Download What Are Cancer Stem Cells?

Hallmarks of Cancer Stem
Cells
Recurrence and Metastasis: A Major Factor in
Cancer-related Deaths
• Cancer is the second leading cause of death in the United
States1
• Despite advances in cancer treatment, many patients develop:
– Disease recurrence2
• Depends on tumor characteristics, disease stage, and other factors3
– Metastasis4
• Over 90% of deaths in patients with cancer are due to disease spread5
• Mechanisms underlying disease recurrence and metastasis
remain unclear6,7
• A small population of tumor cells, known as cancer stem cells
(CSCs), may contribute to recurrence and metastasis8
1. Siegel RL, et al. CA Cancer J Clin. 2015;65:5-29. 2. Dawood S, et al. Oncology (Williston Park).
2014;28:1101-1107, 1110. 3. American Cancer Society. Cancer Treatment & Survivorship Facts & Figures 2014-2015. 2014. http://
www.cancer.org/acs/groups/content/@research/documents/document/acspc-042801.pdf. 4. Wan L, et al. Nat Med.
2013;19:1450-1464. 5. Patel P, et al. Front Endocrinol (Lausanne). 2012;3:125. 6. Harlozinska A. Anticancer Res.
2005;25:3327-3333. 7. Croker A, et al. In: Bagley R, Teicher B, ed. Stem Cells And Cancer. 1st ed. New York: Humana
Press; 2009:141. 8. Bao B, et al. Curr Protoc Pharmacol. 2013;chap 14:Unit 14.25.
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What Are Cancer Stem Cells?
A cell within a tumor that possesses the
capacity to self-renew and to give rise to the
heterogeneous lineages of cancer cells that
comprise the tumor.
─ American Association for Cancer Research
Workshop on Cancer Stem Cells1
• Subpopulation of cancer cells thought to possess these
characteristics2-4:
– Stemness, including the capacity to self-renew and
differentiate into cancer cells
– Aberrant signaling pathways
– Resistance to conventional therapies
– Capacity to contribute to recurrence and metastasis
• Alternative names2: “tumor-initiating cells” or
“tumorigenic cells”
1. Clarke MF, et al. Cancer Res. 2006;66:9339-9344. 2. Ajani JA, et al. Semin Oncol. 2015;42(Suppl 1):S1-S17.
3. Chen K, et al. Acta Pharmacol Sin. 2013;34:732-740. 4. Bao B, et al. Curr Protoc Pharmacol. 2013;chap
14:Unit 14.25.
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Cancer Stem Cells Have Been Identified in
Several Hematologic and Solid Cancers
Molecular and phenotypic markers are used to identify and
enrich CSCs from various tumor types1,2
• Phenotypic markers include in vitro
formation of spherical colonies, and in
vivo initiation and development of
heterogeneous tumors from serially
transplanted CSCs3
• Important caveats4-6:
― Not all CSCs express distinctive
markers
― No marker set is exclusive to CSCs
― CSC marker profiles may be different
between patients with the same
tumor type
― CSC marker profiles may change over
time
CSC Molecular Markers2,7
Tumor Type
Phenotype of CSC Markers
Breast
ESA+, CD44+, CD24-/low, Lineage–,
ALDH1high
Brain
CD133+, BCRP1+, A2B5+, SSEA1+
Colon
CD133+, CD44+, CD166+, EpCAM+,
CD24+, CXCR4+, CK20+, CEA+,
LGR5+, ALDH1high
Head and
neck
CD44+, ALDH+, YAP1+, BMI1+
Leukemia
CD34+, CD38–, HLA-DR–, CD71–,
CD90–, CD117–, CD123+
Liver
CD133+, CD49f+, CD90+
Lung
CD133+, ABCG2high
Multiple
myeloma
CD138–
Pancreatic
CD133+, CD44+, EpCAM+, CD24+,
ABCG2high
Prostate
CD44+, α2β1high, CD133+
1. Tang DG. Cell Res. 2012;22:457-472. 2. Ajani JA, et al. Semin Oncol. 2015;42(Suppl 1):S1-S17. 3. Boman MB, et al.
J Clin Oncol. 2008;26:2795-2799. 4. Chen K, et al. Acta Pharmacol Sin. 2013;34:732-740. 5. Visvander JE, et al. Cell
Stem Cell. 2012;10:717-728. 6. Keysar SB, et al. Mol Cancer Ther. 2010;9:2450-2457. 7. Huang EH, et al. Cancer
Res. 2009;69:3382-3389.
