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Lecture 13

BMS 860 Lecture 13: Cancer Notes 13
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Department
Biomedical Sciences
Course
BMS 860
Professor
Radulovich
Semester
Winter

Description
Lecture 13- Cancer Initiating Cells Stem cells in adult somatic tissues • Tissue specific stem cells are characterized in many somatic tissues- essential for tissue repair, homeostasis • Within a tissue, a small percentage of cells are stem cells – 0.1 to 1%- can reprogram their own genetic makeup and give rise to all cells that are found in that tissue • ex. neural stem cells give rise to all cells in the brain Hierarchy in adult somatic tissues • SCs (long term renewal capacity) --> progenitors (limited renewal capacity) --> differentiated cells (no renewal capacity) --> dead cells • Each stem cell divides occasionally in asymmetric fashion • Can form progenitor cell or transit amplifying cells Characteristics of SCs • self renewal, differentiation into multiple lineages, extensive proliferation potential • Stem cells can undergo both types of division (asymmetrical, symmetrical), depending on context • In beginning of development when organism is growing, stem cells need to increase in number to get tissue to grow- under these circumstances, stem cells will undergo symmetric division • In tissue they will undergo asymmetric division- make a copy of itself and a diff cell Models of tumor growth • cancers are heterogeneous and contain a mix of different tumour cell types plaqued by various genetic abnormalities. Two models are usually proposed to explain tumor growth and heterogeneity. • Stochastic model: tumour cells are heterogeneous, but most cells can proliferate extensively and form new tumours • Cancer stem cell model (CSC): Tumour cells are heterogeneous but only the CSC subset has the ability to form new tumours Characteristics of CSCs • self renewal, differentiation into multiple lineages, extensive proliferation potential • According to CSC theory, CSC cells have same basic properties as corresponding SC in normal tissues. However, unlike normal SCs, cancer stem cells have undergone multiple critical genetic changes resulting in aberrant and uncontrolled cell signaling leading to formation of tumour mass. Assays for SCs and CSCs • Isolation assays- each type of cell that is found in tissue expresses diff surface markers that can be used to identify these cell types- use FACS to sort cells based on surface markers • Functional assays- can see which cell populations have the characteristics of stem cells o In vitro- organoid assay, if u put stem cell on dish, they will form spheroids because they will keep propagating, self renewal properties ▪ Progenitors will divide but will eventually differentiate, will not form spheroid and remain single cells o Transplantation assay- stem cells can be serially transplanted in mice, progenitor have limited ability, and differentiated cells cannot grow tumors Hematopoietic differentiation • All blood cells are made by small percentage of multipotent stem cells that make 2 lineages- lymphoid and myeloid progenitors, transamplifying cells • Can differentiate and make all the diff blood cells • In leukemia, mutations occur in multipotent stem cells and will cause diff types of leukemia- AML, CML • CSCs were actually first discovered in acute myeloid leukemia. (AML) is a malignant disease of the bone marrow in which hematopoietic precursors or myleoid lineage are arrested in an early stage of development resulting in too many immature and abnormal cells called blasts. These blasts circulate throughout the blood stream and lymph system where they disrupt normal function of organs. The First Discovery of CSCs • ex. Took AML cells from patient and separated by cell sorting in 3 diff cell populations, SC, progenitors and mature cells o Injected into mice, and found that only leukemic stem cells gave rise to AML in mice o supports cancer stem cell model • ex. Breast cancer cells that were positive for CD44 and negative for CD24 marker were the only cells that gave rise to tumors in immunosuppressed mice suggesting that these are breast cancer stem cells. • In the past 10 years CSCs were identified in multiple human malignancies based on surface marker expression and tumorigenicity in mice. Pathways involved in self-renewal that are deregulated in cancer cells • Wnt pathway is activated in epidermal/gut cancer • Sonic hedgehog and notch pathway deregulated Clinical Implications of CSCs • recap…according to CSC theory cancer begins from normal stem cells that acquire mutations. These mutations will then be passed to all the daughter cells which will ultimately form the tumor. • Stem cells are known to have resistance to chemotherapy • Currently, most chemotherapy treatments target only proliferating tumour cells. However, these treatment fail to eliminate the dormant stem cells that are capable of replenishing the tumor mass. After a while tumor relapses because the tumor mass becomes repopulated • In 2008 LI and colleagues demonstrated the resistance of tumorigenic breast cancer cells to chemotherapy. They isolated breast cancer stem cells before and after chemotherapy treatment. Their analysis revealed that chemotherapy treatment increased the percentage of highly tumorigenic CD44+/CD24- from 4.7% at baseline to 16% after week 12 following the chemotherapy treatment, suggesting that after treatment there are more stem cells found in tumor The Dendelion Phenomenon • therapies have been developed to target bulk tumor cell populations • although this will eliminate the visible portion of the weeds (differentiated cancer cells responsible for the bulk of the tumor), the unseen roots (cancer stem cells) also need to be eliminated to prevent regrowth of the weeds Potential targets for CSC • surface markers, ABC cassette, microenvironment, and signal cascades CSC theory recap • Cancer stem cells are rare immortal cells within a tumour that can both self-renew by dividing and give rise to many cell types that constitute the tumour, and can therefore form tumours. Such cells have been found in various types of human tumours and might be attractive targets for cancer treatment. Observations supporting CSC theory • The presence of differentiated tumour cells in residual tumour masses after chemotherapy is a favorable prognostic marker, while the
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