The Veterinary Journal 205 (2015) 124–125
Contents lists available at ScienceDirect
The Veterinary Journal j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t v j l
Guest Editorial
Cancer stem cells: Current status and future directions
During the last two decades, the cancer stem cell (CSC) hypothesis has challenged the field of oncology in human and veterinary medicine. CSC biology is rapidly evolving and changing based on development of new biomarkers for their identification and their correlation with specific gene expression. In this issue of The Veterinary Journal, Dr. Lisa Pang and Professor David Argyle of the University of Edinburgh discuss the CSC theory in a comprehensive review article (Pang and Argyle, 2015). The field of chemical carcinogenesis, which relates to carcinogeninduced cancers in various animal models, heralded the involvement of CSCs in tumor pathogenesis long before the CSC theory became established. Researchers hypothesized that stem cells were most likely the initiated tumor cells in chemical-induced tumors in rats and mice, but because of the lack of specific biomarkers at that time they were unable to classify them accordingly (Koestner, 1990). The 2006 American Association for Cancer Research (AACR) Workshop on CSCs defined the main characteristics of tumor-initiated cells and established the criteria for their classification as such. Participants in the Workshop agreed that, to move the CSC field forward, multiple assays need to be validated for putative stem cell populations by multiple methods, including functional assays, marker analysis, and genetic and epigenetic signature analyses (Clarke et al., 2006). There is increasing evidence in some malignancies that the tumor clone is heterogeneous (phenotypically and functionally) in regard to proliferation and differentiation. Tumor cell heterogeneity can be determined by the microenvironment and genomic instability that prevent accurate normal replication and differentiation. An alternative concept is that malignant cell populations may reflect a perturbed differentiation process with a defined hierarchy of heterogeneous phenotypes derived from a small population of malignant tumor cells. The CSC hypothesis implies that not all of the cells in the tumor have the same capacity to proliferate and maintain the growth of the tumor. Only a relatively small fraction of cells in the tumor, termed CSCs, possess the ability to proliferate and selfrenew extensively. The original definition of CSCs evolved and was challenged by new biomarker development and reinterpretations and is now generally accepted in the field of oncology, despite controversies regarding specific biomarkers and methods used for their identification. Pang and Argyle (2015) focus on tumor heterogeneity, cellular plasticity, CSC reprogramming, and resistance to conventional therapy. The authors present the classical dogma of the CSC hypothesis and the still considerable amount of confusion and controversy that exists. Pang and Argyle (2015) explain the tumor cellular heterogeneity through the clonal evolution of cancer via Darwinian selection and finally conclude that clonal evolution occurs http://dx.doi.org/10.1016/j.tvjl.2015.02.002 1090-0233/© 2015 Elsevier Ltd. All rights reserved.
within the context of the CSC model. As has been mentioned in other reviews related to the CSC hypothesis, the CSC phenotype is a functional one, based on cell behavior in an array of in vitro and in vivo experiments aimed to evaluate renewal, differentiation capacity, and tumorigenic potential (Fabian et al., 2013). Additional genetic testing for stemness-related gene expression has improved our understanding of CSC properties at the molecular level. Despite these advances, no specific cell surface marker is exclusive for cells displaying CSC behavior. The expression of a CSC marker is not sufficient to validate a CSC phenotype. Another important issue regarding the CSC hypothesis that needs to be emphasized is the contribution of the tumor microenvironment on the development and dynamic evolution and differentiation of CSCs, which can alter their expression profiles. Fig. 1 illustrates some of the many homeostatic microenvironmental factors that can determine the properties and biological behavior of CSCs in glioblastoma development (Hoelzinger et al., 2007; Stoica et al., 2009). Glioma CSCs exist in a vascular niche that maintains their pool. This hypothesis derives from findings reported on normal stem cells. Stem cells of various tissues exist within protective niches that are composed of a number of differentiated cell types (Fuchs et al., 2004). This cellular microenvironment provides direct cell contacts and secreted factors that maintain stem cells in a quiescent state. In gliomas it is hypothesized that vascular endothelial cells provide such a niche for the glioma CSCs, similar to the situation with normal neuronal stem cells. Disruption of this niche in a mouse model by antivascular endothelial growth factor (VEGF) treatment results in depletion of the CD133+ cells (Calabrese et al., 2007). In veterinary oncology, identification of CSCs might not have a direct practical significance for veterinary practitioners. However, in the context of the ‘One Medicine’ paradigm and the frequent occurrence of spontaneous types of cancers in animals, the isolation of CSCs, their characterization, and the development of novel therapeutic approaches have great scientific significance for the advancement of the oncology field. Clearly the CSC theory has generated novel therapeutic targets that could overcome drug resistance and systemic toxicity. From the academic point of view, this endeavor is a classic example of a philosophy of bridging clinical science with basic science for the benefit of our patients who suffer from (and often succumb to) a disease, the basis of which we are only beginning to understand. George Stoica Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843-4467, USA E-mail address: [email protected]
Guest Editorial/The Veterinary Journal 205 (2015) 124–125
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Fig. 1. Schematic representation of autocrine/paracrine factors in the brain microenvironment, which sustain glioblastoma invasion. Adapted version with permission (02/ 10/2015) from Hoelzinger et al. (2007).
