Cancer Stem Cell Markers in Common Cancers – Therapeutic Implications
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TRMOME-508; No of Pages 11 Review Cancer stem cell markers in common cancers – therapeutic implications Thomas Klonisch1, Emilia Wiechec2, Sabine Hombach-Klonisch1, Sudharsana R. Ande3,4, Sebastian Wesselborg5, Klaus Schulze-Osthoff6* and Marek Los1,3,4,7* 1 Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, R3E 0W3, MB, Canada 2 Institute of Human Genetics, University of Aarhus, DK-8000 Aarhus, Denmark 3 Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, R3E 0V9, MB, Canada 4 Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, R3E 0W3, MB, Canada 5 Department of Internal Medicine I, University of Tu¨ bingen, D-72076 Tu¨ bingen, Germany 6 Interfaculty Institute for Biochemistry, University of Tu¨ bingen, D-72076 Tu¨ bingen, Germany 7 Current address: BioApplications Enterprises, Winnipeg, R2V 2N6, MB, Canada Rapid advances in the cancer stem cell (CSC) field have basis of many (if not all) tumor types. CSCs have been provided cause for optimism for the development of isolated from cancers of the breast, brain, blood (leukemia), more reliable cancer therapies in the future. Strategies skin (melanoma), head and neck, thyroid, cervix, lung, aimed at efficient targeting of CSCs are becoming organs of the gastrointestinal and reproductive tract and important for monitoring the progress of cancer therapy retina [2]. The identification of CSC-specific marker sets and for evaluating new therapeutic approaches. Here, (Table 1) and the targeted therapeutic destruction of CSCs we characterize and compare the specific markers that remain a challenge. Current anticancer therapies mostly have been found to be present on stem cells, cancer cells fail to eradicate CSC clones and instead favor expansion of and CSCs in selected tissues (colon, breast, liver, pan- the CSC pool and/or select for resistant CSC clones, thus creas and prostate). We then discuss future directions of leading to a fatal outcome of the disease. this intriguing new research field in the context of new Here we summarize the current knowledge of CSCs in diagnostic and therapeutic opportunities. some of the most frequent human cancers: pancreatic, hepatocellular, colorectal, breast and prostate carcinomas. Introduction – the biology of stem cells and their surface We discuss their various markers and provide insights into markers new therapeutic approaches for more specific targeting and The ability of adult stem cells to be long-lived and capable eradication of CSCs. of self-renewal and multi-lineage differentiation makes these cells unique and important in normal physiology Pancreas, liver and colorectal stem/progenitor cells and pathological conditions [1]. Their differentiation and CSCs potential and capacity for tissue renewal and damage Pancreas repair make stem cells valuable for regenerative medicine, The pancreas consists of an exocrine part (acini and ducts), tissue engineering and biotechnology applications [2]. which secretes digestive enzymes, and pancreatic islets of However, the same qualities might also pose a serious Langerhans composed of a, b, d and PP endocrine cells. threat to the host organism (Box 1). If stem cell differen- Loss of functional pancreatic islet cells results in type I tiation potential becomes impaired and their proliferative diabetes with deregulated blood glucose homeostasis, and capacity becomes uncontrolled, these mutated, potentially this has been a major incentive for identifying pancreatic tumorigenic, self-renewable stem cells have the potential stem cells, which, if properly programmed, can act as a to cause cancer. Although this is still the subject of con- renewable source for novel b-cell transplantation. A novel siderable debate, it is possible that the development of treatment regime now allows human embryonic stem cells cancer stem cells (CSCs) might involve at least two of the (ESCs) to be programmed to undergo pancreatic develop- following events: (i) a change in the microenvironment of ment and generate hormone-expressing cells in vitro [3]. the stem cell niche within a tissue; (ii) alterations in Potential candidates for adult pancreatic stem cells include cellular metabolism, cell cycle control and/or progression pancreatic ductal cells and cells positive for neurogenin 3 and signaling pathways as a result of mutations and (Ngn3) and pancreatic duodenal homeobox factor 1 (Pdx1). epigenetic changes; and (iii) amplification of cell popu- Pluripotent ductal epithelial stem cells were shown to lations with an altered molecular phenotype that give rise generate islets composed of a, b and d cells during long- to heterogeneous primary tumors and metastases. term culture [4]. Nestin-positive, hormone-negative