Gastroenterology

Gastroenterology

Volume 138, Issue 6, May 2010, Pages 2151-2162
Gastroenterology

Colon Cancer Stem Cells: Promise of Targeted Therapy

https://doi.org/10.1053/j.gastro.2009.12.063Get rights and content

First developed for hematologic disorders, the concept of cancer stem cells (CSCs) was expanded to solid tumors, including colorectal cancer (CRC). The traditional model of colon carcinogenesis includes several steps that occur via mutational activation of oncogenes and inactivation of tumor suppressor genes. Intestinal epithelial cells exist for a shorter amount of time than that required to accumulate tumor-inducing genetic changes, so researchers have investigated the concept that CRC arises from the long-lived stem cells, rather than from the differentiated epithelial cells. Colon CSCs were originally identified through the expression of the CD133 glycoprotein using an antibody directed to its epitope AC133. It is not clear if CD133 is a marker of colon CSCs—other cell surface markers, such as epithelial-specific antigen, CD44, CD166, Musashi-1, CD29, CD24, leucine-rich repeat-containing G-protein–coupled receptor 5, and aldehyde dehydrogenase 1, have been proposed. In addition to initiating and sustaining tumor growth, CSCs are believed to mediate cancer relapse after chemotherapy. How can we identify and analyze colon CSCs and what agents are being designed to kill this chemotherapy-refractory population?

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

References (102)

  • K. Fujimoto et al.

    Identification and isolation of candidate human colonic clonogenic cells based on cell surface integrin expression

    Gastroenterology

    (2002)
  • A. Merlos-Suarez et al.

    Eph-ephrin signalling in adult tissues and cancer

    Curr Opin Cell Biol

    (2008)
  • J. Holmberg et al.

    EphB receptors coordinate migration and proliferation in the intestinal stem cell niche

    Cell

    (2006)
  • R. Douard et al.

    Sonic Hedgehog-dependent proliferation in a series of patients with colorectal cancer

    Surgery

    (2006)
  • S. Miraglia et al.

    A novel five-transmembrane hematopoietic stem cell antigen: isolation, characterization, and molecular cloning

    Blood

    (1997)
  • B. Bussolati et al.

    Isolation of renal progenitor cells from adult human kidney

    Am J Pathol

    (2005)
  • S. Bruno et al.

    CD133+ renal progenitor cells contribute to tumor angiogenesis

    Am J Pathol

    (2006)
  • P.C. Hermann et al.

    Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer

    Cell Stem Cell

    (2007)
  • M. Todaro et al.

    Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4

    Cell Stem Cell

    (2007)
  • M. Shackleton et al.

    Heterogeneity in cancer: cancer stem cells versus clonal evolution

    Cell

    (2009)
  • P. Calabrese et al.

    Pretumor progression: clonal evolution of human stem cell populations

    Am J Pathol

    (2004)
  • H.J. Lenz

    First-line combination treatment of colorectal cancer with hepatic metastases: choosing a targeted agent

    Cancer Treat Rev

    (2008)
  • J.H. van Es et al.

    Notch and Wnt inhibitors as potential new drugs for intestinal neoplastic disease

    Trends Mol Med

    (2005)
  • M.T. Mueller et al.

    Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer

    Gastroenterology

    (2009)
  • R. Majeti et al.

    CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells

    Cell

    (2009)
  • C.M. Verfaillie et al.

    Stem cells: hype and reality

    Hematology Am Soc Hematol Educ Program

    (2002)
  • D.S. Krause

    Plasticity of marrow-derived stem cells

    Gene Ther

    (2002)
  • R. Zhang et al.

    Stroke transiently increases subventricular zone cell division from asymmetric to symmetric and increases neuronal differentiation in the adult rat

    J Neurosci

    (2004)
  • M. Ito et al.

    Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding

    Nature

    (2007)
  • C. Vicente-Dueñas et al.

    The role of cellular plasticity in cancer development

    Curr Med Chem

    (2009)
  • S. Liu et al.

    Mammary stem cells, self-renewal pathways, and carcinogenesis

    Breast Cancer Res

    (2005)
  • M.S. Wicha et al.

    Cancer stem cells: an old idea—a paradigm shift

    Cancer Res

    (2006)
  • C. Gonzalez

    Spindle orientation, asymmetric division and tumour suppression in Drosophila stem cells

    Nat Rev Genet

    (2007)
  • C. Booth et al.

    Gut instincts: thoughts on intestinal epithelial stem cells

    J Clin Invest

    (2000)
  • C.S. Potten et al.

    Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt

    Development

    (1990)
  • C.S. Potten et al.

    Measurement of in vivo proliferation in human colorectal mucosa using bromodeoxyuridine

    Gut

    (1992)
  • M. Brittan et al.

    Gastrointestinal stem cells

    J Pathol

    (2002)
  • C.L. Bevins

    Paneth cell defensins: key effector molecules of innate immunity

    Biochem Soc Trans

    (2006)
  • H. Cheng et al.

    Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian Theory of the origin of the four epithelial cell types

    Am J Anat

    (1974)
  • S.M. Karam

    Lineage commitment and maturation of epithelial cells in the gut

    Front Biosci

    (1999)
  • C.S. Potten et al.

    Estimates of the number of clonogenic cells in crypts of murine small intestine

    Virchows Arch B Cell Pathol Incl Mol Pathol

    (1987)
  • U. Paulus et al.

    A model of the control of cellular regeneration in the intestinal crypt after perturbation based solely on local stem cell regulation

    Cell Prolif

    (1992)
  • B.A. Ponder et al.

    Derivation of mouse intestinal crypts from single progenitor cells

    Nature

    (1985)
  • R.A. Meguid et al.

    Is there a difference in survival between right- versus left-sided colon cancers?

    Ann Surg Oncol

    (2008)
  • B. Iacopetta

    Are there two sides to colorectal cancer?

    Int J Cancer

    (2002)
  • M. Lipkin et al.

    Cell proliferation kinetics in the gastrointestinal tract of man. i. cell renewal in colon and rectum

    J Clin Invest

    (1963)
  • M. Okabe et al.

    Intrinsic and extrinsic determinants regulating cell fate decision in developing nervous system

    Dev Neurosci

    (1997)
  • S. Nishimura et al.

    Expression of Musashi-1 in human normal colon crypt cells: a possible stem cell marker of human colon epithelium

    Dig Dis Sci

    (2003)
  • T. Imai et al.

    The neural RNA-binding protein Musashi1 translationally regulates mammalian numb gene expression by interacting with its mRNA

    Mol Cell Biol

    (2001)
  • N. Barker et al.

    Identification of stem cells in small intestine and colon by marker gene Lgr5

    Nature

    (2007)
  • Cited by (388)

    • Targeting stemness of cancer stem cells to fight colorectal cancers

      2022, Seminars in Cancer Biology
      Citation 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].

    View all citing articles on Scopus

    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.

    View full text