stem cells and cancer stem cells

stem cells types source uses
stem cell cancer what is it, pathways

1. Stem Cells & Cancer Stem Cells BY Marwa Mahmoud Khalifa Amr Elfeky Ahmed Elmoughazy

2. What are stem cells ?? Undifferentiated cells Able to develop into many different cell types in the body during early life and growth. Serve as a sort of internal repair system, dividing essentially without limit to replenish other cells

3. Characteristics Self renewal Unspecialized but can give rise to specialized cells ( differentiation) In some organs, such as the gut and bone marrow, stem cells regularly divide. In other organs, however, such as the pancreas and the heart, stem cells only divide under special conditions.

4. Types of stem cells Embryonic stem cells  Non-embryonic "somatic" or "adult" stem cells. Induced pluripotent stem cells ( ipscs ) 

5. Potency Totipotent: differentiate into all possible cell types. Examples: zygote formed at egg fertilization and the first few cells that result from the division of the zygote. Pluripotent: differentiate into almost all cell types. Examples: embryonic stem cells and cells that are derived from the mesoderm, endoderm, and ectoderm germ layers.

6. Potency Multipotent : differentiate into a closely related family of cells. Examples: hematopoietic (adult) stem cells that can become red and white blood cells or platelets. Oligopotent : differentiate into a few cells. Examples: (adult) lymphoid or myeloid stem cells. Unipotent : only produce cells of their own type, but have the property of self-renewal required to be labeled a stem cell. Examples : (adult) muscle stem cells

7. Embryonic Stem Cells Embryonic stem cells are derived from a four- or five-day-old human embryo that is in the blastocyst phase of development, fertilized  in vitro then donated for research purposes with informed consent of the donors.

8. Embryonic Stem Cells Human embryonic stem cells ( hESCs ) are generated by transferring cells from a preimplantation-stage embryo into a plastic laboratory culture dish that contains a nutrient broth known as culture medium. 

9. Embryonic stem cells are considered pluripotent instead of totipotent because they do not have the ability to become part of the extra-embryonic membranes or the placenta. Embryonic Stem Cells

10. Adult stem cells supply new cells as an organism grows and to replace cells that get damaged. Adult stem cells are said to be multipotent Examples Hematopoietic stem cells:  give rise to all the types of blood cells:. Mesenchymal stem cells:   Those from bone marrow (bone marrow stromal stem cells, skeletal stem cells) give rise to a variety of cell types: bone cells (osteoblasts and osteocytes), cartilage cells (chondrocytes), fat cells (adipocytes), and stromal cells that support blood formation Adult stem cells

11. Adult stem cells supply new cells as an organism grows and to replace cells that get damaged. Adult stem cells are said to be multipotent Examples Neural stem cells: in the brain give rise to its three major cell types: nerve cells (neurons) and two categories of non-neuronal cells—astrocytes and oligodendrocytes . Epithelial stem cells: in the lining of the digestive tract in deep crypts and give rise to : absorptive cells, goblet cells, Paneth cells, and enteroendocrine cells. Adult stem cells

12. Adult stem cells supply new cells as an organism grows and to replace cells that get damaged. Adult stem cells are said to be multipotent Examples Skin stem cells: occur in the basal layer of the epidermis and at the base of hair follicles. The epidermal stem cells give rise to keratinocytes. The follicular stem cells can give rise to both the hair follicle and to the epidermis. Adult stem cells

13. What are the similarities and differences between embryonic and adult stem cells? Embryonic stem cells can become all cell types of the body because they are pluripotent. Adult stem cells are thought to be limited to differentiating into different cell types of their tissue of origin. Embryonic stem cells can be grown relatively easily in culture. Adult stem cells are rare in mature tissues, so isolating these cells from an adult tissue is challenging, and methods to expand their numbers in cell culture have not yet been worked out. 

14. Induced Pluripotent Stem Cells Adult cells that have been genetically reprogrammed to an embryonic stem cell–like state by being forced to express genes and factors important for maintaining the defining properties of embryonic stem cells.  Human iPSCs express stem cell markers and are capable of generating cells characteristic of all three germ layers.

15. Induced Pluripotent Stem Cells Viruses are currently used to introduce the reprogramming factors into adult cells, and this process must be carefully controlled and tested before the technique can lead to useful treatment for humans.

16. Stem cell lines Once stem cells have been allowed to divide and propagate in a controlled culture, the collection of healthy, dividing, and undifferentiated cells is called a stem cell line. Once under control, the stem cells can be stimulated to specialize as directed by a researcher - a process known as directed differentiation.

17.   Potential uses of human stem cells

18. Studies of human embryonic stem cells will yield information about the complex events that occur during human development Some of the most serious medical conditions, such as cancer and birth defects, are due to abnormal cell division and differentiation Human stem cells are currently being used to test new drugs. Cancer cell lines, for example, are used to screen potential anti-tumor drugs.

19. Generation of cells and tissues that could be used for cell-based therapies. Stem cells, directed to differentiate into specific cell types, offer the possibility of a renewable source of replacement cells and tissues to treat diseases including macular degeneration, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis, and rheumatoid arthritis.

20. Stem cells could be used to generate new organs for use in transplants. Currently, damaged organs can be replaced by obtaining healthy organs from a donor, however donated organs may be 'rejected' by the body as the immune system sees it as something that is foreign.

21. how stem cells can be used to produce retinal pigment epithelium (RPE) cells that can be used to treat patients with age-related macular degeneration (AMD).

