The emerging biology of cancer stem cells

Supplement to Nature Publishing GroupCANCER

The concept of the cancer stem cell (CSC) has taken off rapidly over the past 10 years. CSCs are cellswith properties that are similar to those described for tissue stem cells: self-renewal and asymmetric
division resulting in the generation of daughter cells destined to differentiate, enabling theregeneration of a tissue. Initial research into the properties of CSCs was based on identifying andverifying markers of this subset of cancer cells. However, most studies have now moved on tounderstanding the biology of CSCs and the cancers in which they maintain tumour growth, as well as
how and why they are able to serially generate a tumour. It is thought that a key element regulating

the biology of stem cells is their niche — cells and extracellular matrix that support self-renewal andsurvival. As we begin to understand the pathways that are crucial for the properties of CSCs, including
signals provided by the niche, we will hopefully be able to effectively target this cell population.
Linked to the identification of CSCs is the cell of origin. These are cells that when mutated are able togive rise to a tumour. Although these cells may share properties with CSCs, in most cases it is not yet
clear whether these cells are one and the same. This poster highlights some of the recent findings
regarding the biology of CSCs and the identification of cell types from which cancers can arise.

Glioblastoma1–4

Breast tissue stem cells and cancer10–12

Glioblastoma stem cells are enriched in a population of cells that express PROM1 (also known as CD133).
Although this marker remains controversial, expression of PROM1 has been linked to poor clinicaloutcome. Glioblastoma is a highly angiogenic tumour, and CSCs are thought to reside in theperivascular niche, where PROM1+ cells have been observed to reside in close contact withendothelial cells. Moreover, PROM1+ cells secrete high levels of VEGF, and depletionof endothelial cells from glioblastoma xenografts suppresses their growth. Recent
Neuronal
findings have indicated that stem-like cells in glioblastomas can differentiate intoprogenitor
endothelial cells (defined by the expression of CD31 and CD144), thereby
contributing to the generation of the tumour vasculature. Several pathways
involved in the regulation of stem cell function, such as Notch, TGFβ, sonicCommonprogenitor
hedgehog and hypoxia inducible factors, have also been implicated inregulating glioblastoma stem cell function. Other glioblastoma cells withstem-cell-like characteristics have been shown to express high levels of CD44 andGlial
progenitor
the transcription factor ID1. The cell of origin for glioblastoma has yet to be identified.

Cells with CSC-like characteristics (expression of aldehyde
5VGOEGNN
dehydrogenase and CD44hi and CD24lo) have beenr$CUCNNKPGCIGRTKOGF!
r'R%#/.Q%&H CPF%&shown to be enriched in patients withr%&sCPF241%
breast cancer treated withr$/+906CPFR
chemotherapy, addingr'4s24sCPF'4$$sweight to the argumentthat CSCs are a/WNVKNKPGCIG RTGEWTUQT EGNN
chemoresistant/[QGRKVJGNKCNEGNN'R%#/ %&H #NFGȯWQT 'R%#/.Q%&H %& population in a tumour
CPF55'#
s%& %& CPF%&that needs to betargeted. A directcomparison between.WOKPCNTGUVTKEVGFRTQIGPKVQTEGNN!
normal breast tissue'R%#/ %&H '4sQT'4 )#6# stem cells and CSCs
CPF/7%
indicated that TGFβ1,dynamin, fibronectin,
calveolin and casein kinase II were more
highly expressed in CD44+ CSCs, suggesting that&WEVCNCPFNQDWNCTEGNNU
targeting CSCs could be possible. However, studies in'R%#/ %&Hs%& mice indicate that the presence of cells with CSC-like'4sQT'4 CPF/7%
characteristics can depend on which pathways aremutated. Whether this is because certain cell types(stem, progenitor or mature cells) are more susceptible to specific mutations is not clear.
As research on breast CSCs has progressed alongside studies of human breast stem cells, it
has become apparent that stem cells with different characteristics exist in the breast atdifferent stages of development. Moreover, although stem cells exist in the basal layer, theluminal compartment contains cells from which breast cancer can arise.

Oligodendrocyteprogenitor

NeuronGlioblastoma

Astrocyte
progenitor

241/ %& CPF+&!

Astrocyte

Chronic myeloid leukaemia9CML cells with in vivo repopulating activity display the same surface marker profiles as normal primitive haematopoietic stem cells (HSCs; which areLin–, CD34+, CD90+ and CD133+ and have aldehyde dehydrogenase activity). Interestingly, CML stem cells with a primitive phenotype are rare, andin patients with chronic phase disease are outnumbered by normal HSCs. CML stem cells also self-renew poorly in vitro compared with HSCs,however, the progeny produced by CML stem cells proliferateand survive much better than their normal counterparts, leading*5%
0QTOCNto the clinical manifestation of the chronic phase of CML.
%/.UVGOEGNNHowever, CML stem cells are implicated in disease persistance.
%JTQPKE)/2Primitive CD34+CD38− CML cells have an increased expression ofRJCUG
BCR–ABL protein that has been linked to genomic instability and.GWMCGOKE)/2!
resistance to kinase inhibitors. Interestingly, several reports have.GWMCGOKE)/2%/.
indicated the emergence of a subclone in blast crisis (theQHCFXCPEGF%/.
!
advanced form of CML) that seems to have arisen from a
2TQIGP[NGWMQE[VGprogenitor CML cell. It is currently unclear whether this means$NCUVEGNN#FXCPEGF
that the 'CML stem cell' can change between chronic phase andFKUGCUG
5GNHTGPGYCN
blast crisis.

