The Biology of the Cancer Stem Cell Model and Potential Therapeutic Targets

Andreas Neophytou 1309539 Professor Viant

The Biology of the Cancer Stem Cell Model and Potential Therapeutic Targets

Introduction

Malignant tumours arise from uncontrolled cellular growth, they are better known as cancer. The driving force behind tumour growth has long been the subject of debate, one theory which is gaining much reputation as a result of experimental evidence is the cancer stem cell model. This model depicts a specific subpopulation of cancer cells as having similar properties to healthy stem cells, the most important being the ability of self-renewal and the production of more differentiated cells. Cancer stem cells (CSCs) are what initiate tumourigenesis and may be the cause of metastasis and relapse in sufferers of cancer.14

This essay focuses on the biological mechanisms of CSCs and how targeting these cells may prove to be the source of more prolific cancer treatment. Evidence for Cancer Stem Cell Existence

The identification of cells with tumourigenic potential through specific biomarker expression in multiple cancer types has provided evidence for the CSC model and exposed prospective therapeutic targets, the following are a few examples of tumours where CSCs have been identified and extracted.

Acute Myeloid Lymphoma The theory of CSCs was not supported by experimental evidence until 1997 where cells thought to be CSCs were identified and extracted from human acute myeloid lymphoma (AML) and shown to drive AML after xenotransplantation into NOD/SCID mice. The identification of CSCs was achieved by classifying cells by their cell surface receptors, specifically the CD34 and CD38 cell markers. These biomarkers were chosen due to haemopoetic stem cells (HSCs) expressing a CD34+ CD38- phenotype, as HSCs are the most likely target for the site of malignant transformation in AML it was hypothesised CSCs from AML would have the same phenotype. It was shown that xenotransplantation of CD34+ CD38- AML cells initiated tumourigenesis in the NOD/SCID mice. Only CD34+ CD38- AML cells had tumourigenic capabilities, therefore proving a single sub-population was responsible for driving tumour growth. This CSC subpopulation represented only one cell for every five-hundred AML cells, this suggested CSCs only constitute for a minute fraction of the total cancer cell population.1 However, as will be explained later, this is not always the case.

Figure 1: The ability to distinguish between CSCs and non-stem cancer cells due to their heterogeneous expression of cell surface biomarkers has allowed therapies to be designed that are specific to CSCs. One such therapeutic target of CSCs is aurora A kinase (AURKA) and aurora B kinase (AUKRB), enzymes associated with G2 phase transition to M phase during the cell cycle and cell growth. They are seen to be over-expressed in CD34+ CD38- cells when compared to healthy HSCs and non-stem AML cells. Inhibition of AKURA in CD34+ CD38- cells lead to increased programmed cell death and decreased cell growth with failure to transition from G2 phase to M phase.15 Source: http://onlinelibrary.wiley.com/doi/10.1002/ijc.28277/full


Brain Tumour Brain tumour cultures from fourteen patients were exposed to conditions which allow the identification and extraction of normal neural stem cells, as neurospheres, in order to detect brain tumour stem cells (BTSCs). Neurospheres were formed by a minor part of the tumour population in the cultures. The biomarker CD133, expressed by neural stem cells and HSCs, was shown to be present on BTSCs thus allowing their isolation and extraction. The BTSC neurosphere structures were allowed to grow in conditions used to culture healthy neurospheres for one week, this resulted in the formation of cells that are more differentiated than BTSCs and express a phenotype similar to that of the original tumour. In order to ensure only CD133+ cells had tumourigenic capabilities both CD133+ and CD133- cells were cultured, only CD133+ cells exhibited tumourigenesis whilst CD133-

cells showed no such potential. This therefore proved only a subpopulation of brain tumours expressed tumour initiating capabilities as defined by the CSC model.5

Breast Cancer The principles used to isolate AML CSCs were applied to breast cancer cells in order to determine whether CSCs were also present in breast cancers. Biomarkers CD44 and CD24 were used in order to classify which cells were tumourigenic, this is due to the heterogeneity of breast cancer cells with respect to these biomarkers. Breast cancer cells that were xenotransplanted into NOD/SCID mice and expressed a CD44+ CD24- phenotype resulted in tumour formation, whereas CD44- CD24+ cells had no tumourigenic potential. Analysis of the tumour formed by the xenotransplanted cells revealed it expressed a phenotype similar to that of the original tumour.21

The identification and extraction of CSCs from other cancers, including melanoma, prostate, colon, pancreatic and many others, by their specific cell-surface biomarker phenotype has proven the existence of CSCs and has allowed insight into their potential origin and biological processes. The heterogeneity of cancer cells has facilitated the identification and extraction of CSCs as they express a different phenotype to that of non-stem cancer cells.

