This document summarizes recent research on cancer stem cells. It discusses that some cancers are driven by rare cancer stem cells that have properties similar to normal stem cells, such as self-renewal. These cancer stem cells can be identified in several cancers including colorectal cancer, breast cancer, and leukemias. Several signaling pathways important for regulating normal stem cells, such as Wnt and Notch, also appear to play roles in cancer stem cells. Targeting and eliminating cancer stem cells may be necessary for more effective cancer treatments.

1. Stem Cells in Cancer: A Review Jovana J. Grbi ć Schultz Group Seminar October 18, 2005

8. Endothelial Gut Lining: Physiology and Stem Cell Renewal Science . 2005 Mar 25;307(5717):1904-9 Colon epithelium

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

19. Mammary Stem Cell Progression Model CANCER!!! NORMAL TISSUE

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

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. 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

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. 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