Prostate cancer13,14
In the normal prostate, epithelial cells with tissue-regenerating capacity that are Sca1+,
CD49fhi, TROP2hi, CD44+, CD133+ and CD117+ (mouse) or CD133+, CD44+, CD49fhi andTROP2+ (human) seem to reside in the basal layer of the prostate. However, studies inmice indicate the existence of luminal cells with progenitor characteristics that canregenerate the prostate after androgen withdrawal. As castration resistance is also aproperty of basal stem cells in the prostate, it suggests a complex cellular hierarchy.
Studies in mice indicate that prostate tumours can arise after transformation of basal
stem cells and luminal progenitor cells. A subset of cells that are CD133+, a2b1+ andCD44+ and have basal cell characteristics have been shown to be tumorigenic, butwhether these cells can serially propagate tumours in mice has yet to be verified.

LGR5-positive cells and intestinal cancer5–8/CVWTGEGNNU
Cells within the crypts of the stomach, small intestine and colon that express leucinerich-repeat-containing G protein-coupled receptor 5 (LGR5) are long-lived stem cells.
Lineage tracing was used to show that cells that express LGR5 give rise to microadenomas
and adenomas when expression of the tumour suppressor APC is lost. Moreover, deletion of0QVWOQWT
6TCPUKV
Apc in the progenitor cell population rarely produced adenomas. PROM1 is a stem cell
CORNKH[KPI
marker in the mouse small intestine. The distribution of Prom1 and Lgr5 largely overlap
EGNNUand PROM1 cells can give rise to all cells of the small intestinal epithelium. In geneticallyengineered mice prone to developing tumours in the small intestine, these arose from
PROM1+ cells.
2CPGVJEGNN
Importantly, LGR5+ cells can give rise to crypt-villus structures in vitro that contain stemcells, Paneth cells and all other colonic epithelial cell types. Recent findings have shown.)4
6WOQWT
that Paneth cells express proteins known to be important for stem cell function, such as
UVGOEGNNWNT, EGF and the Notch ligand delta-like 4. Moreover, Paneth cells seem to be essential forthe maintenance of stem cells and crypts in mice. As LGR5+ stem cells can generate Panethcells, these findings suggest that stem cells can generate their own supporting niche cells, similar to findings in Drosophila melanogaster.
Thus, a CSC might be capable of similar acts of self-sufficiency and so identifying and understanding the CSC niche would seem to be a priority.

Abcam
Abcam's catalogue of over 70,000 reagents for life
science research includes comprehensive portfolios forstem cells and cancer. We have an ongoingcommitment to support researchers throughsponsoring events, our worldwide Abcam meeting
portfolio, pathways, posters and listening to key
opinion leaders. Our independent review system(Abreview) ensures you can select the best product foryour application and view your peers’ opinions.
Abcam’s cancer stem cell portfolio includes antibodies

and proteins to: Ankrd26, Breast carcinoma amplified
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VGLL2, an extensive CD Marker range, Notch, Wnt andSHH signaling pathways amongst others.
Search www.abcam.com for your target of interest. If you
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Visit our dedicated poster page to be entered into
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Cell of origin and CSCs15
These two terms are often used interchangeably in the literature, but they are
not necessarily the same cell. For example, the PROM1+ and LGR5+ stem cells
that can generate cancers in the intestine have not yet been shown to beCSCs: the cells that can propagate the tumour when transplanted into a
syngeneic mouse. Indeed, even when a more differentiated cell type has beenshown to be the probable cell of origin, as has occurred in medulloblastoma, it
does not follow that this cell has to have acquired CSC properties. Such a cell
may undergo further changes and mutations before a CSC phenotypeemerges. Further work is needed in each individual cancer type to establish
the relationship between the cell of origin and the CSC.

6WOQWTEGNNU#4

Relevant products from Abcam:

Abbreviations

References

CD10 (ab951); CD117 (c-Kit) (ab5506);
CD117 (c-Kit) ELISA (ab45924); CD144 (VE cadherin)(ab33168);
CD24 (FITC) (ab30350); CD31(ab28364);
CD34 (ab8158); CD38 (ab9391);
CD49f (Integrin Alpha 6) (ab20142);
Dynamin (ab13251);
EpCAM (ab32392); Fibronectin (ab6328);
LGR5 (GPCR GPR49) (ab75732); MUC1 (ab15481);
SSEA4 (ab16287); Trop2 (TACD2) (ab79976).

APC, adenomatous polyposis coli; AR,androgen receptor; CML, chronic myeloid
leukaemia; EGF, epidermal growth factor;
ER, oestrogen receptor; GMP, granulocyte
macrophage progenitor; hi, highexpression levels; lo, low expression
levels; MUC1, mucin 1; PR, progesterone
receptor; TGFb, transforming growth
factor-b; VEGF, vascular endothelial
growth factor.

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12. Petersen, O. W. & Polyak, K. Cold Spring Harb. Perspect. Biol. 2a003160 (2010)
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Acknowledgements
Poster advisors: Hans Clevers, Connie Eaves, Richard Gilbertson, Gail Risbridger andJane Visvader. Edited by Nicola McCarthy; copyedited by Catriona Rodwell; designed
by Lara Crow.
© 2011 Nature Publishing Group.
http://www.nature.com/nrc/posters/cancerstemcells