Despite this research providing the evidence that CSCs exist their origin is still the subject of debate. As they possess the ability of self-renewal and have differentiative capabilities, normal stem cells are the obvious target for the site of the malignant transformations which lead to the production of CSCs. As pathways that regulate self-renewal are also involved in tumourigenesis, such as the Wnt/-catenin signalling pathway, this connection between stem cells and cancer made sense as less mutations would be needed to maintain the capability of self-renewal compared to ectopic activation. Also this self-renewal capability means stem cells remain in the body much longer when compared to more differentiated cells, therefore the probability of a series of mutations leading to malignant transformation is much greater in stem cells when compared to other cells. Evidence supports this as CSCs isolated from AML express a CD34+ CD38- phenotype identical to that of HSCs, this therefore suggests HSCs and not progenitor cells to be the site of malignant transformation in AML.1

Figure 2: The adjacent table shows currently discovered cell surface biomarker expression that is specific to CSCs from various cancer types.

Source: http://www.allthingsstemcell.com/wp-content/uploads/2009/07/CancerStemCellMarkers2.jpg


Plasticity in the Cancer Stem Cell Model

As other theories exist which explain the process of tumourigenesis, such as the clonal evolution (CE) model, the CSC model was not initially accepted as being the explanation. The main difference between these two models is how they explain the heterogeneity between cancer cells, the CSC model states this occurs due to variances in epigenetics whereas the CE model is based on genetic differences. However recent research suggests that both of the models may be correct, and the CSC subpopulation is not always a small percentage of the entire cancer population. The link between the models has been made by the identification of plasticity in the cancer cell hierarchy, this means that the differentiation of CSCs into more differentiated cells can be reversed. This ability of dedifferentiation by non-stem cancer cells also makes them targets for evolutionary mutations within the tumour, and so allows the concept of CSCs to co-exist with the CE model.17

The ability of prostate cancer cells to alternate between CD44+ and CD44- phenotype is evidence for this plasticity in cancer cells, however it also shows that there is an established dynamic equilibrium between CSCs and more differentiated cancer cells which is affected by the micro-environment of the cells.17 Certain micro-environmental conditions promote the dedifferentiation of non-stem cancer cells into CSCs, such as hypoxic and acidic conditions. This is due to these conditions playing a role in the regulation of signalling pathways, such as P13K/Akt/mTOR, and secretion of cytokines, such as IL-6 and TGF-, which control cellular expression of stem-like properties.9 This plasticity therefore means the number of CSCs present in a specific tumour can and will alter as the tumour progresses, thus the CSC subpopulation will not always constitute for a minute percentage of the entire tumour as initially hypothesised. This therefore disputes claims that the CSC model is invalid due to the presence of large numbers of cells with tumourigenic potential in certain cancers. For example Quintana et al. published data showing that CSCs constituted for more than one quarter of melanoma cells under certain conditions and under these conditions more than one cellular phenotype expressed tumourigenic capabilities.3 However the occurrence of dedifferentiation was not considered to be the cause of this seemingly unspecific tumour initiating property of melanoma cells. Recently it has been shown that melanoma cells expressing a CD271+ phenotype exclusively initiate melanoma in human skin grafted onto RG mice,20 this therefore suggests the conditions utilised by Quintana et al. may promote dedifferentiation and therefore provides an explanation as to why they concluded CSCs were non-existent in melanoma. This plasticity may also prove to be an obstacle in therapies designed to specifically target CSCs. CSCs present at the time of administration of the therapy may be killed and therefore reduce or remove the malignant nature of the tumour. However as the non-stem cancer cells have the ability to dedifferentiate this removal of malignancy may only be temporary.11

Figure 3: This figure depicts the equilibrium exhibited by CSCs and non-stem cancer cells. It shows under initial conditions of tumourigenesis the rate of dedifferentiation is low as the micro-environmental condition are not ideal. However as the tumour progresses transitions in the micro-environment and cellular processes occur which stimulate dedifferentiation to occur at the same rate as differentiation. Dedifferentiation of non-stem cancer cells can also be experimentally induced leading the rate of dedifferentiation exceeding that of differentiation.17

Source: http://www.naure.com/cr/journal/v22/n3/fig_tab/cr201213f3.html


Regulation of Stem-like Properties

As previously discussed certain micro-environmental factors are able to induce stem-like properties in more differentiated cancer cells, the biological mechanisms of key signalling pathways involved in the maintenance of these properties are summarised below.

