Cancer stem cells

Overview

Cancer stem cells (CSCs) are the "roots" of a tumor. Also known as tumor initiating cells (TICs), CSCs represent a small subpopulation of the tumor that initiates and perpetuates tumor growth. CSCs give rise to various differentiated progeny that make up the bulk of the rapidly dividing tumor.1,2

"Stemness" features of CSCs1-4:

  • Ability to remain relatively quiescent
  • Enhanced self-renewal and growth
  • Altered metabolism
  • Expression of multidrug resistance transporters and DNA damage repair enzymes
  • High resistance to oxidative stress
  • Homing ability (metastatic potential)
  • Reproliferation of differentiated progeny

Implications in cancer

CSCs sustain cancer survival and progression.

  • CSCs are often innately less sensitive to chemotherapy and radiation than the bulk of the tumor cells that they generate.2,5
    • Thus, CSCs can contribute to recurrence after elimination of the bulk of the tumor.
  • CSCs can regenerate the heterogenous cell populations of the parental tumor.4

Strategies aimed at eliminating CSCs include targeting specific surface markers, sensitizing CSCs to therapy, and modulating "stemness" signaling pathways.3,4

Oncogenic Expression

Acute Myeloid Leukemia (AML)

  • Multiple studies have shown that AML follows a CSC model.4,6

Breast Cancer

  • Multiple laboratories have shown that highly metastatic TNBC tumors are often composed of cells harboring epithelial-mesenchymal (E-M) plasticity that can lead to the emergence of highly migratory, mesenchymal CSCs.7

Brain Cancer

  • Studies have identified brain cancer cells with the capacity for self-renewal and regeneration of the original tumor, supporting the CSC theory in brain cancer.8

Colorectal Cancer

  • Stem cell crypt cell populations in the gastrointestinal tract give rise to all the differentiated cell types within the homeostatic intestinal epithelia and are proposed to serve as the cells of origin for intestinal cancers.9

Lung Cancer

  • Evidence suggests that lung carcinoma tumors contain CSCs that are resistant to conventional chemotherapy and are responsible for tumor maintenance and spreading.10
  • Whole transcriptome sequencing of tumor-initiating cells (TICs) isolated from small-cell lung cancer (SCLC) and large-cell neuroendocrine cancer (LCNEC) patient-derived xenografts showed that DLL3, a protein expressed during neuroendocrine development that has minimal to no expression in normal adult tissue, is expressed in most SCLCs and LCNECs.11,12
  1. Aponte PM, Caicedo A. Stemness in cancer: stem cells, cancer stem cells, and their microenvironment. Stem Cells Int. 2017;2017:5619472.
  2. Williams SA, Anderson WC, Santaguida MT, Dylla SJ. Patient-derived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century. Lab Invest. 2013;93(9):970-982.
  3. Dragu DL, Necula LG, Bleotu C, Diaconu CC, Chivu-Economescu M. Therapies targeting cancer stem cells: Current trends and future challenges. World J Stem Cells. 2015;7(9):1185-1201.
  4. Baccelli I, Trumpp A. The evolving concept of cancer and metastasis stem cells. J Cell Biol. 2012;198(3):281-293.
  5. Botelho M, Alves H. Significance of cancer stem cells in anti-cancer therapies. Int J Immunother Cancer Res. 2016;2(1):14-16.
  6. Hope KJ , Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol. 2004;5(7):738-743.
  7. Doherty MR, Cheon H, Junk DJ, et al. Interferon-beta represses cancer stem cell properties in triple-negative breast cancer. Proc Natl Acad Sci U S A. 2017. pii: 201713728.
  8. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature. 2004;432:396-401.
  9. Junttila MR, Mao W, Wang X, et al. Targeting LGR5+ cells with an antibody-drug conjugate for the treatment of colon cancer. Sci Transl Med. 2015;7(314):314ra186.
  10. Eramo A, et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ. 2008;15:504-514.
  11. Saunders LR, Bankovich AJ, Anderson WC, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med. 2015;7(302):1-28.
  12. Rudin CM, Pietanza MC, Bauer TM, et al. Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study. Lancet Oncol. 2017;18(1):42-51.

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