References Calabrese, C., Poppleton, H., Kocak, M., Hogg, T.L., Fuller, C., Hammer, B., Oh, E.Y., Gaber, M.W., Finklestein, D., Allen, M., et al., 2007. A perivascular niche for brain tumor stem cells. Cancer Cell 11, 69–82. Clarke, M.F., Dick, J.E., Dirks, P.B., Eaves, C.J., Jamieson, C.H.M., Jones, D.L., Visvader, J., Weissman, I.L., Wahl, G.M., 2006. Cancer stem cells: Perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Research 66, 9339–9344. Fabian, A., Vereb, G., Szollosi, J., 2013. The hitchhikers guide to cancer stem cells theory: Markers, pathways and therapy. Cytometry 83A, 62–71.
Fuchs, E., Tumbar, T., Guasch, G., 2004. Socializing with the neighbors: Stem cells and their niche. Cell 116, 769–778. Hoelzinger, D.B., Demuth, T., Berens, M.E., 2007. Autocrine factors that sustain glioma invasion and paracrine biology in the brain microenvironment. Journal of the National Cancer Institute 99, 1583–1593. Koestner, A., 1990. Characterization of N-nitrosourea-induced tumors of the nervous system: Their perspective value for studies of neurocarcinogenesis and brain tumor therapy. Toxicologic Pathology 18, 186–192. Pang, L.Y., Argyle, D.J., 2015. The evolving cancer stem cell paradigm: Implications in veterinary oncology. The Veterinary Journal doi.org/10.1016/j.tvjl.2014.12.029. Stoica, G., Lungu, G., Martini-Stoica, H., Waghela, S., Levine, J., Smith, R., 3rd., 2009. Identification of cancer stem cells in dog glioblastoma. Veterinary Pathology 46, 391–406.
Contents lists available at ScienceDirect
The Veterinary Journal j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t v j l
Guest Editorial
Cancer stem cells: Current status and future directions
During the last two decades, the cancer stem cell (CSC) hypothesis has challenged the field of oncology in human and veterinary medicine. CSC biology is rapidly evolving and changing based on development of new biomarkers for their identification and their correlation with specific gene expression. In this issue of The Veterinary Journal, Dr. Lisa Pang and Professor David Argyle of the University of Edinburgh discuss the CSC theory in a comprehensive review article (Pang and Argyle, 2015). The field of chemical carcinogenesis, which relates to carcinogeninduced cancers in various animal models, heralded the involvement of CSCs in tumor pathogenesis long before the CSC theory became established. Researchers hypothesized that stem cells were most likely the initiated tumor cells in chemical-induced tumors in rats and mice, but because of the lack of specific biomarkers at that time they were unable to classify them accordingly (Koestner, 1990). The 2006 American Association for Cancer Research (AACR) Workshop on CSCs defined the main characteristics of tumor-initiated cells and established the criteria for their classification as such. Participants in the Workshop agreed that, to move the CSC field forward, multiple assays need to be validated for putative stem cell populations by multiple methods, including functional assays, marker analysis, and genetic and epigenetic signature analyses (Clarke et al., 2006). There is increasing evidence in some malignancies that the tumor clone is heterogeneous (phenotypically and functionally) in regard to proliferation and differentiation. Tumor cell heterogeneity can be determined by the microenvironment and genomic instability that prevent accurate normal replication and differentiation. An alternative concept is that malignant cell populations may reflect a perturbed differentiation process with a defined hierarchy of heterogeneous phenotypes derived from a small population of malignant tumor cells. The CSC hypothesis implies that not all of the cells in the tumor have the same capacity to proliferate and maintain the growth of the tumor. Only a relatively small fraction of cells in the tumor, termed CSCs, possess the ability to proliferate and selfrenew extensively. The original definition of CSCs evolved and was challenged by new biomarker development and reinterpretations and is now generally accepted in the field of oncology, despite controversies regarding specific biomarkers and methods used for their identification. Pang and Argyle (2015) focus on tumor heterogeneity, cellular plasticity, CSC reprogramming, and resistance to conventional therapy. The authors present the classical dogma of the CSC hypothesis and the still considerable amount of confusion and controversy that exists. Pang and Argyle (2015) explain the tumor cellular heterogeneity through the clonal evolution of cancer via Darwinian selection and finally conclude that clonal evolution occurs http://dx.doi.org/10.1016/j.tvjl.2015.02.002 1090-0233/© 2015 Elsevier Ltd. All rights reserved.
