Stem Cells in Cancer: A Review

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A seminar I gave as a PhD student reviewing the role of stem cells in the development of various different kinds of cancers, as well as emerging treatment options.

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Stem Cells in Cancer: A Review

  1. 1. Stem Cells in Cancer: A Review Jovana J. Grbi ć Schultz Group Seminar October 18, 2005
  2. 2. Stem Cells in Cancer: A Review <ul><li>Introduction and Background </li></ul><ul><ul><li>What is a stem cell? What is a cancer stem cell? </li></ul></ul><ul><ul><li>Epithelial cancer stem cell characteristics </li></ul></ul><ul><ul><li>How many insults could you take? </li></ul></ul><ul><ul><li>How do you know it’s the stem cells? </li></ul></ul><ul><ul><li>Therapeutic Implications </li></ul></ul><ul><ul><li>Where no scientist has gone before…. </li></ul></ul><ul><li>Specific Case Studies: </li></ul><ul><ul><li>Colorectal Cancer (CRC) and epithelial stem cell renewal </li></ul></ul><ul><ul><li>Breast Cancer: mammary stem cells </li></ul></ul><ul><ul><li>AML/CML leukemias: leukemic stem cells </li></ul></ul>
  3. 3. What is a Stem Cell? What is a Cancer Stem Cell? <ul><li>Fundamental homeostatic system for replacing terminally differentiated cells of the body due to senescence and injury </li></ul><ul><li>Involves stages of division with decreasing reproductive capacity and increased commitment to differentiation </li></ul><ul><li>Self-replication and progeny production </li></ul><ul><li>Cancerous growth is abberant normal tissue homeostasis </li></ul><ul><ul><li>Stem cell ->committed progenitor->diff. cell </li></ul></ul><ul><li>Tumor stem cell model mimics normal tissue models </li></ul><ul><li>Variations in tumor growth rates: variations in homeostatic mechanisms of SC regulation and preturbations in the niche microenvironment </li></ul><ul><li>CSC’s arise from a multi-step process that parallels the slow development of cancer from normal tissues </li></ul>Biochim Biophys Acta. 2005 Sep 25;1756(1):25-52 Nat Rev Cancer. 2005 Apr;5(4):275-84
  4. 4. How Many Insults Could You Take??? <ul><li>I: Pretumor Progression </li></ul><ul><ul><li>Mutational acquisition (prenatal) </li></ul></ul><ul><ul><li>Additional mutations </li></ul></ul><ul><ul><li>Clonal expansion of stem cell “niche” </li></ul></ul><ul><li>II: Patches </li></ul><ul><ul><li>CSC ventures outside its niche </li></ul></ul><ul><ul><li>Present in phenotypically normal epithelia </li></ul></ul><ul><li>III: Fields </li></ul><ul><ul><li>Larger regions of clonal outgrowth, may begin to manifest histologic atypia </li></ul></ul>
  5. 5. Therapeutic Implications <ul><li>Multi-Drug Resistant Proteins </li></ul><ul><ul><li>ABCG2 inhibitors, ABCG2 antibodies, stem cell inhibitors, immunotherapy </li></ul></ul><ul><li>Irradiation </li></ul><ul><ul><li>Stem cells may be more sensitive to irradiation </li></ul></ul><ul><li>Differentiation, apoptosis, and senscence </li></ul>
  6. 6. Where No Scientist Has Gone Before <ul><li>Identification of CSCs </li></ul><ul><ul><li>Similar phenotype, slow cycling, constitute small percentage, BUT contain many unique markers as well. </li></ul></ul><ul><li>Why can’t ablate with traditional chemotherapy? </li></ul><ul><ul><li>Target rapidly dividing cells, overexpress a lot of ABC drug-transporters </li></ul></ul><ul><li>How do early epithelial CSCs migrate? </li></ul><ul><ul><li>Form temporary migratory phenotype (i.e. wound healing, patches/fields) </li></ul></ul><ul><li>How are CSCs removed from a tumor population? </li></ul><ul><ul><li>No mechanism as of yet for total progression from CSC to committed cell lineage with loss of stem cell population </li></ul></ul><ul><li>Different cancers in the same organ: </li></ul><ul><ul><li>Different malignant stem cells or different “packaging” of the same stem cell? </li></ul></ul>