Wnt/-catenin Signal Pathway The Wnt/-catenin signalling pathway is classically associated with CSCs as its regulation ensures stability of differentiation and self-renewal. In CSCs this pathway is up-regulated leading to the constant association of Wnt to its Frizzled receptors, this results in the dissociation of -catenin from its degradation complex and its translocation into the nucleus. Once in the nucleus -catenin promotes the gene transcription of proteins which play vital roles in maintaining self-renewal and differentiative properties. This pathway has been shown to maintain the tumourigenic abilities of CSCs in AML and breast cancers.19

NF-B Signal Pathway This transcription factor is usually inactive in normal cells and located in the cytoplasm, its activation follows cellular stimulation by cytokines, growth factors, ultra-violet light and reactive oxygen species (ROS). Once activated it plays a pivotal role in the regulation of multiple genes which are involved in several cellular functions, however its primary function is the stimulation of anti-apoptotic proteins synthesis thus preventing programmed cell death.13 Notch Signal Pathway This signal pathway is involved in development and maintenance of stem-like properties, it regulates cell-cell signalling during differentiation and programmed cell death; it is also essential for neural stem cell maintenance. The pathway is activated by Notch receptor-ligand binding between adjacent cells, once activated the Notch receptor is cleaved from the receptor-ligand complex. This releases its intracellular domain (NICD) which is able to enter to nucleus and regulate gene transcription of specific target genes. Activation of these genes up-regulates the synthesis of proteins involved in self-renewal therefore promoting the maintenance of stem-like properties. Expression of Notch4 has been shown to be amplified in breast cancer stem cells.19 These three signalling pathways seem to be key in controlling the stemness of CSCs, however four more pathways have also been linked to regulating self-renewal and proliferation of CSCs. The intermediaries and effects of these pathways are summarised in figure 4.The up-regulation of these pathways in CSCs is a similarity they have with embryonic stem cells, this therefore provides further proof that there are cells within a tumour that are capable of initiating and re-establishing a malignant growth.


Metastasis and Cancer Stem Cells When a secondary tumour forms in a different location of the body to the initial site of cancer formation it is termed as a metastatic tumour. The discovery of CSCs provides an explanation for the mechanism of metastasis and how it is possible for a secondary malignant tumour to form in a distant part of the body. Due to the tumourigenic properties of CSCs they have been labelled the initiators of metastatic tumours. The mechanism by which they arrive at the site of metastasis can be explained by epithelial-mesenchymal transition (EMT) and the plasticity of CSCs. EMT involves the loss of cell adhesion and polarity by epithelial cells thus transforming them into mesenchymal cells, this is a process required for multiple bodily processes such as wound healing. However it is also related to the initiation of metastasis, due to the lack of cellular adhesion presented by mesenchymal cells the invasive and migratory capabilities of the affected cells increases. The transformation of CSCs to mesenchymal cells by EMT therefore mediates the invasion of tumourigenic CSCs into a secondary site in the body, here they are able to induce the formation of a new metastatic tumour.12

EMT in CSCs is initiated by dysregulation of various signalling pathways, transforming growth factor- (TGF-) seems to play a vital role in the initiation of EMT. TGF- is initially involved in the prevention of tumourigenesis however as the tumour progresses it gains resistance to the anti-growth effects of TGF-. As the tumour gains resistance to TGF- it simultaneously over expresses the cytokine. High TGF- levels are often associated with greater potential for a metastatic tumour to form and the unlikelihood of survival.4 TGF- has been shown to induce EMT in cancer cells by activating Smad proteins, which regulates the transcription of specific genes, thus altering the synthesis of certain protein and cytokines. Smad proteins form complexes with EMT associated transcription factors, such as Snail1, Zeb1/2 and -catenin, in order to stimulate mesenchymal genes and inactivate epithelial genes. This is well exhibited by the binding of Smads to Snail1, resulting in E-cadherin inhibition and a loss of cell-cell adhesion; thus promoting mesenchymal transformation of CSCs.10 NF-B is also thought induce EMT through interaction with Ras proteins, and its removal results in the initiation of mesenchymal-epithelial transition (MET).2 NF-B activation has been shown to be induced by TGF--activated kinase 1, therefore suggesting a TGF-/NF-B pathway may be key in EMT.23 Nevertheless NF-B is vital for EMT initiation and its inhibition will result in impaired metastatic capabilities of the tumour.2