In recent years, CSCs have been recognized as import- mesenchymal cells were also described as endocrine pre- ant components in carcinogenesis, and they could form the cursor cells within the pancreatic islets and ducts [5], but these cells do not contribute to insulin-producing cells in Corresponding author: Los, M. ([email protected]) * Both authors share senior authorship. the human pancreas [6]. Instead, endocrine progenitor 1471-4914/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.molmed.2008.08.003 Available online xxxxxx 1 TRMOME-508; No of Pages 11 Review Trends in Molecular Medicine Vol.xxx No.x Box 1. Cancer stem cells (CSCs) carcinoma also contains 1–3% of CD133+ cancer cells, some of which also show high expression of CXC chemokine Tissue stem cells form a small population of cells (usually much less + + than 1% within a given tissue), have self-renewing potential and receptor 4 (CXCR4). These CD133 , CXCR4 cells, but + À display significant plasticity. The capacity of stem cells for tissue not CD133 , CXCR4 cells, were able to metastasize, renewal and damage repair has great potential applications for and abrogation of signaling by CXCR4 similarly blocked biotechnology and medicine. Unfortunately, the same qualities that tissue invasion [10]. Thus, there might be more than one make stem cells so valuable for regenerative medicine, tissue engineering and biotechnology, can pose a serious threat to the type of CSC in pancreatic adenocarcinoma. host organism if their differentiation potential becomes uncon- trolled. Mutations within regulatory pathways can impair stem cell Liver functions so that their high proliferative potential, and frequently The liver has high regenerative potential, and hepatic their migratory capabilities as well, make these mutated stem cells small oval progenitor cells around the peripheral branches tumorigenic. In addition, mutations in normal differentiated cells can also produce cancer, and the precise origin (stem cells or of the bile ducts, the canals of Hering, can differentiate into differentiated cells) of cancerous cells remains unclear. In either biliary epithelial cells and hepatocytes [11]. These oval case, these tumorigenic stem/progenitor cell populations are liver progenitor cells share molecular markers with adult collectively named CSCs. hepatocytes (albumin, cytokeratin 7 [CK7], CK19, oval cell markers OV6, A6, OV1, chromogranin-A, NCAM [neural cell adhesion molecule, connexin-43]) and fetal hepatocytes cells were shown to express the transcription factors Ngn3 (a-fetoprotein) (Table 1) [11,12]. They are also positive for (and Isl1 and NeuroD), whereas cells positive for Pdx1 more common stem cell markers such as CD34+, Thy-1+,c- contributed to exocrine, endocrine and ductal tissue in the Kit+ and Flt-3+ (FMS-like tyrosine kinase 3) [5], and thus it pancreas [7]. currently remains unclear whether these stem cells are Pancreatic adenocarcinoma is the fourth most common derived from the bone marrow and just migrate to this cause of cancer death in the USA, displays extensive local periportal niche or whether they represent true resident destruction and early metastasis and has the worst prog- liver stem/progenitor cells. Binding of stromal-derived nosis of all human tumors (3% five-year survival). Pdx1 has factor 1a (SDF-1a) to its surface receptor CXCR4 activates been detected in pancreatic cancer [8], but no association oval hepatic cells [13]. Novel antigen profiles emerge with with pancreatic CSCs has been reported for any of the CD117+, CD133+ hepatic precursors in regenerating liver factors involved in pancreatogenesis. Pancreatic CSCs tissue [14] and with a resident CD45–, CD90+ subpopu- represent less than 1% of all pancreatic cancer cells and lation of tumor cells in hepatocellular carcinoma (HCC), express the surface markers CD44+, CD24+ and epithelial- both of which might qualify as hepatic CSCs [15]. specific antigen (ESA)+. When injected into non-obese HCC is highly prevalent in Africa and Asia, has a high diabetic/severe combined immunodeficiency (NOD/SCID) mortality and does not respond well to conventional mice, these CSCs, but not cancer cells devoid of these therapy [16]. The CD90+ cells are not present in the normal surface markers, self-renewed, produced differentiated liver and, when injected into immunodeficient mice, create progeny, had a 100-fold increased tumorigenic potential, tumors repeatedly. In human HCC and HCC cell lines, generated a tumor morphology similar to the patient’s specifically CD133+ cells, not CD133– cells, had the ability primary cancer and maintained their surface marker phe- to self-renew, create differentiated progenies and form notype after repeated passages as xenographs. The CD44+, tumors [17]. This coincided with the expression