related extrinsic and intrinsic influential factors. In summary, we suggest CSCs as the prime therapeutic target for cancer treatment.

Therapeutic approaches targeting cancer stem cells.

Increasing studies have demonstrated that most tumors consisted a subpopulation of cells with stem cell properties, known as cancer stem cells (CSCs). Accumulating evidence indicated that CSCs may be critical driving force for several types of cancer. Hence, it was necessary to develop therapeutic approaches specifically targeting CSCs. In this review, first, the biological properties of CSCs were introduced, including the self-renewal and differentiation, high tumorigenesis and invasiveness, resistance to chemotherapy and radiotherapy, genetic and epigenetic variations. Meanwhile, CSCs-targeted therapeutic strategies were summarized, including targeting cell surface markers, signaling pathways, CSC niches, differentiation therapy, and drug resistance for CSCs. Furthermore, clinical trials on anti-CSCs therapies supported the efficacy of these therapies, as well as their combination with conventional chemotherapy and radiotherapy. CSCs could be significantly eradicated, eventually resulting in inhibited tumor growth, metastasis, and recurrence. Thus, selectively targeting CSCs with various agents may be a novel and promising therapeutic strategy against cancer.

Abstract 2335: Pancreatic cancer stem cell function is regulated by HNF1A

Abstract Pancreatic ductal adenocarcinoma (PDA) is a hierarchal cancer consisting of tumor-initiating cancer stem cells (CSCs) and transiently proliferating bulk tumor cells. Despite this understanding, the biological properties of CSCs remain incompletely defined, including the role of transcriptional programs like epithelial-mesenchymal transition (EMT). Using flow cytometry in conjunction with epithelial-cell surface marker ESA (EpCAM) and mesenchymal-cell surface marker CD44, we identified three subpopulations of PDA cells derived from primary patient samples: CD44highESAlow, CD44lowESAhigh, and CD44highESAhigh cells, each with different biological characteristics. CD44highESAlow cells exhibited a more mesenchymal phenotype characterized by high expression of vimentin and low expression of E-cadherin. CD44lowESAhigh cells, by contrast, highly epithelial in appearance, expressed high levels of E-cadherin and low levels of vimentin. Finally, CD44highESAhigh cells showed a phenotype intermediate between CD44highESAlow and CD44lowESAhigh cells. In isolation, all subpopulations were able to self-renew, however, only CD44highESAhigh cells could give rise to all three cell subpopulations. Additionally, CD44highESAhigh cells exhibited the highest ability to form tumorspheres, an indicator of CSC-functionality, in vitro, and had a greater ability to form tumors in vivo, suggesting that this subpopulation enriched for CSC functional activity. Using microarray analysis, we identified a set 50 genes, including the CSC marker CD24 and the transcription factor HNF1A, which showed significant up-regulation in CD44highESAhigh cells CSC population compared to either CD44highESAlow or CD44lowESAhigh cells. We hypothesized that these genes might be critical to CSC biology in PDA. Using bioinformatics analysis to identify possible transcriptional regulators of these 50 genes, we identified HNF1A as the factor with most highly overrepresented binding sites in the promoter regions of (17/50 genes), suggesting a possible role in regulating CD44highESAhigh-specific genes and serving as a key biological regulator of the CSC state. Supporting this hypothesis, knockdown of HNF1A decreased expression of a number of the candidate genes, including CD24, in the CD44highESAhigh population. By contrast, ectopic expression of HNF1A resulted in the up-regulation of a similar set of candidate genes, including CD24, and promoted the formation of tumorspheres. These findings shine light on the complexity of PDA tumor cell heterogeneity, suggesting the CSCs exist in a state between EMT and mesenchymal-epithelial transition, and implicates HNF1A as a key regulator of CSC-associated genes and CSC functionality. Citation Format: Ethan V. Abel, Masashi Goto, Nikita Ramanathan, Chandan Kumar, Lesa Begley, Michele L. Dziubinski, Lidong Wang, Meghna Waghray, Sumithra Urs, Diane M. Simeone. Pancreatic cancer stem cell function is regulated by HNF1A. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2335. doi:10.1158/1538-7445.AM2015-2335