Figure 5: This illustration depicts the processes involved in metastasis. EMT leads to cellular mobility in select CSCs most of which are likely to resituate locally. However some CSCs may enter a blood vessel, where trans-differentiation may occur, leading to its transportation to a secondary site where a metastatic tumour will form.

Source: http://www.nature.com/nm/journal/v17/n9/fig_tab/nm.2437_F1.html


The ability to reprogramme fibroblasts into neurons and hepatocytes by inducing and repressing the expression of certain transcription factors has proven cells have the ability to transdifferentiate. For metastasis to successfully occur CSCs must travel to the metastatic site, therefore they must also experience and survive multiple and varying microenvironments.17 As the genetic material in cancer cells is much more prone to mutation when compared to normal cells it is likely CSCs have the ability to alter their epigenetics and are able to transdifferentiate. If CSCs are able to transdifferentiate it would increase their chance of survival during the initiation of metastasis, due to the ability to adapt to the various micro-environments and differing conditions they will be exposed to.18

The induction of EMT in CSCs combined with their potential to transdifferentiate and tumourigenic capabilities strongly suggests they are the cause of metastatic cancers. This information can therefore be utilised to design therapies directed at preventing EMT or inducing MET in order to decrease the invasive potential of tumours.

Figure 6: Glioblastoma stem cells (GSCs) have been shown to generate pericytes in order to increase blood and oxygen transport to the tumour micro-environment, therefore showing CSCs have transdifferentiative capabilities. Pericytes presence in the tumour micro-environment has been shown to correlate with resistance to various cancer therapies. Methods of removing pericytes from a tumour in an attempt to reduce this resistance have proven successful and has resulted in tumour deterioration at the initial site.8 However due to the sudden induction of a hypoxic micro-environment by removing pericytes, EMT is initiated at an elevated rate resulting in metastasis.14

Source: http://origin-ars.els-cdn.com/content/image/1-s2.0-S0092867413002109-fx1.jpg

Figure 7: Induction of hypoxia has also been linked to the overexpression of the Met receptor protein and increased synthesis of hepatocyte growth factors. Activation of Met receptors by hepatocyte growth factors results increased cellular mobility and increased invasive capabilities. Therefore the ability for hypoxia to initiate EMT in CSCs may be partly due to the increased expression of Met receptors and its over-activation. The adjacent image shows the effects of Met inhibition on metastasis. NG2-tk+GCV mice, which have impaired pericyte synthesis, were shown to over-express Met and undergo lung metastasis. However inhibition of Met in NG2-tk+GCV mice showed almost complete suppression of metastasis.14 Source: http://origin-ars.els-cdn.com/content/image/1-s2.0-S1535610811004478-gr5.jpg


