Stem Cells & Cancer Lecture F2024 PDF

Stem Cells & Cancer September 27, 2024 Bre-Anne Fifield, PhD Research Associate Adjunct Professor  Historical Views On Cancer Normal Tissue Cell with Genetic Microscopic Cancer Disorganization of Change Cells Tissue 1...

Stem Cells & Cancer September 27, 2024 Bre-Anne Fifield, PhD Research Associate Adjunct Professor  Historical Views On Cancer Normal Tissue Cell with Genetic Microscopic Cancer Disorganization of Change Cells Tissue 1. Cancer is a proliferative disease 2. All tumour cells within a tumour can form a new tumour 3. Increased expression of genes that promote cell proliferation and silencing of growth inhibitory genes and blunting of cell death.  Cancer Stem Cell Hypothesis Stem Cell Normal Tissue Stem Cell Disruption Microscopic Cancer Disorganization of Cells Tissue 1. Tumours arise from cells termed cancer stem cells that have properties of normal stem cells (self-renewal, multi-potency) 2. Unregulated cell growth is due to disruptions in stem cell renewal 3. Cancer is a stem cell disorder, not strictly a disruption in cell proliferation/death Cancer Stem Cell (CSC) Hypothesis Reprinted from “Stochastic vs Cancer Stem Cell Models”, by BioRender.com (2024). Retrieved from https://app.biorender.com/biorender-templates Discovery of CSCs The cancer stem cell: premises, promises and challenges | Nature Medicine Discovery of CSCs The cancer stem cell: premises, promises and challenges | Nature Medicine  Discovery of CSCs 1994 Discovery that only a select population of cells within the cancer can re-constitute the tumour. These cells were more Dr. John Dick ‘immature’ than the bulk tumour U. of Toronto mass. Discovery of CSCs Sort patient AML samples on basis of cell surface marker expression Limiting dilution assay: assess frequency of cell population (bulk population) Stem Cell Characteristics  CSC Identifying Properties Capable of reforming a heterogenous tumour Self renew High proliferation potential Long-lived cells Give rise to short lived, differentiated cells Highly influenced by signals from their microenvironment Highly drug resistant  CSC Identifying Properties Debatable points: Are the minority subpopulation in a given tissue Mainly appear to be in a quiescent cell-cycle state Characterized by specific surface markers Methods of Identifying CSCs Sphere Forming Assays Culture cells in ultra- low attachment dishes with no serum Can be serially passaged Sphere forming efficiency can indicate number of CSCs present PLoS ONE. 2009; 4(4): e5329. Flow Cytometry Sorting cells on basis of markers Can quantify percentage of population  CSC Markers Table of current ID’d cancer stem cells and markers The cancer stem cell: premises, promises and challenges | Nature Medicine Xenotransplantation  Identification of CSCs Acute myelogenous leukemia: [CD34+,CD38-] Breast cancer: [CD44+&CD24-/low, Lin-, ALDH+] Brain cancer: [CD133+, CD44+, CD15+] Prostate cancer: [CD44+] Colon cancer: [CD133+]  First Evidence of CSCs in Solid Tumours Found in Breast Cancer Used breast cancer patient samples Sorted into multiple populations Orthotopic injections (in mammary gland) CD44+ CD24- Cells Have Tumourigenic Properties CD44+ and CD24- cells formed tumours As few as 100 CD44+CD24- cells could form a tumour PNAS April 1, 2003 100 (7) 3983-3988; https://doi.org/10.1073/pnas.0530291100  Breast CSCs Recapitulate Heterogenous Tumour Serially passage CSC in mice Continue to form heterogenous tumour each time No differences found in cell cycle of CSCs vs other cell types  Breast CSCs Recapitulate Heterogenous Tumour Serially passage What about CSCother markers? in mice Continue[CD44+, to formCD24-/low, Lin-, ALDH+] heterogenous tumour each time No differences found in cell cycle of CSCs vs other cell types ALDH Can Also Mark CSCs in Breast Cancer Isolated ALDH+ cells Injected different populations into mammary fat pad ALDH+ cells formed tumours with higher proliferative potential Cell Stem Cell. 2007 Nov 15; 1(5): 555–567. doi: 10.1016/j.stem.2007.08.014  ALDH+CD44+CD24- CSCs Have Highest Tumour Potential ALDH+ nonCD44+CD24- ALDH- CD44+CD24- 1500-15000 cells injected ALDH+ CD44+CD24- 20-2000 cells injected Cell Stem Cell. 2007 Nov 15; 1(5): 555–567. doi: 10.1016/j.stem.2007.08.014 Where Do CSCs Come From? Cancer Stem Cells: From an Insight into the Basics to Recent Advances and Therapeutic Targeting - PMC (nih.gov) Where Do CSCs Come From? Cancer Stem Cells: From an Insight into the Basics to Recent Advances and Therapeutic Targeting - PMC (nih.gov) Where Do CSCs Come From? Cancer Stem Cells: From an Insight into the Basics to Recent Advances and Therapeutic Targeting - PMC (nih.gov) Higher Lineage CSCs Correlate with Poor Prognosis Mouse markers Human markers Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis (cshlp.org)  Higher Lineage CSCs Correlate with Poor Prognosis Poor Prognosis & Increased Aggressiveness Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis (cshlp.org) Plasticity of CSCs Cancer stem cells revisited | Nature Medicine CSC Niche Dictates Fate of CSCs Following Division Cancer stem cells revisited | Nature Medicine Loss of Niche Dependency Can Promote CSC Expansion Cancer stem cells revisited | Nature Medicine CSC Interactions With Niche CSCs receive cues from niche to sustain stem-like features CSCs also signal to niche Cancer Stem Cells: The Architects of the Tumor Ecosystem: Cell Stem Cell  CSCs Drive Metastasis and Relapse Detection of cells with CSC markers in pleural fluid and in sites of metastasis Enrichment of cells with CSC phenotype following treatment EMT factors can regulate CSC fate – ZEB1 breast CSCs: can mediate plasticity of cells  Therapeutic Implications of CSCs Resistant to treatment Drivers of metastasis and relapse Tumour Regression Complete Cancer Stem Cell Remission Specific Therapy Conventional Therapy Relapse How Do CSCs Evade Therapy? How Do CSCs Evade Therapy? Increased expression of anti-apoptotic Bcl2 family members Chemoresistant cells and CSCs share similar properties and markers More efficient DNA repair – Increased RAD51 expression (breast cancer, glioblastoma)  Strategies to Target CSCs Immunotherapy against stem cell specific markers Inhibition of key CSC signaling pathways Promote differentiation of cancer stem cells Treatments that target quiescent cells Inhibition of DNA damage response Acute Promyelocytic Leukemia (APL) Differentiation as a Treatment Strategy Acute promyelocytic leukemia: from highly fatal to highly curable Zhen-Yi Wang1, and Zhu Chen1,2 Blood. 2008 Mar 1;111(5):2505-15. CSCs and Immunotherapy Frontiers | Cancer Stem Cells: Emerging Key Players in Immune Evasion of Cancers (frontiersin.org)  Immunotherapy Approaches to Target CSCs Target Innate CSC Immune Antigens System Immunization T-cell Strategies Activation Cancer stem cells: advances in knowledge and implications for cancer therapy | Signal Transduction and Targeted Therapy (nature.com)  Targeting DNA Damage Response: PARP Inhibitors PARP involved in base excision repair: single strand breaks (SSB) When SSB not repaired, cells use homologous recombination repair: BRCA1/2 Use PARP inhibitors (olaparib, talazoparib) in cells with homologous recombination repair deficiency An Overview of PARP Inhibitors for the Treatment of Breast Cancer - PMC (nih.gov)  Targeting DNA Damage Response: PARP Inhibitors An Overview of PARP Inhibitors for the Treatment of Breast Cancer - PMC (nih.gov) Drug Delivery Systems Targeting CSCs Specific targeting through receptor ligand interactions Controlled or delayed drug release Cancer stem cells: advances in knowledge and implications for cancer therapy | Signal Transduction and Targeted Therapy (nature.com)  Potential Limitations of Treatment Strategies Markers of CSCs are shared among normal cells Targeting signaling pathway: acquired resistance and side effects on healthy cells Limited knowledge on specific features of quiescent cells Plasticity of cells Important Remaining Questions Does abnormal growth of normal stem cells sensitize organisms to cancer? How can we more accurately detect the CSC population with a heterogenous population? How do we better target the CSC population as a potential therapy?