  7. 7. Stem Cells in Cancer: A Review <ul><li>Introduction and Background </li></ul><ul><ul><li>What is a stem cell? What is a cancer stem cell? </li></ul></ul><ul><ul><li>Epithelial cancer stem cell characteristics </li></ul></ul><ul><ul><li>How many insults could you take? </li></ul></ul><ul><ul><li>How do you know it’s the stem cells? </li></ul></ul><ul><ul><li>Therapeutic Implications </li></ul></ul><ul><ul><li>Where no scientist has gone before…. </li></ul></ul><ul><li>Specific Case Studies: </li></ul><ul><ul><li>Colorectal Cancer (CRC) and epithelial stem cell renewal </li></ul></ul><ul><ul><li>Breast Cancer: mammary stem cells </li></ul></ul><ul><ul><li>AML/CML leukemias: leukemic stem cells </li></ul></ul>
  8. 8. Endothelial Gut Lining: Physiology and Stem Cell Renewal Science . 2005 Mar 25;307(5717):1904-9 Colon epithelium
  9. 9. Canonical Wnt Signaling Maintains Crypt Progenitor Compartments Cell . 2002 Oct 18;111(2):251-63 Nat Genet . 1998 Aug;19(4):379-83 Wnt cascade is dominant force in controlling cell fate along crypt-villus axis: ~Staining for nuclear β -catenin mainly observed in crypts ~Tcf4 -/- mice lack proliferative compartments for maintaing progenitors
  10. 10. Intestinal Tumorigenesis: Mutational Wnt Pathway Activation <ul><li>Most molecular insights of CRC come from hereditary studies (5-10% of cases) </li></ul><ul><li>Familial adenomatous polyposis (FAP): patients carry numerous polyps, invariably develop CRC around age 40 </li></ul><ul><li>Carry one mutant copy of APC </li></ul><ul><ul><li>C-terminal truncation </li></ul></ul><ul><li>Inappropriate activation of intestinal TCF4—imposes proliferative phenotype in crypt epithelial cells </li></ul>Cell. 2002 Oct 18;111(2):241-50 Science. 1997 Mar 21;275(5307):1784-7
  11. 11. Notch/bHLH Signaling <ul><li>Important for regulating cell fate decisions/differentiation </li></ul><ul><li>Most likely target is Hes family of bHLH proteins </li></ul><ul><ul><li>Notch target genes control intestinal homeostasis </li></ul></ul><ul><li>Hes1-/- mice contain increased secretory cells at the expense of absorptive enterocytes </li></ul>Science . 2005 Mar 25;307(5717):1904-9 Nat Genet. 2000 Jan;24(1):36-44.
  12. 12. CRC: Conclusions <ul><li>Crypt-villus unit represents one of the simplest self-renewing entities in mammalian biology </li></ul><ul><li>Regulatory signaling pathways have emerged from embryonic development studies as a key in maintenance of this structure </li></ul><ul><li>Transformation process probably manipulates key physiological regulators of normal intestinal epithelium as most efficial roadblocks towards cancer (not mutational changes in generic oncogenes or tumor suppressors) </li></ul>
  13. 13. Stem Cells in Cancer: A Review <ul><li>Introduction and Background </li></ul><ul><ul><li>What is a stem cell? What is a cancer stem cell? </li></ul></ul><ul><ul><li>Epithelial cancer stem cell characteristics </li></ul></ul><ul><ul><li>How many insults could you take? </li></ul></ul><ul><ul><li>How do you know it’s the stem cells? </li></ul></ul><ul><ul><li>Therapeutic Implications </li></ul></ul><ul><ul><li>Where no scientist has gone before…. </li></ul></ul><ul><li>Specific Case Studies: </li></ul><ul><ul><li>Colorectal Cancer (CRC) and epithelial stem cell renewal </li></ul></ul><ul><ul><li>Breast Cancer: mammary stem cells </li></ul></ul><ul><ul><li>AML/CML leukemias: leukemic stem cells </li></ul></ul>