Therapeutic Targets of Cancer Stem Cells The signalling pathways that control their stem-like properties and the biomarkers specific to CSCs are being exploited as therapeutic targets of CSCs.6 However other novel targets of CSCs have been discovered, a select few are mentioned below. Arachidonate 5-Lipoxygenase (Alox5) Gene The Alox5 gene encodes Arachidonate 5-lipoxygenase (5-LO) which has been shown to regulate leukaemic stem cells. The transplantation of leukaemic stem cells from bone marrow cells containing the BCR-ABL gene were utilised in order to induce chronic myeloid leukaemia (CML) in test mice. The test mice had either Alox5+ or Alox5- phenotype, the mice with Alox5- phenotype failed to develop CML after transplantation of BCR-ABL cells and the presence of leukaemic stem cells completely disappeared after 49 days. The test mice expressing Alox5 developed CML and died after 28 days. The BCR-ABL cells that form the leukaemic stem cells were shown to be either long-term leukaemic stem cells, short-term leukaemic stem cells or multipotent progenitor cells. The loss of Alox5 expression resulted in a loss of long-term leukaemic stem cells by preventing self-renewal and forcing them to differentiate, therefore resulting in a loss of tumourigenic potential. Zileuton, a drug currently used to treat asthma, has been shown to inhibit 5-LO function and has produced results in test mice transplanted with BCR-ABL cells similar to that of mice with an Alox5- phenotype. This therefore suggests Zileuton could potentially be redeployed as an anti-leukaemic drug.7 PAFAH1B1 Gene The PAFAH1B1 gene encodes Lis1, a protein which regulates the role of dynein during the proper binding of the mitotic spindle to the cellular cortex, thus guarantees the proper separation of daughter cells during cellular division. It is therefore a key regulator of asymmetric division and is responsible for proper gene inheritance by daughter cells. Recent data shows that the deletion of the PAFAH1B1 gene in HSCs results in a complete loss of erythrocyte production and a loss of HSC function. Xenotransplantation of human AML and CML into mouse models which lack Lis1 expression results in no malignant growth, this therefore suggests Lis1 is required for the proper division of CSCs in AML and CML. The loss of Lis1 expression was also shown to increase the inheritance of the NUMB gene by daughter cells which results in the suppression of the Notch signal pathway. This therefore resulting in a loss of stem-like properties by daughter cells and significantly lowers or completely removes their tumourigenic capabilities. Numb has also been shown to induce apoptosis in cancer cells by degrading TP53. Drugs targeting Lis1 may therefore prove to be valuable in cancer treatment by dysresgulating the cellular division of CSCs and increasing Numb levels in subsequent daughter cells.22 Nanoparticles CSCs have been shown to have resistance to current chemotherapies which target the bulk of tumours, this property has been accredited to their overexpression of ABC transporters. ABC transporters have been shown to be a cause of antibiotic resistance in bacterial cells due to increased exportation of drugs from within the cells, the same mechanism has been detected in CSCs thus providing them with resistance to current chemotherapies. However nanoparticles have been shown to evade this resistance in CSCs proving that alterations to current chemotherapies available may prove to target CSCs efficiently. One such example is Doxrubicin, an intercalating agent that not only have CSCs shown resistance to, but it also induces the dedifferentiation of non-stem cancer cells. Doxorubicin conjugated to gold nanoparticles conversely has been proven to overcome this resistance and shown to kill CSCs and decrease tumour progression. Chemotherapies intermediated by nanoparticles may therefore also prove to be an effective method of targeting CSCs.16


Conclusion

The discovery of CSCs has given us greater knowledge into how a tumour develops and thus may shed light on new, more successful ways to treat cancer. However, CSCs are resistant to current cancer therapies which attack the bulk of the tumour which is mostly made up of non-stem cancer cells. Therefore even if the bulk of the tumour is removed patients will still be vulnerable to a relapse as only a single CSC is required to survive in order to re-initiate tumourigenesis. Therapies should be and are being designed in order to specifically target and destroy CSCs therefore removing cells with self-renewal capabilities and so reducing the likelihood of any form of relapse. However due to the plasticity of cancer cells it is possible that solely targeting CSCs may prove to be ineffective, instead a combination of current cancer therapies and CSC targeting therapies should be used to ensure successful treatment. Targeting CSCs will also reduce the occurrence of a metastatic tumour, however ways of blocking EMT in CSCs must also be discovered in order to further reduce the risk of metastasis. Overall the discovery and understanding of how CSCs function should prove to be extremely important in future cancer therapies.

References

1. Bonnet, D. & Dick, J.E., 1997. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Medicine, 3(7), pp.730737.

2. Huber, M.A. et al., 2004. NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. The Journal of clinical investigation, 114(4), pp.569581.

3. Quintana, E. et al., 2008a. Efficient tumor formation by single human melanoma cells. Nature, 456(7222), pp.593598.

4. Tsekrekou. M. et al., 2012. Stem cell characters in primary and metastatic tumour establishment. Springer Science. pp. 536-563.

5. Singh, S.K. et al., 2003. Identification of a Cancer Stem Cell in Human Brain Tumors. Cancer Research, 63(18), pp.58215828.

6. Chen, K., Huang, Y. & Chen, J., 2013. Understanding and targeting cancer stem cells: therapeutic implications and challenges. Acta pharmacologica Sinica, 34(6), pp.732740.

