Cancer stem cell

Cancer stem cells (CSCs) are a sub-population of cancer cells (found within tumors or hematological cancers) that possess characteristics normally associated with stem cells. These cells are believed to be tumorigenic (tumor-forming), in contrast to the bulk of cancer cells, which are thought to be non-tumorigenic. CSCs have stem cell properties such as self-renewal and the ability to differentiate into multiple cell types. A theory suggests such cells persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumours. Development of specific therapies targeted at cancer stem cells holds hope for improvement of survival and quality of life of cancer patients, especially for sufferers of metastatic disease.

Existing cancer treatments were mostly developed on animal models, where therapies able to promote tumor shrinkage were deemed effective. However, animals could not provide a complete model of human disease. In particular, in mice, whose life spans do not exceed two years, tumor relapse is exceptionally difficult to study.

The efficacy of cancer treatments are, in the initial stages of testing, often measured by the amount of tumour mass they kill off. As cancer stem cells would form a very small proportion of the tumour, this may not necessarily select for drugs that act specifically on the stem cells. The theory suggests that conventional chemotherapies kill differentiated or differentiating cells, which form the bulk of the tumor but are unable to generate new cells. A population of cancer stem cells, which gave rise to it, could remain untouched and cause a relapse of the disease.

Evidence for cancer stem cells

Opponents of the paradigm do not deny the existence of cancer stem cells as such. Cancer cells must be capable of continuous proliferation and self-renewal in order to retain the many mutations required for carcinogenesis, and to sustain the growth of a tumor since differentiated cells cannot divide indefinitely (constrained by the Hayflick Limit). However, it is debated whether such cells represent a minority. If most cells of the tumor are endowed with stem cell properties there is no incentive to focusing on a specific subpopulation. There is also debate on the cell of origin of these cancer stem cells - whether they originate from stem cells that have lost the ability to regulate proliferation, or from more differentiated population of progenitor cells that have acquired abilities to self-renew (which is related to the issue of stem cell plasticity).

The first conclusive evidence for cancer stem cells was published in 1997 in Nature Medicine. Bonnet and DickBonnet D and Dick JE. (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. "Nat Med" 3:730-7. Entrez Pubmed|9212098] isolated a subpopulation of leukaemic cells that express a specific surface marker CD34, but lacks the CD38 marker. The authors established that the CD34⁺/CD38^- subpopulation is capable of initiating tumors in NOD/SCID mice that is histologically similar to the donor. (Matsui, 2004)

In cancer research experiments, tumor cells are sometimes injected into an experimental animal to establish a tumor. Disease progression is then followed in time and novel drugs can be tested for their ability to inhibit it. However, efficient tumor formation requires thousands or tens of thousands of cells to be introduced. Classically, this has been explained by poor methodology (i.e. the tumor cells lose their viability during transfer) or the critical importance of the microenvironment, the particular biochemical surroundings of the injected cells. Supporters of the cancer stem cell paradigm argue that only a small fraction of the injected cells, the cancer stem cells, have the potential to generate a tumor. In human acute myeloid leukemia the frequency of these cells is less than 1 in 10,000.

Further evidence comes from histology, the study of tissue structure of tumors. Many tumors are very heterogeneous and contain multiple cell types native to the host organ. Heterogeneity is commonly retained by tumor metastases. This implies that the cell that produced them had the capacity to generate multiple cell types. In other words, it possessed multidifferentiative potential, a classical hallmark of stem cells.

The existence of leukaemic stem cells prompted further research into other types of cancer. Cancer stem cells have recently been identified in several solid tumours, including:
*Breast cancer [Al-Hajj et al. (2003) Prospective identification of tumorigenic breast cancer cells. "Proc Natl Acad Sci USA" 100(7):3983-8. Entrez Pubmed|12629218]
*Brain cancer [Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB. (2003) Identification of a cancer stem cell in human brain tumors. "Cancer Res." 63:5821-8. Entrez Pubmed|14522905]
*Colon cancers [O'Brien CA, Pollett A, Gallinger S, Dick JE. (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. "Nature." 445:106-10. Entrez Pubmed|17122772]
*Pancreatic cancer [Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM. [http://cancerres.aacrjournals.org/cgi/content/full/67/3/1030 Identification of Pancreatic Cancer Stem Cells] . Cancer Res. 2007 Feb 1;67(3):1030-7.]
*Ovarian cancerMor, G. Yale Medical School. Presentation of unpublished data at University of Missour, Kansas City Medical School. Jan 7, 2008.]

Importance of stem cells

Not only is finding the source of cancer cells necessary for successful treatments, but if current treatments of cancer do not properly destroy enough cancer stem cells, the tumor will reappear. Including the possibility that the treatment of for instance, chemotherapy, will leave only chemotherapy-resistant cancer stem cells, then the ensuing tumor will most likely also be resistant to chemotherapy. If the cancer tumor is detected early enough, enough of the tumor can be killed off and marginalized with traditional treatment. But as the tumor size increases, it becomes more and more difficult to remove the tumor without conferring resistance and leaving enough behind for the tumor to reappear.