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Multifunctional Hallmarks of Cancer Stem Cells
May Drive Cancer Pathogenesis
Self-renewal1
Differentiation1
Stemness1
Abnormal
Signaling2
Recurrence/
Metastasis3
Therapy
Resistance3
1. Ajani JA, et al. Semin Oncol. 2015;42(Suppl 1):S1-S17. 2. Chen K, et al. Acta Pharmacol Sin.
2013;34:732-740. 3. Bao B, et al. Curr Protoc Pharmacol. 2013; chap 14:Unit 14.25.
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Functional Hallmarks of CSCs: Stemness
Unregulated self-renewal and differentiation in CSCs allow for tumor
growth1
• CSCs may derive via mutation of normal stem cells or progenitor cells2
• Non-stem cell progeny of CSCs may have more plasticity than those of
normal stem cells3,4
Cellular Origins of CSCs
― CSCs may derive from
dedifferentiation of non-
tumorigenic cancer cells4
• CSCs exist within a microenvironment of neighboring cellular and acellular
components that create a niche to1:
― Promote CSC survival
― Maintain CSC stemness
1. Ajani JA, et al. Semin Oncol. 2015;42(Suppl 1):S1-S17. 2. Jordan CT, et al. N Engl J Med.
2006;355:1253-1261. 3. Chaffer CL, et al. Proc Natl Acad Sci U S A. 2011;108:7950-7955. 4. Tang DG.
Cell Res. 2012;22:457-472.
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Functional Hallmarks of CSCs: Stemness
(cont’d)
Clonal expansion of CSCs may drive tumor heterogeneity1
• Stochastic tumor heterogeneity2:
intrinsic (eg, genetic) and extrinsic (eg,
host immune response) factors allow
any cell to be tumorigenic
• Hierarchical tumor heterogeneity2:
CSCs
are the only tumorigenic cell population
and generate full diversity of tumor
heterogeneity through differentiation
Models of Tumor Heterogeneity
• Unified model3,4: CSCs may be
responsible for cancer initiation and
give rise to early tumor cell diversity
― Subsequent mutation of CSCs may
result in clonal expansion of CSC subpopulations that propagate later
stages of heterogeneous tumor
development
1. Zellmer VR, et al. Cell Biosci. 2014;4:69. 2. Dick JE. Blood. 2008;112:4793-4807. 3. Kreso A, et al.
Cell Stem Cell. 2014;14:275-291. 4. Fulawka L, et al. Biol Res. 2014;47:66.
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Functional Hallmarks of CSCs: Aberrant
Signaling
CSC signaling pathways maintain stemness and promote
clonogenicity, tumorigenicity, and treatment resistance1-3
• Stringent regulation of stemness
pathways in normal stem cells
controls normal development and
limits their expansion in healthy
tissue4
• Several dysfunctional stemness and
developmental signaling pathways
underlie CSC function5,6
• Interactions between CSCs and their
microenvironments support CSC
signaling functions7
Key Signaling Pathways in CSCs
1. Kroon P, et al. Cancer Res. 2013;73:5288-5298. 2. Lin L, et al. Cancer Res. 2011;71:7226-7237. 3. Merchant AA,
et al. Clin Cancer Res. 2010;16:3130-3140. 4. Clarke MF. Biol Blood Marrow Transplant. 2005;11(2 Suppl 2):14-16.
5. Chen K, et al. Acta Pharmacol Sin. 2013;34:732-740. 6. Karamboulas C, et al. Biochim Biophys Acta.
2013;1830:2481-2495. 7. Ablett MP, et al. Eur J Cancer. 2012;48:2104-2116.