7. Chen, Y., Li, D. & Li, S., 2009. The Alox5 gene is a novel therapeutic target in cancer stem cells of chronic myeloid leukemia. Cell cycle (Georgetown, Tex.), 8(21), pp.34883492.

8. Cheng, L. et al., 2013. Glioblastoma Stem Cells Generate Vascular Pericytes to Support Vessel Function and Tumor Growth. Cell, 153(1), pp.139152.

9. Chin, A.R. & Wang, S.E., 2014. Cytokines driving breast cancer stemness. Molecular and cellular endocrinology, 382(1), pp.598602.

10. Perinando. H. et al., 2003. Transforming growth factor-beta1 induces Snail transcription factor in epithelial cell lines. Mechanisms for epithelial-mesenchymal transitions. Journal of Biological Chemistry. 278.23: 21113-21123.


11. Gupta, P.B., Chaffer, C.L. & Weinberg, R.A., 2009. Cancer stem cells: mirage or reality? Nature Medicine, 15(9), pp.10101012.

12. Larue, L. & Bellacosa, A., 2005. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3 kinase/AKT pathways. Oncogene, 24(50), pp.74437454.

13. Lobo, N.A. et al., 2007. The biology of cancer stem cells. Annual review of cell and developmental biology, 23, pp.675699.

14. Cooke, V.G. et al., 2012. Pericyte Depletion Results in Hypoxia-Associated Epithelial-to-Mesenchymal Transition and Metastasis Mediated by Met Signaling Pathway. Cancer Cell, 21(1), pp.6681.

15. Yang, J. et al., 2013. CD34+/CD38 acute myelogenous leukemia cells aberrantly express Aurora kinase A. International journal of cancer. Journal international du cancer, 133(11), pp.27062719.

16. Sun, T.-M. et al., 2014. Cancer stem cell therapy using doxorubicin conjugated to gold nanoparticles via hydrazone bonds. Biomaterials, 35(2), pp.836845.

17. Tang, D.G., 2012. Understanding cancer stem cell heterogeneity and plasticity. Cell research, 22(3), pp.457472.

18. Li, Z., 2012. Plasticity of Cancer Stem Cells. Stem Cells and Human Diseases. Springer Science. pp. 581-591.

19. Tang, S.-N. Et al. 2012. Cross talks among Notch, Wnt, and Hedgehog signaling pathways regulate stem cell characteristics. Springer Science. pp. 582-606.

20. Boiko, A.D. et al., 2010. Human Melanoma Initiating Cells Express Neural Crest Nerve Growth Factor Receptor CD271. Nature, 466(7302), pp.133137.

21. Al-Hajj, M. et al., 2003. Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 100(7), pp.39833988.

22. Zimdahl, B. et al., 2014. Lis1 regulates asymmetric division in hematopoietic stem cells and in leukemia. Nature Genetics, advance online publication.

23. Freudlsperger, C. et al., 2012. TGF- and NF-B signal pathway cross-talk is mediated through TAK1 and SMAD7 in a subset of head and neck cancers. Oncogene, 32(12), pp.15491559.

Figures Figure 1: http://onlinelibrary.wiley.com/doi/10.1002/ijc.28277/full. Accessed:[1st February 2014] Figure 2: http://www.allthingsstemcell.com/wp-content/uploads/2009/07/CancerStemCellMarkers2.jpg. Accessed:[1st February 2014] Figure 3: http://www.naure.com/cr/journal/v22/n3/fig_tab/cr201213f3.html. Accessed:[1st February 2014]


Figure 4: http://link.springer.com/static-content/images/923/art%253A10.1007%252Fs12015-007-0004- 8/MediaObjects/12015_2007_4_Fig1_HTML.gif. Accessed:[1st February 2014] Figure 5: http://www.nature.com/nm/journal/v17/n9/fig_tab/nm.2437_F1.html. Accessed:[1st February 2014] Figure 6: http://origin-ars.els-cdn.com/content/image/1-s2.0-S0092867413002109-fx1.jpg. Accessed:[2nd February 2014] Figure 7: http://origin-ars.els-cdn.com/content/image/1-s2.0-S1535610811004478-gr5.jpg. Accessed:[2nd February 2014]

Word Count: 3124

The Biology of the Cancer Stem Cell Model and Potential Therapeutic Targets

Documents

Transcript of The Biology of the Cancer Stem Cell Model and Potential Therapeutic Targets