Some treatments with chemotherapy, such as paclitaxel in ovarian cancer (a cancer usually discovered in late stages), may actually serve to promote certain cancer growth (55-75% relapse <2 yearsEngland's National Institute of Health and Clinical Excellence. [http://www.nice.org.uk/nicemedia/pdf/55_Paclitaxel_ovarianreviewfullguidance.pdf Full guidance on the use of paclitaxel in the treatment of ovarian cancer] , 22 January 2003.] ). It potentially does this by destroying only the cancer cells susceptible to the drug (targeting those that are CD44-positive, a trait which has been associated with increased survival time in some ovarian cancers), and allowing the cells which are unaffected by paclitaxel (CD44-negative) to regrow, even after a reduction in over a third of the total tumor size. There are studies, though, which show how paclitaxel can be used in combination with other ligands to affect the CD44-positive cells. [Edmond Auzenne, Sukhen C Ghosh, Mojgan Khodadadian, Belinda Rivera, David Farquhar, Roger E Price, Murali Ravoori, Vikas Kundra, Ralph S Freedman, and Jim Klostergaard. [Hyaluronic Acid-Paclitaxel: Antitumor Efficacy against CD44(+) Human Ovarian Carcinoma Xenografts http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1899257] . Neoplasia. 2007 June; 9(6): 479–486.] While paclitaxel alone, as of late, does not cure the cancer, it is effective at extending the survival time of the patients.

Mechanistic and mathematical models

Once the pathways to cancer are hypothesized, it is possible to develop predictive mathematical biology models, [Preziosi, L. (2003) "Cancer Modelling and Simulation". Chapman Hall/CRC Press. ISBN 1-58488-361-8.] e.g., based on the cell compartment method. For instance, the growths of the abnormal cells from their normal counterparts can be denoted with specific mutation probabilities. Such a model has been employed to predict that repeated insult to mature cells increases the formation of abnormal progeny, and hence the risk of cancer. [Ganguly R. and Puri I.K. (2006) Mathematical model for the cancer stem cell hypothesis. "Cell Prolif" 39:3-14. Entrez Pubmed|16426418.] Considerable work needs to be done, however, before the clinical efficacy of such models is established.

Origins

This is still an area of ongoing research. Logically, the smallest change (and hence the most likely mutation) to produce a cancer stem cell would be a mutation from a normal stem cell. Also, in tissues with a high rate of cell turnover (such as the skin or GI epithelium, where cancers are common), it can be argued that stem cells are the only cells that live long enough to acquire enough genetic abnormalities to become cancerous. However it is still possible that more differentiated cancer cells (in which the genome is less stable) could acquire properties of 'stemness'.

It is likely that in a tumour there are several lines of stem cells, with new ones being created and others dying off as a tumour grows and adapts to its surroundings. [ Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL and Wahl GM. (2006) Cancer Stem Cells--Perspectives on Current Status and Future Directions: AACR Workshop on Cancer Stem Cells. "Cancer Research" 39:3-14. Entrez Pubmed|16990346.] Hence, tumour stem cells can constitute a 'moving target', making them even harder to treat.

Implications for cancer treatment

The existence of cancer stem cells have several implications in terms of future cancer treatment and therapies. These include disease identification, selective drug targets, prevention of metastasis, and development of new strategies in fighting cancer.

Normal somatic stem cells are naturally resistant to chemotherapeutic agents - they have various pumps (such as MDR) that pump out drugs, DNA repair proteins and they also have a slow rate of cell turnover (chemotherapeutic agents naturally target rapidly replicating cells). Cancer stem cells, being the mutated counterparts of normal stem cells, may also have similar functions which allows them to survive therapy. These surviving cancer stem cells then repopulates the tumour, causing relapse. By selectively targeting cancer stem cells, it would be possible to treat patients with aggressive, non-resectable tumours, as well as preventing the tumour from metastasizing. The hypothesis implies that if the cancer stem cells are eliminated, the cancer would simply regress due to differentiation and cell death.

There has also been a lot of research into finding specific markers that may distinguish cancer stem cells from the bulk of the tumour (as well as from normal stem cells), with some success. [Al-Hajj et al. (2003) Prospective identification of tumorigenic breast cancer cells. "Nat Med" 3:730-7. Entrez Pubmed| 12629218] Proteomic and genomic signatures of tumours are also being investigated. Success in these area would enable faster identification of tumour subtypes as well as personalized medicine in cancer treatments by using the right combination of drugs and/or treatments to efficiently eliminate the tumour.

Cancer stem cell pathways

A normal stem cell may be transformed into a cancer stem cell through disregulation of the proliferation and differentiation pathways controlling it. Scientists working on cancer stem cells hope to design new drugs targeting these cellular mechanisms. The first findings in this area were made using haematopoietic stem cells (HSCs) and their transformed counterparts in leukemia, the disease whose stem cell origin is most strongly established. However, these pathways appear to be shared by stem cells of all organs.

