ANAT 416 Stem Cells and Cancer PDF

ANAT 416 Stem Cells and Cancer Prof. Luke McCaffrey, PhD Goodman Cancer Institute Department of Oncology Department of Biochemistry Department of Medicine, Division of Experimental Medicine Cancer survival rates Why is there so much variability in survival rates? what factors contribute to this dive...

ANAT 416 Stem Cells and Cancer Prof. Luke McCaffrey, PhD Goodman Cancer Institute Department of Oncology Department of Biochemistry Department of Medicine, Division of Experimental Medicine Cancer survival rates Why is there so much variability in survival rates? what factors contribute to this diversity? Testis Men 1. Ease of detection the earlier its detected, Melanoma the higher the survival Larynx rate NHL 2. Funding for research Rectum - good correlation between survival and Leukaemia funding Brain 3. Anatomical site of cancer and aggression Oesophagus of treatement Pancreas 4. Whether or not its Hodgkin's lymphoma metastatic 5. some cancers have Uterus different molecular Bladder subtypes and will have different mutations Rectum 6. therapeutic Kidney resistance - recurrence Ovary is a major problem 24% Brain Oesophagus Pancreas 95% More than 50% survival: 38% of cases diagnosed 10-50% survival: 29% of cases diagnosed less than 10% survival: 24% of cases diagnosed Women 13% 12% 7% 6% 3% 51% 46% 45% 45% 38% 84% 78% 71% 67% 61% 22% 15% 13% 8% 6% 2% 52% 48% 45% 43% 36% 34% 61% 68% 90% 83% 79% More than 50% survival: 50% of cases diagnosed 76% Five-year relative survival 10-50% survival: 27% of cases diagnosed less than 10% survival: 15% of cases diagnosed Phenotypic heterogeneity —> what are some of the genotypic variations that impact the phenotypes of cancer Cancer heterogeneity Genetic Phenotypic Clinical Response to therapy Relapse Survival Cancer is a collection of rare genetic diseases with diverse phenotypes and clinical outcomes many different diseases that accumulate in the cancer phenotype Cancer heterogeneity some cells may be resistent to drugs, some may be radiation resistance, some cells may metastasize —> where does this heterogeneity come from? Genetic Phenotypic Drug resistance Metastasis Radiation resistance How does this heterogeneity arise? different cells of origin, different mutations that can arise between different populations of cells Clonal evolution creates genetic diversity different mutational events can occur, at different stages of stage development —> not every single mutation will be beneficial to the cancer —> those are called passenger mutations, and then there are DRIVER mutations that progress the growth of the cancer TRANSFORMATION Normal cell Tumour cell Primary tumour Metastasis Cancer stem cell (Hierarchal model) Phenotypic heterogeneity —> you can have a differentiation process, so it is not drvien by mutations but by phenotypic variations. It suggests that you have a Cancer cell that acts like a stem cell that can self renew and differentiate into different types of cancer cells. TRANSFORMATION CSC Normal cell Self-renewal this doesnt mean that it nevessarily have to arise from normal stem cells in adults, BUT this is likely what happens most of the time Does not imply that normal stem cells are the cell-oforigin of the cancer (although this is often be the case) Clonal Evolution vs Cancer Stem Cells Which populations are tumourigenic? Clonal evolution model: All cells in the dominant population(s) have tumourigenic potential Cancer stem cell model: A subset of cells have tumourigenic potential ALL cells in the Clonal evolution model are tumourigenic!! BUT in the cancer stem cell model only a small subset of cells have tumourigenic potential, but not all. Functionally testing prospective cancer stem cells 1. Sphere-forming assay (mouse and human) 2. Transplantation assay (mouse and human) 3. Lineage tracing (mouse only) Sphere-forming assay You would observe this for a hierarchical model, but if you had multiple cell types that form spheres you would have the cancer stem cell model *stress conditions where only stem/ tumour cells can grow Take population of tumour cells, put them into single cell population, and put them in culture as single cells. Only cancer cells are able to grow into balls/spheres, indicating stem cell-like properties Cells from many cancer tissues can form spheres (including: breast, prostate, pancreatic, ovarian, others) Stem cells are not the only cells that can form spheres (progenitors, transit amplifying cells) Quiescent stem cells do not form spheres Lack of tumour microenvironment Amenable to screening Nat Rev Cancer. 2013 Oct;13(10):727-38. Transplant assay Have to inject into the mouse, to see what real tissue responses are. You see whether those cells form a tumour or not. Lineage tracing: have a label for a cell of origin, and track wehther that cell remains in the tumour that grows. Check for differentiation: put in one population of cells, and take the tumour back and see if there are multiple populations of cells Currently the gold standard Usually performed in immunocompromised mice (can affect estimate of true number of CSCs) Does not indicate whether the cells are necessary for growth/maintenance of the primary tumor Nat Rev Cancer. 