  14. 14. <ul><li>Most common malignant disease in Western women </li></ul><ul><li>Despite advances, metastatic breast cancer remains a death sentence </li></ul><ul><ul><li>Current treatment is limited by emergence of therapy-resistant cells </li></ul></ul><ul><ul><li>Early detection/treatment have drastically cut overall death rates </li></ul></ul><ul><li>Adequate predictions of metastatic invasion are KEY </li></ul><ul><ul><li>80% of women receive adjuvant chemotherapy, only 40% need it </li></ul></ul>Breast Cancer Background Info J Cell Sci. 2005 Aug 15;118(Pt 16):3585-94 Mammary Arbor Architecture and Cell Engineering <ul><li>Label-retention studies: 5-Br2-dU </li></ul><ul><li>Cell-surface markers (Sca-1, CD49f) </li></ul><ul><li>DNA-binding dyes: Hoechst efflux </li></ul><ul><li>Hormone Receptor Status (ER, PR) </li></ul>
  15. 15. Signalling Pathways and Mammary Stem Cell Regulation <ul><li>Originally identified as a viral insertion in a MMTV-induced mammary tumor </li></ul><ul><li>Stabilization of β -catenin in >50% breast cancer tumors (poor prognosis) </li></ul><ul><li>Knockout mice lacking LEF/mice expressing Dickkopf (Wnt inhibitor) fail to develop mammary glands </li></ul><ul><li>Wnt signaling plays a role in several human ovarian/breast cancer cell lines </li></ul><ul><li>Important role in neoplastc mammary stem-cell-like progenitors </li></ul><ul><ul><li>Expansion of Sca1+ progenitors in Wnt+ transgenic mice </li></ul></ul><ul><ul><li>Did not observe such expansion in non-Wnt mediated tumor models </li></ul></ul>Wnt Cancer Cell. 2004 Nov;6(5):497-506 Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15853-8
  16. 16. Signalling Pathways and Mammary Stem Cell Regulation <ul><li>Originally identified as a viral insertion in a MMTV-induced mammary tumor </li></ul><ul><li>Stabilization of β -catenin in >50% breast cancer tumors (poor prognosis) </li></ul><ul><li>Knockout mice lacking LEF/mice expressing Dickkopf (Wnt inhibitor) fail to develop mammary glands </li></ul><ul><li>Wnt signaling plays a role in several human ovarian/breast cancer cell lines </li></ul><ul><li>Important role in neoplastc mammary stem-cell-like progenitors </li></ul><ul><ul><li>Expansion of Sca1+ progenitors in Wnt+ transgenic mice </li></ul></ul><ul><ul><li>Did not observe such expansion in non-Wnt mediated tumor models </li></ul></ul>Wnt Cancer Cell. 2004 Nov;6(5):497-506 Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15853-8 Keratin-6 staining
  17. 17. Signalling Pathways and Mammary Stem Cell Regulation-II <ul><li>Important in normal mammary development and identified as MMTV insertion site in mammary tumors </li></ul><ul><li>Notch4 transgenic mice develop mammary tumors </li></ul><ul><li>Role of Notch in formation of mammospheres: </li></ul><ul><li>Important for normal development of virtually every organ system </li></ul><ul><li>Pathway components shown to be OE in many cancer types (including breast) </li></ul><ul><li>Majority of human breast cancers show uniform OE of PTCH1 and nuclear Gli1 </li></ul><ul><li>Cyclopamine confers growth inhibition of a subset of breast cancer cell lines in vivo </li></ul>Notch Hedgehog Breast Cancer Res . 2004;6(6):R605-15. Cancer Res. 2004 Sep 1;64(17):6071-4.
