Colon Cancer Stem Cells: Promise of Targeted Therapy
Section snippets
SC Definition, Classification, and Roles
SCs are undifferentiated cells that, through an asymmetric cell division, give rise to 2 different daughter cells. One daughter is identical to the mother and contains SC properties (self-renewal), whereas the other is a more specialized cell.1 Based on their ability to differentiate, SCs are classified as either totipotent (cells able to give rise to a new individual on their own), pluripotent (cells able to give rise to almost all tissues of the body), or multipotent (cells able to generate
Histology of the Colon
The colon, or large intestine, comprises the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, rectum, and anal canal. Four layers characterize the colon wall; from inside to outside these are the mucosa, submucosa, muscularis externa, and serosa. The most external mucosal surface is lined by an absorptive and secretory epithelium (simple columnar) that is folded to form a number of invaginations embedded in the connective tissue. These test-tube–shaped structures,
Molecular Markers of Normal Colon SCs
Bromodeoxyuridine labeling was initially used to identify the SC compartment of several tissues including colon,28 based on the assumption that SCs divide infrequently and retain the DNA label for a longer time than the more rapidly dividing progenitor cells. This method of SC identification was replaced by the identification of stemness markers, usually on the cell surface, that allow SCs to be isolated by flow cytometry.
The RNA-binding protein Musashi-1 (Msi-1) was the first molecule
Intestinal SC Niche
Niches are the physical environments that maintain SCs in a variety of tissues, including human colon.39 In the colon, they have been described as structures most likely formed by intestinal subepithelial myofibroblasts (ISEMFs) located at the base of the crypt. ISEMFs are activated and proliferate in response to various growth factors, including members of the platelet-derived growth factor family.40 ISEMFs within the intestine are involved in organogenesis, protection from harmful agents, and
Colorectal Carcinoma
Maintenance of genomic integrity is ensured in colonic and other types of cells by a series of cell cycle checkpoints. These prevent transmission of damaged or incompletely replicated chromosomes by stalling the cell cycle until repairs are made or, if repairs cannot be made, by targeting the cell for destruction via programmed cell death. Factors involved in checkpoint signaling can be classified as sensors, mediators, transducers, or effectors.46 The tumor suppressor p53 is an effector
CSC Markers
Cancer cells with stem-like features were first observed in acute myeloid leukemia (AML) and later found in other tumor types. In most cases, such cells have been identified through their expression of specific cell surface markers. The CD34+CD38− and the CD44+CD24− phenotypes were the first signatures associated with AML and breast tumors, respectively.57, 58 One of the next CSC markers identified was CD133, a pentaspan transmembrane glycoprotein also known in humans as Prominin 1. The CD133+
Identification of Colon Cancer–Initiating Cells
The existence of colon CSCs was first reported by the research groups of John Dick and Ruggero De Maria,66, 67 which independently described a small population of cancer cells capable of initiating tumor growth in immunodeficient mice. By implanting limiting dilutions of human colon cancer cell suspensions into preirradiated nonobese diabetic severe combined immunodeficient mice, O'Brien et al demonstrated that only a small subset of colon cancer cells (1/5.7 × 104 total cells) initiated tumor
Limitations of CSC Theory
The CSC theory has been proven in xenograft experiments. However, studies in animal models might underestimate the frequency of cells with tumorigenic potential. Quintana et al reported faster growth of human melanoma and a higher frequency of melanoma cancer-initiating cells in nonobese diabetic combined immunodeficient interleukin-2b receptor knockout mice (NOD/SCID Il2rgl−, which lack T, B, and natural killer cells.88 Moreover, injection with or without Matrigel also strongly affected the
Clinical Perspectives
CRC is the second leading cause of cancer-related death in the world.93 Nearly all colon cancers begin as benign polyps that can slowly develop into malignant tumors. Colonoscopy can be used to screen for precancerous polyps so that they can be removed before malignant transformation. However, only about 39% of CRCs are found at an early stage; CRC is metastatic (CRM) at the time of diagnosis in >60% of cases. When metastases are found at distant sites, 5-year survival is <10%. The liver is the
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2022, Seminars in Cancer BiologyCitation Excerpt :Besides leukemia, CD44 and especially CD44 variant isoforms are CCSC markers, either individually or in combination with other molecules [126]. In CRC, targeting CD44 expressing CSCs with anti-CD44 monoclonal antibody improves cellular uptake and antitumor efficacy of liposomal doxorubicin, representing an important anti-CSC approach [127,128]. At the time of writing, various antibodies against CD44 or CD44 variant isoforms can inhibit human CRC [129].
Conflicts of interest The authors disclose no conflicts.
Funding This study was supported by grants from AIRC to Drs Stassi and Todaro, Istituto Superiore di Sanità, Rome, Oncoproteomica, Italia-Usa (prot. 527/B/3A/3) and PRIN 2007TE8NFY to Dr Stassi, NWO VICI-scheme and Dutch Cancer Society grant 2009-4416 to Dr Medema.