Bmi-1

The Polycomb group transcriptional repressor Bmi-1 was discovered as a common oncogene activated in lymphoma [Haupt Y, Bath ML, Harris AW and Adams JM. (1993) bmi-1 transgene induces lymphomas and collaborates with myc in tumorigenesis. "Oncogene", 8:3161-4. Entrez Pubmed|8414519.] and later shown to specifically regulate HSCs. [Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL, Morrison SJ and Clarke MF. (2003) Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. "Nature", 423:302-5. Entrez Pubmed|12714971.] The role of Bmi-1 has also been illustrated in neural stem cells. [Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF and Morrison SJ. (2003) Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. "Nature", 425:962-7. Entrez Pubmed|14574365.] The pathway appears to be active in cancer stem cells of pediatric brain tumors. [Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M and Kornblum HI. (2003) Cancerous stem cells can arise from pediatric brain tumors. "PNAS" 100:15178-83. PMC|299944]

Notch

The Notch pathway has been known to developmental biologists for decades. Its role in control of stem cell proliferation has now been demonstrated for several cell types including haematopoietic, neural and mammary [Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS. (2004) Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. "Breast Cancer Res." 6:R605-15. PMC|1064073] stem cells. Components of the Notch pathway have been proposed to act as oncogenes in mammary [Dievart A, Beaulieu N and Jolicoeur P. (1999) Involvement of Notch1 in the development of mouse mammary tumors. "Oncogene". 18:5973-81. Entrez Pubmed|10557086] and other tumors.

onic hedgehog and Wnt

These developmental pathways are also strongly implicated as stem cell regulators. [Beachy PA, Karhadkar SS and Berman DM. (2004) Tissue repair and stem cell renewal in carcinogenesis. "Nature". 432:324-31. Entrez Pubmed|15549094] Both Sonic hedgehog(SHH) and Wnt pathways are commonly hyperactivated in tumors and are required to sustain tumor growth. However, the Gli transcription factors that are regulated by SHH take their name from gliomas, where they are commonly expressed at high levels. A degree of crosstalk exists between the two pathways and their activation commonly goes hand-in-hand. [Zhou BP and Hung MC. (2005) Wnt, hedgehog and snail: sister pathways that control by GSK-3beta and beta-Trcp in the regulation of metastasis. "Cell Cycle". 4:772-6. Entrez Pubmed|15917668] This is a trend rather than a rule. For instance, in colon cancer hedgehog signalling appears to antagonise Wnt. [Akiyoshi T, Nakamura M, Koga K, Nakashima H, Yao T, Tsuneyoshi M, Tanaka M and Brian McDonald. (2005) Gli1, down-regulated in colorectal cancers, inhibits proliferation of colon cancer cells involving Wnt signalling activation. "Gut". [Epub ahead of print] . Entrez Pubmed|16299030]

Sonic hedgehog blockers are available, such as cyclopamine. There is also a new water soluble cyclopamine that may be more effective in cancer treatment. There is also DMAPT, a water soluble derivative of parthenolide that targets AML (leukemia) stem cells, and possibly other cancer stem cells as in myeloma or prostate cancer. A clinical trial of DMAPT is to start in England in late 2007 or 2008. Furthermore, GRN163L was recently started in trials to target myeloma stem cells. If it is possible to eliminate the cancer stem cell, than a potential cure may be achieved if there are no more cancer stem cells to repopulate a cancer.

External links

* [http://www.ncbi.nlm.nih.gov/pubmed/18511937 Exploring the role of cancer stem cells in radioresistance] Abstract of a review by Michael Baumann, Mechthild Krause, Richard Hill, "Nat Rev Cancer" 2008(Jul); 8(7):545-54
* [http://www.crmagazine.org/archive/Summer2006/Pages/ATumorsLifeblood.aspx "A Tumor's Lifeblood"] , Jessica Gorman, "CR" magazine, Summer 2006
* [http://www.umdnj.edu/gsbsnweb/stemcell/scofthemonth/CSCsci.htm "Cancer Stem Cell Scientific Literature Review"] , "UMDNJ Stem Cell Research and Regenerative Medicine", June 17, 2006
* [http://www.news-medical.net/?id=14891 "Stem cells may cause some forms of bone cancer"] , "News-Medical.Net", December 7, 2005
* [http://www.sciencenews.org/articles/20040320/bob8.asp "The Bad Seed: Rare stem cells appear to drive cancers"] , "Science News Online", March 20, 2004
* [http://www.genomenewsnetwork.org/articles/03_03/stem_c.shtml "The Real Problem in Breast Tumors: Cancer Stem Cells"] , "Genome News Network", March 7, 2003
* [http://www.stemcellcordblood.net Stem Cell and Cord Blood information database]

References