within the context of the CSC model. As has been mentioned in other reviews related to the CSC hypothesis, the CSC phenotype is a functional one, based on cell behavior in an array of in vitro and in vivo experiments aimed to evaluate renewal, differentiation capacity, and tumorigenic potential (Fabian et al., 2013). Additional genetic testing for stemness-related gene expression has improved our understanding of CSC properties at the molecular level. Despite these advances, no specific cell surface marker is exclusive for cells displaying CSC behavior. The expression of a CSC marker is not sufficient to validate a CSC phenotype. Another important issue regarding the CSC hypothesis that needs to be emphasized is the contribution of the tumor microenvironment on the development and dynamic evolution and differentiation of CSCs, which can alter their expression profiles. Fig. 1 illustrates some of the many homeostatic microenvironmental factors that can determine the properties and biological behavior of CSCs in glioblastoma development (Hoelzinger et al., 2007; Stoica et al., 2009). Glioma CSCs exist in a vascular niche that maintains their pool. This hypothesis derives from findings reported on normal stem cells. Stem cells of various tissues exist within protective niches that are composed of a number of differentiated cell types (Fuchs et al., 2004). This cellular microenvironment provides direct cell contacts and secreted factors that maintain stem cells in a quiescent state. In gliomas it is hypothesized that vascular endothelial cells provide such a niche for the glioma CSCs, similar to the situation with normal neuronal stem cells. Disruption of this niche in a mouse model by antivascular endothelial growth factor (VEGF) treatment results in depletion of the CD133+ cells (Calabrese et al., 2007). In veterinary oncology, identification of CSCs might not have a direct practical significance for veterinary practitioners. However, in the context of the ‘One Medicine’ paradigm and the frequent occurrence of spontaneous types of cancers in animals, the isolation of CSCs, their characterization, and the development of novel therapeutic approaches have great scientific significance for the advancement of the oncology field. Clearly the CSC theory has generated novel therapeutic targets that could overcome drug resistance and systemic toxicity. From the academic point of view, this endeavor is a classic example of a philosophy of bridging clinical science with basic science for the benefit of our patients who suffer from (and often succumb to) a disease, the basis of which we are only beginning to understand. George Stoica Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843-4467, USA E-mail address: [email protected]
Guest Editorial/The Veterinary Journal 205 (2015) 124–125
125
Fig. 1. Schematic representation of autocrine/paracrine factors in the brain microenvironment, which sustain glioblastoma invasion. Adapted version with permission (02/ 10/2015) from Hoelzinger et al. (2007).
References Calabrese, C., Poppleton, H., Kocak, M., Hogg, T.L., Fuller, C., Hammer, B., Oh, E.Y., Gaber, M.W., Finklestein, D., Allen, M., et al., 2007. A perivascular niche for brain tumor stem cells. Cancer Cell 11, 69–82. Clarke, M.F., Dick, J.E., Dirks, P.B., Eaves, C.J., Jamieson, C.H.M., Jones, D.L., Visvader, J., Weissman, I.L., Wahl, G.M., 2006. Cancer stem cells: Perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Research 66, 9339–9344. Fabian, A., Vereb, G., Szollosi, J., 2013. The hitchhikers guide to cancer stem cells theory: Markers, pathways and therapy. Cytometry 83A, 62–71.
Fuchs, E., Tumbar, T., Guasch, G., 2004. Socializing with the neighbors: Stem cells and their niche. Cell 116, 769–778. Hoelzinger, D.B., Demuth, T., Berens, M.E., 2007. Autocrine factors that sustain glioma invasion and paracrine biology in the brain microenvironment. Journal of the National Cancer Institute 99, 1583–1593. Koestner, A., 1990. Characterization of N-nitrosourea-induced tumors of the nervous system: Their perspective value for studies of neurocarcinogenesis and brain tumor therapy. Toxicologic Pathology 18, 186–192. Pang, L.Y., Argyle, D.J., 2015. The evolving cancer stem cell paradigm: Implications in veterinary oncology. The Veterinary Journal doi.org/10.1016/j.tvjl.2014.12.029. Stoica, G., Lungu, G., Martini-Stoica, H., Waghela, S., Levine, J., Smith, R., 3rd., 2009. Identification of cancer stem cells in dog glioblastoma. Veterinary Pathology 46, 391–406.