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Functional Hallmarks of CSCs: Aberrant Signaling
(cont’d)
Several important CSC signaling pathways have been identified
• STAT3: Regulates stemness genes required for
modulating self-renewal and maintains stem Key Signaling Pathways in CSCs
cell niche1,2
• Wnt/β-catenin: Controls cell fate, embryonic
development, and adult tissue homeostasis3
• Hedgehog: Modulates genes involved in cell
cycling, cell fate, and therapy resistance4
• Notch: Regulates cell cycle progression, cell
fate, and differentiation5
• NANOG: Maintains self-renewal and regulates
embryonic cell fate6
Signaling components may be overexpressed
or overactivated in CSCs5-11
1. Chambers I. Cloning Stem Cells. 2004;6:386-391. 2. Stine RR, et al. Adv Exp Med Biol. 2013;786:247-267. 3.
Holland JD, et al. Curr Opin Cell Biol. 2013;25:254-264. 4. Huang FT, et al. Int J Oncol. 2012;41:1707-1714. 5.
Karamboulas C, et al. Biochim Biophys Acta. 2013;1830:2481-2495. 6. Jeter CR, et al. Stem Cells.
2015;33:2381-2390. 7. Lamb R, et al. PLoS One. 2013;8: e67811. 8. Peacock CD, et al. Proc Natl Acad Sci U S A.
2007;104:4048-4053. 9. Kroon P, et al. Cancer Res. 2013;73:5288-5298. 10. Hernandez-Vargas H, et al. Epigenetics. 2011;6:428-439. 11. D’Angelo RC, et al. Mol Cancer Ther.
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Functional Hallmarks of CSCs: Treatment
Resistance
CSCs may be responsible for treatment resistance to conventional therapies such as chemo- and radiotherapy1-3
• Post-treatment tumor cell populations may be enriched with
CSCs4
• Several factors mediate CSC treatment resistance5:
Anti-apoptosis protein overexpression
Treatment-resistant CSCs
Drug efflux proteins
DNA repair activation
Low reactive oxygen species (ROS) levels
– Quiescence
– Aberrant developmental signaling
– Microenvironmental stimuli
–
–
–
–
1. Chen S, et al. J Gastrointest Surg. 2014;18:1040-1048. 2. Tang DG. Cell Res. 2012;22:457-472. 3. Wicha MS et
al. Cancer Res. 2006;66:1883-1890. 4. Lee HE, et al. Br J Cancer. 2011;104:1730-1738. 5. Kim JK, et al. Arch
Pharm Res. 2015;38:389-401.
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Functional Hallmarks of CSCs: Tumor
Recurrence
CSC therapy resistance may cause tumor recurrence1
• CSCs may survive conventional
therapy and reconstitute tumors
with greater heterogeneity2,3
CSC-mediated Tumor Recurrence
– Subsequent use of conventional
therapies may further select for
treatment-resistant CSCs and
induce disease progression2
• CSC microenvironments may support tumor recurrence
– Nurture CSC stemness and facilitate
therapy resistance1
• Cellular microenvironmental
components, such as endothelial
and stromal cells, may secrete proangiogenic and stemness factors in
response to therapy1,4
1. Kim JK, et al. Arch Pharm Res. 2015;38:389-401. 2. Anderson EC, et al. Cancers (Basel).
2011;3:319-339. 3. Sottoriva A, et al. Cancer Res. 2010;70:46-56. 4. Li L, et al. Ochsner J.
2013;13:109-118.
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Functional Hallmarks of CSCs: Metastasis
CSCs may contribute to local tumor invasion and distant metastases1
• Activation of epithelial to mesenchymal transition (EMT) may drive
CSC dissemination2
– EMT: developmental process that converts interconnected, anchored epithelial cells to disconnected, motile mesenchymal-like cells3
Intravasation of CSCs into Blood or Lymphatic Vessels
• Subpopulations of proliferative epithelial CSCs and quiescent mesenchymal CSCs may coreside in primary tumors4
– Combination of intracellular signaling and microenvironmental stimuli may regulate EMT and select for metastatic CSCs in primary tumors4,5
1. Sampierki K, et al. Semin Cancer Biol. 2012;22:187-193. 2. Geng SQ, et al. Cancer Lett. 2014;349:1-7. 3. Tsai
JH, et al. Genes Dev. 2013;27:2192-2206. 4. Liu S, et al. Stem Cell Reports. 2013;2:78-91. 5. Oskarsson T, et al.