Abstract A65: Pancreatic cancer stem cell function is regulated by HNF1A

Abstract Pancreatic ductal adenocarcinoma (PDA) is a hierarchal cancer consisting of tumor-initiating cancer stem cells (CSCs) and transiently proliferating bulk tumor cells. Despite this understanding, the biological properties of CSCs remain incompletely defined, including the role of transcriptional programs like epithelial-mesenchymal transition (EMT). Using flow cytometry in conjunction with epithelial-cell surface marker ESA (EpCAM) and mesenchymal-cell surface marker CD44, we identified three subpopulations of PDA cells derived from primary patient samples: CD44highESAlow, CD44lowESAhigh, and CD44highESAhigh cells, each with different biological characteristics. CD44highESAlow cells exhibited a more mesenchymal phenotype characterized by high expression of vimentin and low expression of E-cadherin. CD44lowESAhigh cells, by contrast, highly epithelial in appearance, expressed high levels of E-cadherin and low levels of vimentin. Finally, CD44highESAhigh cells showed a phenotype intermediate between CD44highESAlow and CD44lowESAhigh cells. In isolation, all subpopulations were able to self-renew, however, only CD44highESAhigh cells could give rise to all three cell subpopulations. Additionally, CD44highESAhigh cells exhibited the highest ability to form tumorspheres, an indicator of CSC-functionality, in vitro, and had a greater ability to form tumors in vivo, suggesting that this subpopulation enriched for CSC functional activity. Using microarray analysis, we identified a set 50 genes, including the CSC marker CD24 and the transcription factor HNF1A, which showed significant up-regulation in CD44highESAhigh cells CSC population compared to either CD44highESAlow or CD44lowESAhigh cells. We hypothesized that these genes might be critical to CSC biology in PDA. Using bioinformatics analysis to identify possible transcriptional regulators of these 50 genes, we identified HNF1A as the factor with most highly overrepresented binding sites in the promoter regions of (17/50 genes), suggesting a possible role in regulating CD44highESAhigh-specific genes and possibly a key biological regulator of the CSC state. Supporting this hypothesis, knockdown of HNF1A resulted in decreased expression of a number of the candidate genes, including CD24, in the CD44highESAhigh population. By contrast, ectopic expression of HNF1A resulted in the up-regulation of a similar set of candidate genes, including CD24, and promoted the formation of tumorspheres. These findings shine light on the complexity of PDA tumor cell heterogeneity, suggesting the CSCs exist in a state between EMT and mesenchymal-epithelial transition, and implicates HNF1A as a key regulator of CSC-associated genes and CSC functionality. Citation Format: Ethan V. Abel, Masashi Goto, Michele L. Dziubinski, Chandan Kumar, Nikita Ramanathan, Diane M. Simeone. Pancreatic cancer stem cell function is regulated by HNF1A. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A65.

Identification of cancer stem cells: from leukemia to solid cancers

Cancer stem cells (CSCs) are widely considered to be a small cell population in leukemia and many solid cancers with the properties including self-renewal and differentiation to non-tumorigenic cancer cells. Identification and isolation of CSCs significantly depend on the special surface markers of CSCs. Aberrant gene expression and signal transduction contribute to malignancies of CSCs, which result in cancer initiation, progression and recurrence. The inefficient therapy of cancers is mainly attributed to the failure of elimination of the malignant CSCs. However, CSCs have not been detected in all cancers and hierarchical organization of tumors might challenge cancer stem cell models. Additionally, opinions about the validity of the CSC hypothesis, the biological properties of CSCs, and the relevance of CSCs to cancer therapy differ widely. In this review, we discuss the debate of cancer stem cell model, the parameters by which CSCs can or cannot be defined, and the advances in the therapy of CSCs.

The increasing complexity of the cancer stem cell paradigm.

The investigation and study of cancer stem cells (CSCs) have received enormous attention over the past 5 to 10 years but remain topics of considerable controversy. Opinions about the validity of the CSC hypothesis, the biological properties of CSCs, and the relevance of CSCs to cancer therapy differ widely. In the following commentary, we discuss the nature of the debate, the parameters by which CSCs can or cannot be defined, and the identification of new potential therapeutic targets elucidated by considering cancer as a problem in stem cell biology.

Cancer stem cells in solid tumors

Cancer stem cells (CSCs) are cells that drive tumorigenesis, as well as giving rise to a large population of differentiated progeny that make up the bulk of the tumor, but that lack tumorigenic potential. CSCs have been identified in a variety of human tumors, as assayed by their ability to initiate tumor growth in immunocompromised mice. Further characterization studies have demonstrated that gene expression profiles in breast cancer correlate with patient prognosis, and brain CSCs are specifically resistant to radiation through DNA damage repair. In addition, specific signaling pathways play a functional role in CSC self renewal and/or differentiation, and early studies indicate that CSCs are associated with a microenvironmental niche. Thus the biological properties of CSCs are just beginning to be revealed, and the continuation of these studies should lead to the development of CSC-targeted therapies for cancer treatment.