  18. 18. Identification and Isolation of Tumorigenic Breast Cancer Cells <ul><li>Exponential increase in breast cancer with woman’s age </li></ul><ul><li>Stem cells are an attractive target due to unlimited replicative potential </li></ul><ul><li>Cell-surface markers used to identify/isolate subpopulation of tumorigenic cells </li></ul><ul><ul><li>CD44 + /CD24 - cells show increased tumor formation </li></ul></ul><ul><ul><li>As few as 100 cells can recapitulate human tumors </li></ul></ul><ul><ul><li>CD44 + /CD24 - cells can be cultured indefinitely </li></ul></ul>PNAS U S A . 2003 Apr 1;100(7):3983-8
  19. 19. Mammary Stem Cell Progression Model CANCER!!! NORMAL TISSUE
  20. 20. Conclusion: Clinical Implications Proposed Future Breast Cancer Treatment Kaplan-Meier Survival Plot Based on CD44 Expression Histopathology . 2003 Jun;42(6):546-54 CD44+ breast tumor cells confer both lower rates of overall and disease-free survival LESSONS FROM CURRENT TREATMENTS: -Tumors can undergo accelerated repopulation between daily radiation doses (clonogenic assays) -Tumor stem cells likely more resistant to both chemotherapy/radiation (repopulate from added stress of treatment) -Treatment of Sca1+ mammary cells with taxol or radiation leads to increase in clonogens formed in matrigel
  21. 21. Stem Cells in Cancer: A Review <ul><li>Introduction and Background </li></ul><ul><ul><li>What is a stem cell? What is a cancer stem cell? </li></ul></ul><ul><ul><li>Epithelial cancer stem cell characteristics </li></ul></ul><ul><ul><li>How many insults could you take? </li></ul></ul><ul><ul><li>How do you know it’s the stem cells? </li></ul></ul><ul><ul><li>Therapeutic Implications </li></ul></ul><ul><ul><li>Where no scientist has gone before…. </li></ul></ul><ul><li>Specific Case Studies: </li></ul><ul><ul><li>Colorectal Cancer (CRC) and epithelial stem cell renewal </li></ul></ul><ul><ul><li>Breast Cancer: mammary stem cells </li></ul></ul><ul><ul><li>AML/CML leukemias: leukemic stem cells </li></ul></ul>
  22. 22. Hematopoiesis Nat Rev Immunol. 2005 Jun;5(6):497-508 Hematopoietic system constantly generates specialized cell types from HSC progenitors: The stem cell niche supports HSC regeneration/maintenance via stromal cells and osteoblasts Earliest bifurcation is the multi-potent progenitor, which branches off into the common myeloid progenitor (E, M, MK, G) or common lymphoid progenitor Lymphoid progenitors can branch into the pro-T-Cell or pro-B-Cell differentiation pathways depending on gene expression Blood. 2005 Apr 1;105(7):2631-9.
  23. 23. Acute Myelogenous Leukemia Models Nat Rev Cancer. 2005 Apr;5(4):311-21 Leukemias are myeloproliferative disorders that are clonal in nature Earliest identified model for CSCs (LSC): only 1/1,000-5,000 cells could form colonies…massive cell injections in mice to replicate leukemias LSCs express similar surface markers (CD34+/CD38-), telomerase levels, and are able to repopulate diverse cancer progenitors in mouse models Stem cell pathway candidates for LSC transformation NOD/SCID Mouse expansion of normal and neoplastic HSCs
  24. 24. Alternative HSC transformation model Leuk Res. 2005 Sep 21 Epub Polycomb group gene Bmi-1 determines the proliferative capacity of normal and leukemic stem cells <ul><li>Indispensable for generating AML in mice </li></ul><ul><li>Only 1% of Bmi-1 -/- cells could form colonies (>10 10 cells) while 24% of Bmi-1+/+ cells did </li></ul><ul><li>Bmi-1 -/- weakly leukemogenic in vivo (transplants), but the effect is rescued by forced expression of Bmi-1 in these cells </li></ul><ul><li>From this data, we may construct more sophisticated models for LSC generation (i.e. cooperating genetic events, TLS-ERG) </li></ul>Nature. 2003 May 15;423(6937):255-60. Leukemia. 2005 Oct;19(10):1794-805
  25. 25. Chronic Myelogenous Leukemia Nat Rev Cancer. 2005 Mar;5(3):172-83. The Philadelphia Chromosome: t(9;22)(q34;q11) Largely viewed as biphasic: Bcr-Abl translocation/expression in HSCs followed by expansion of CML-chronic phase granulocytes Additional mutations (many discussed today) lead to blast phase CML: uncontrolled expansion of either myeloid (2/3) or lymphoid (1/3) blast cells Gleevec
  26. 26. Therapeutic Directions Nature. 2005 Jun 30;435(7046):1169-70 Nat Rev Cancer. 2005 Apr;5(4):311-21 Mathematical model of CML reoccurence post-Gleevec treatment: S= LSC P= Leukemic progenitors D=differentiated LS TD=terminally differentiated Nature. 2005 Jun 30;435(7046):1267-70 Leukemic stem cells are NOT depleted by Gleevec treatment Future cocktail therapies must address this problem

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