Cell Stem Cell. 2014;14:306-321.
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Functional Hallmarks of CSCs: Metastasis (cont’d)
Subpopulation of CSCs among circulating tumor cells may propagate tumors at metastatic sites1,2
• A permissive microenvironment at distal sites facilitates metastatic
colonization by circulating CSCs
Circulating CSCs Colonize Metastatic Sites
– Activates stemness signaling3
– Reverses EMT4
– Circulating CSCs may procure metastatic niches by5:
•
•
•
Occupying host stem cell niches
Recruiting niche-supporting cells
Secreting factors that promote niche functions
• Circulating CSC identification and isolation techniques are under development1
• Circulating CSCs may be predictive of tumor metastasis and shorter duration until tumor recurrence and may be prognostic of poor survival in specific cancer types6,7
1. Kantara C, et al. Lab Invest. 2015;95:100-112. 2. Geng SQ, et al. Cancer Lett. 2014;349:1-7. 3. Quail DF, et al.
Nat Med. 2013;19:1423-1437. 4. Brabletz T, et al. Nat Rev Cancer. 2005;5:744-749. 5. Oskarsson T, et al. Cell Stem
Cell. 2014;14:306-321. 6. Li M, et al. BioMed Res International. 2014;2014:1-7. 7. Pilati P, et al. Ann Surg Oncol.
2012;19:402-408.
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Investigational Therapies: Focus on CSCs, Signaling
Pathways, and Mediators of Therapy Resistance
Combination of CSC-targeting and tumor debulking approaches may yield durable therapeutic response1
• Targeting CSC surface markers
– May be associated with poor survival in some tumor types2-4
– May be used to home cytotoxic immunotherapies specifically to CSCs5
Anti-
signaling6
• Targeting CSC stemness signaling or supporting niche components may decrease6-8:
– Tumor mass
– Tumorigenicity
– Metastasis
• Targeting CSC survival may sensitize tumors to therapy
– Targeting multiple redundant signaling pathways may mitigate interpathway crosstalk to limit treatment resistance9
Anti-surface
– Inhibiting drug efflux proteins may directly markers6
abrogate treatment resistance5
– Antagonizing DNA repair enzyme and ROS scavenging functions may decrease radioresistance5
1. Ajani JA, et al. Semin Oncol. 2015;42(suppl 1):S1-S17 2. Wu B, et al. J Exp Clin Cancer Res. 2015;34:44. 3. Collina
F, et al. BioMed Research International. 2015;2015:1-10. 4. Burgos-Ojeda D, et al. Cancer Lett. 2012;322:1-7. 5.
Frank NY, et al. J Clin Invest. 2010;120:41-50. 6. Chen K, et al. Acta Pharmacol Sin. 2013;34:732-740. 7. Yi SY, et al.
Cancer Treat Rev. 2013;39:290-296.
8. Plaks V, et al. Cell Stem Cell. 2015;16:225-238. 9. Takebe N, et al. Nat Rev Clin Oncol. 2015;12:445-464.
Antiresistance6
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Summary
• Despite advances in cancer treatment, recurrence and metastasis
remain major causes of cancer-related deaths
• CSCs are tumor cells that can self-renew and give rise to
heterogeneous lineages of cancer cells comprising tumors
• Molecular and phenotypic markers are used to identify and isolate
CSCs
• CSCs are characterized by:
– Stemness, including the capacity to self-renew and differentiate
into cancer cells
– Aberrant signaling pathways
– Resistance to conventional therapies
– Capacity to contribute to recurrence and metastasis
• Therapeutic strategies are focusing on CSC:
– Signaling pathways
– Mediators of therapy resistance
– Surface markers
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