2013 Oct;13(10):727-38. Variations of transplant assays Transplantation does not indicate if the cell is responsible for tumour growth in original tumor Nat Rev Cancer. 2013 Oct;13(10):727-38. Big bang theory: major event at early tumourigenesis, where a huge amount of tumour mutations develops Comparison of transplantation assay outcomes Clonal evolution Cancer stem cell hierarchy Phenotypic change Phenotypic change All populations are tumourigenic Only some populations are tumourigenic Phenotype of secondary tumour cells matches the cell type transplanted (i.e. no heterogeneity) Phenotype of secondary tumour cells matches heterogeneity of the original tumour The first example of cancer stem cells identified from patients first ever identification driven by a hierarchical model: Acute myeloid leukemia Hematopoietic stem cells can develop into red blood cells, white blood cells, or platelets. These myeloid cells are the ones that are abnormal in AML. Immature cells that develop into leukemic cells are called leukemic blast cells. Normal immune function is impaired. Hematopoietic stem cell (SCID-repopulating cell) Long-term culture initiating cell Leukemic stem cell (SCID-leukemia initiating cell) Colony forming unit CD34+ CD38+ CD34+ CD38+ the population of cells that makes 98% of the tumour is the one we should target - but only the 0.2 was the one in transplantation assays, they basically grew and gave rise to the tumour AML – Cancer stem cells Cell transplantation of cells from AML patients into mice (regenerate AML in mice) the dominant population is the double positive CD34/38 cells Only the CD34+/CD38- fraction has tumourinitiating capacity (minor fraction; there is a lot of research on this Targetting the queiscent cells is well and good, but instead of targetting it, try to leave it alone and prevent it from exiting that dormant state Targeting CSC quiescence Targeting CSC self-renewal/differentiation European Journal of Cancer Volume 48, Issue 14 2012 2104 - 2116 Targeting quiescent CSCs Many anti-cancer therapies only work against proliferating cells Granulocyte colony stimulating factor (G-CSF) can induce quiescent cells to proliferate, making them susceptible to standard therapy. Targeting the CSC niche CSCs reside next to vasculature, so to disrupt the tumour vasculator to choke out the tumour cells if you can maintain it as a stem cell that isnt able to give rise to the bulk of the tumour through differentiation, then thats another method Immunotherapy Improve or induce immunological surveillance recognition and destruction of residual CSC after debulking with chemotherapy, radiation therapy, or surgery. Immunotherapy to stimulate immune destruction of tumours Pancreatic CSCs expresses high levels of EpCAM on the surface MT110 – bispecific antibody that recognizes 2 specific antigens 1) CD3, lymphocyte marker 2) EpCAM Redirects cytotoxic CD8+ T lymphocytes to the primary tumour (xenografts) Cioffi et al. Clin Cancer Res. 2012 Jan 15; 18(2)465-74. Cancer Vaccines Two types of cancer vaccines (not specific to cancer stem cells): 1.Preventative (e.g. hepatitis B virus, human papilloma virus (HPV) 2.Therapeutic (e.g. Provenge – dendritic cellbased vaccine to treat metastatic prostate cancer) Stem Cell Rev Rep. 20, 2-24, 2024. Cancer vaccines Cancer stem cell vaccines Vaccinate against cell surface markers on CSCs Dendritic cells (DCs) exposed to CSC or non-CSC cell lysates Success in mice following transfer of DCs exposed to CSC, but not non-CSC Reduced growth and metastasis of melanoma cancer H-TPDC = DC cells exposed to heterogeneous cancer cells CSC-TPDC = DC cells exposed to cancer stem cells Cancer Res. 2012 Apr 1;72(7):1853-64. Cancer Stem Cell Vaccines MUC1 is hypoglycosylated on colorectal cancer stem cells. Guo et al. Int Immunopharmacol 2020 Aug, 85:106631 Cancer Stem Cell Vaccines vaccinate with cell lysates and they inject into mice, and look at immune system ability to repsond or inactive the tumours. They use cancer stem cells as their vaccination onject Guo et al. Int Immunopharmacol 2020 Aug, 85:106631 Cancer Target Therapeutic Mechanism AML mTOR Rapamycin Inhibit self-renewal CD44 Anti-CD44 antibody Immunotherapy CD47 Anti-CD47 antibody Immunotherapy NF-κB pathway Parthenolide thiocarbamates Differentiation NOTCH pathway Gamma-secretase inhibitors Inhibit self-renewal AKT Perifosine Inhibit self-renewal VEGF Bevacizumab Niche targeting Hedgehog pathway Cyclopamine Inhibit self-renewal BMPR2 BMP4 Differentiation MHC and NK ligands δγT-lymphocytes Immunotherapy IL-4 IL-4R antagonists or Reversal of anti IL-4 antibody chemoresistance Breast cancer Glioblastoma Colorectal cancer