Abstract IA13: The complexity of tumor cell hierarchies
Authors: Jeremy N. Rich
Journal: Cancer Research (2011)

Abstract Cancer research has rediscovered the complexity of tumors through the incorporation of cellular heterogeneity into tumor models with cellular subsets displaying stem cell characteristics. The cancer stem cell hypothesis posits that tumor cells are organized in a hierarchy with cancer stem cells at the apex and functionally defined by the ability to self renew and propagate tumors similar to the parental tumors from which they are derived, cancer stem cells remain controversial due to unresolved relationships with cell of origin, frequency, and defining universal markers but it has been nearly impossible to create absolute rules for even a single cancer type so it is likely that the cancer stem cell phenotype can be acquired through convergent evolution and may be governed by variable rules based on tumor type, grade, course, and therapeutic treatment. Cancer stem cells have been studied in multiple cancer types, most heavily in leukemias, glioblastomas, breast, and colon cancers. Cancer stem cells also yield the non-tumorigenic tumor bulk cells that display a more differentiated phenotype. The ability to prospectively isolate and interrogate cancer stem cells is defining molecular mechanisms responsible for the tumor maintenance and growth. The clinical relevance of cancer stem cells has been supported by cancer stem cell resistance to cytotoxic therapies and promotion of tumor angiogenesis. Cancer stem cells reside in specific functional niches in perivascular and hypoxic niches that may offer the ability to disrupt tumor maintenance and therapeutic resistance through targeting the niche. The cancer stem cell phenotype is regulated by both cell intrinsic and microenvironmental influences that may further increase the complexity of tumor modeling. Notably, cell lines and standard culture conditions used in preclinical studies fail to recapitulate the tumor heterogeneity and do not predict patient responses, supporting the development of improved tumor models. The study of cellular heterogeneity and cancer stem cells has already yielded novel molecular targets and pathways that are amenable to therapeutic targeting, perhaps permitting attenuation of tumor resistance. The conventional pyramidal unidirectional differentiation cascade with cancer stem cells at the apex has been called into question by studies demonstrating plasticity of the cancer stem cell phenotype, thus suggesting that targeting only cancer stem cells will likely fail to cure patients and require simultaneous targeting of cancer stem cells and the bulk tumor. In conclusion although the field of cancer stem cell biology is relatively young, continued elucidation of the tumor hierarchy holds promise for the development of novel patient therapies. References: 1. Eyler CE, Wu Q, Yan K, Macswords JM, Chandler-Militello D, Misuraca KL, Lathia JD, Forrester MT, Lee J, Stamler JS, Goldman SA, Bredel M, McLendon RE, Sloan AE, Hjelmeland AB, Rich JN. Glioma stem cell proliferation and tumor growth are promoted by nitric oxide synthase-2. Cell. 2011 Jul 8;146(1):53–66. 2. Guryanova OA, Wu Q, Cheng L, Lathia JD, Huang Z. Yang J, Macswords J, Eyler CE, McLendon RE, Heddleston JM, Shou W, Hambardzumyan D, Lee J, Hjelmeland AB, Sloan AE, Bredel M, Stark GR, Rich JN, Bao S. Non-receptor tyrosine kinase BMX maintains self-renewal and tumorigenic potential of glioblastoma stem cells by activating STAT3. Cancer Cell. 2011 Apr 12;19(4):498–511. 3. Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB, Shi Q, McLendon RE, Bigner DD, and Rich JN. Stem cell-like glioblastoma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res. 2006;66(16):7843–8. 4. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006;444(7120):756–60. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr IA13.