The hypothesis of cancer stem cells (CSCs) was proposed for the first time for nearly a century ago. However, most of the weight in cancer research was initially not focused on this particular area for the treatment of cancer and it was not until recently the focus has shifted towards CSCs, due to the identification of stem cell subcomponents that has been found in a number of human malignancies. For instance they have been found in hematologic malignant neoplasm and tumours in prostate, breast, brain, pancreas and a few other tissues/organs(Korkaya & Wicha, 2007; Al-hajj et al, 2003). (However look up on Li et al, 2007 saying that pancreatic csc was not found). However another study that was done by Li during 2007 pancreatic cancer stem cells was not found. CSCs are a subset of malignant cell found in hierarchically organized tumors and hematological cancers, in which evidence are suggesting that they contain stem cell like properties that includes self-renewal and differentiation (Schatton et al, 2009 and Korkaya & Wicha, 2007). Hence the name CSCs and are sometimes considered as the origin of tumorigenic cells, because of its stem cell like properties it has the ability to constitutively activate survival pathways and proliferate indefinitely (Eramo et al, 2007). This literature review will be looking at the evidence showing the theory of CSC existence as well as the evidence disapproving the existence of CSCs. We will also be looking at the implications of using conventional cancer therapy from the CSC perspective and finally what opportunities the theory of CSC can provide for the treatment and diagnosis of cancer in modern days.
2. Stem cells
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Stem cells can be defined as “undifferentiated cells that are capable of self-renewing and differentiating into a large number of diverse mature progeny” (Gua et al, 2006). There are several different types of stem cells such as, the embryonic stem cell (ESC) which has the ability to differentiate into many different cell types if the right conditions are given in vitro and in vivo it can differentiate into all tissue types if the condition permits it to do so. ESC is termed totipotent due to its ability to differentiate into any cell type. (REFERENCE?) Somatic stem cells or also known as adult stem cells is another type of stem cells and they are pluripotent and are responsible for the regeneration and reparation of damaged tissues. Adult stem cells are found in the hematopoietic system, brain, skin mammary glands and lung. It is however still uncertain if somatic stem cells are present in any other adult organs apart from the ones that are mentioned (Blau et al, 2001).
The ability for stem cells to self-renew is required of the reparation and regeneration of damaged tissues and it is crucial for the system to find a balance between self-renewing and differentiation, ensuring that the generation of mature cells does occur without the depletion of stem cell reserves during the lifetime of the organism (Rossi & Weissman, 2006). However, due to the error prone nature of DNA there is a risk of genetic alteration to occur in its DNA causing uncontrolled generation of new cells. Thus, this process is highly regulated by several complex pathways that involves Wnt, Notch and Hedgehog proteins, these proteins are known to regulate the self-renewal property in normal stem cells and to complicate things further tumor suppressor genes such as phosphates and tensin homolog on chromosome 10 (PTEN) and tumor protein p53 (TP53) are also involved. It is believed that these pathways are deregulated in cancer cells leading to uncontrolled self-renewal of CSCs generating tumor cells that are resistant to conventional therapies. This is because that the conventional cancer therapy may target and kills differentiated tumor cells but fails to kill the cancer stem cell population. Thus the conventional cancer therapy is not a hundred percent and often leads to resistance once the tumor regenerates (Korkaya &Wicha, 2007).
3. Stem cell self-renewal pathways
3.1 Hedgehog (Hh) signaling pathway
The Hh gene was first identified when screening for genes of drosophilia that were required for the patterning of the early development in embryos (Nusslein-volhard & Wieschaus, 1980) where the discovery led to the Nobel prize for physiology or Medecine in 1995 nominated to Edward B Lewis, Christiane Nusslein-Volhard and Eric F wieschaus for their work done on genetic mutation in drosophilia embryogenesis (Nobel Prize Organization). Three families of the Hh gene have been identified in mammalians; Sonic (SHH) is the best studied in vertebrates and is widely expressed during embryogenesis acting as a morphogen and has a key role in the formation of neural tube, primitive gut, tracheobronchial tree and the axial skeleton (Mahlapuu et al 2001), Desert (DHH) and Indian (IHH) by identifying the subset of Hh it was possible to demonstrate the role it had in human malignant development (Ingham & McMahon, 2001). The signaling pathway contributes of four components (a) one of the three family member of the Hh acting as the ligand all binding to the same receptor elicting a similar response, (b) a transmembrane receptor-patched homolog 1 and 2 named; ptch 1/2, (c) a G-protein coupled receptor named smoothened (smo) and (d) a complex that regulates the cubitus interruptus or glioma associated oncogene homolog of transcriptional effectors (Velcheti & Govindan, 2007).
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Al-Hajj. M., Wicha. M.S., Benito-Hernandez, A., Morrison. S.J., and Clarke, M.J. Prospective identification of tumorigenic breast cancer cells. Proceeding of the national academy of science (PNAS) 100 (7) 3983-3988.
Blau. H.M., Brazelton. T.R., and Weimann. J.M. The evolving concept of a stem cell: entity or function? Cell 105 june 29. 829-841. (2001)
Eramo. A., Lotti. F., Sette. G., Pilozzi. E., Biffoni. M., Di Virgilio. A., Conticello. C., Ruco. L., Peschle. C. and De Maria. R. Identification and expansion of tumorigenic lung cancer stem cell population. Cell death and differentiation 15: 504-514 (2008)
Gua. W., Lasky III, J.L. and Wu. H. Cancer stem cells. International pediatric research foundation 59: (4) 59-64 (2006)
Ingham. P.W. & McMahon. A.P. Hedgehog signaling in animal development: paradigms and principles. Genes Development Dec 1; 15 (23): 3059-3087. (2001)
Li. C., Heidt. D.G., Dalerba. P., Burant. C.F., Zhang. L., Adsay. V., Wicha. M., Clarke. M.F. and Simeone. D.M. Identification of pancreatic cancer stem cells. Cancer Research 67: (3) febuary 1 (2007)
Mahlapuu. M., Enerbäck. S. and Carlsson. P. Haploinsufficiency of the forkhead gene Foxf1, a target for sonic hedgehog signaling, causes lung and foregut malformations. Development 128; 2397-2406 (2001)
Nusslein. C. and Wieschaus. E. mutation affecting segment number and polarity in drosophilia. Nature oct 30; 287 (5785): 795-801. (1980)
Korkaya. H. & Wicha. M.S. Selective targeting of cancer stem cells: A new concept in cancer therapeutics. Biodrugs 21(5): 299-310. (2007)
Rossi. D.J. and Weissman. I.L. PTEN, Tumorigenesis, and stem cell self-renewal. Cell 125 april 21. 229-231.
Schatton. T., Frank. N.Y and Frank. M.H. Identification and targeting of cancer stem cells. Bioessays 31: 1038-1049. (2009) (review)
Velcheti. V. and Govindan. R. Hedghog signaling pathway and lung cancer. Journal of thoracic oncology vol 2, number 1, January 2007.
http://www.cellsignal.com/pathways/wnt-hedgehog.jsp good website for cell signaling pathways
Nobel prize: http://nobelprize.org/nobel_prizes/lists/1995.html (accessed November 2009)