22. Cancer Stem Cells (CSCs)

23. What are cancer stem cells (CSCs)? immortal tumor-initiating cells that can self-renew and have pluripotent capacity can generate tumor cells with different phenotypes, which results in the growth of the primary tumor and emergence of new tumors. Found in multiple malignancies, including leukemia and various solid cancers (breast, lung cancer, colon cancer, prostate cancer, ovarian cancer, brain cancer, and melanoma).  

24. CSC biomarkers the most common method used to identify CSCs is fluorescence-activated cell sorting (FACS) based on cell surface markers or intracellular molecules.

25. Cancer Cell Hypothesis (1) Only a small fraction of the cancer cells within a tumor have tumorigenic potential when transplanted into immunodeficient mice. (2) the CSC subpopulation can be separated from the other cancer cells by distinctive surface markers; (3) tumors resulting from the CSCs contain the mixed tumorigenic and nontumorigenic cells of the original tumor and

26. Cancer Cell Hypothesis (4) the CSC subpopulation can be serially transplanted through multiple generations, indicating that it is a self-renewing population” . Therefore, CSCs are capable of self-renewal and differentiating into other distinctive cells that make up the tumor mass.

27. Origin of cancer stem cells

28. Models For Cancer Development every cancer cell is able to initiate new tumor growth equally every tumor contains a rare population of cells termed CSCs or cancer initiating cells

29. STEM CELL NICHE Physiological stem cells and CSCs depend on their immediate microenvironment or niche for their survival and function. The cellular and noncellular components of the niche provide signals that regulate proliferative and self-renewal signals, thereby helping CSCs to maintain their undifferentiated state. Nonepithelial stromal cells, inflammatory cells and the vasculature have been proposed as key components of the niche that support and sustain CSCs.

30. Cancer stem cells in disease progression and metastasis

31. Cancer stem cell and drug resistance ATP-binding cassette (ABC) transporters are membrane transporters that can pump various distinct and structurally unrelated small molecules (such as cytotoxic drugs and dyes) out of cells at the expense of ATP hydrolysis Anti–tumor drugs can be pumped out, thereby resulting in low intracellular drug concentrations. Thus, the elevated levels of ABC transporters enable cancer stem cells to resist current cancer therapies

32. Key signaling pathways Pathways and elements involved in the control of self-renewing and differentiation of cancer stem cells as well as normal stem cells include PI3K/ Akt , JAK/STAT, Wnt /β-catenin, hedgehog, Notch, NF- κB , ABC superfamily and so on. Depending on these aberrant pathways, cancer stem cells acquire its unique ability to initiate carcinoma and promote recurrence after surgery.

33. JAK/STAT signaling pathway The JAK/STAT signaling pathway is activated through the binding of diverse ligands, such as interleukins, interferons, hormones, and growth factors, to their respective receptors. JAK/STAT signaling in stem cells has been shown to be involved in maintaining embryonic stem cell self-renewal properties, hematopoiesis, and neurogenesis Evidence that this pathway is activated aberrantly in CSCs has been found in stem-like cells isolated from tumors of the breast, prostate, blood, and glia.

34. JAK/STAT signaling pathway Modulation of the JAK/STAT pathway in CSCs has been shown to enhance or repress the expansion of these cancer-forming cells in solid tumor model systems. Tumor growth factor-beta (TGF-β) was shown to regulate the self-renewal and differentiation properties of glioma-initiating cells derived from patient samples of glioblastoma multiforme.

35. Hedgehog pathway The Hedgehog pathway is essential for the development and proper patterning of many organs during embryogenesis, including the nervous system, skeleton, limbs, lung, heart, and gut, by controlling cellular proliferation, differentiation, and migration. the Hedgehog pathway is largely inactive in most postnatal tissues except the adult central nervous system, skin, hair, and teeth.

36. Hedgehog pathway The role for Hedgehog signaling in CSC function has been documented in various cancers, including basal cell carcinoma (BCC), multiple myeloma, glioblastoma, chronic myeloid leukemia (CML), and colon cancer. Chemical inhibition of the Smoothened protein attenuated proliferation, stemness maintenance, and self-renewal in CSCs, suggesting strongly that Hedgehog signaling promotes these CSC functions in multiple myeloma. Treatment of glioma CSCs with a Hedgehog signaling inhibitor resulted in a decrease in proliferation, survival, self-renewal, and clonogenicity.

37. Wnt pathway Mutations in genes encoding Wnt pathway mediators are commonplace in many cancers including medulloblastoma, lymphoma, and leukemia, as well as breast, gastric, and colorectal cancer (CRC).

38. Notch pathway The Notch pathway has been demonstrated to regulate the properties of tumor cells in many cancers, including leukemia, glioblastoma, and those of the breast, colon, pancreas, and lung the Notch pathway may be activated in nearly three-quarters of primary esophageal adenocarcinoma samples as compared with normal esophageal mucosa. In xenograft models of tumorigenesis using esophageal adenocarcinoma cells, inhibition of the Notch pathway via treatment with a γ-secretase inhibitor greatly reduced primary tumor growth. Notch may serve as a tumor suppressor in murine skin. Deletion of Notch1 in the epidermis resulted in the development of spontaneous BCC-like skin tumors.

39. Therapies Targeting Cancer Stem Cells

40. Targeting signal cascades The Notch ligand, DLL4, has been another popular targeting strategy in cancer. Treatment with anti-DLL4 monoclonal antibody results in disorganized angiogenesis due to its effect on endothelial cells and in clinical trial inhibition of DLL4 has demonstrated good safety and preliminary efficacy Targeting STAT3 was shown to reduce glioblastoma brain Tumor stem cells in pre-clinical models. WP1066, a STAT3 inhibitor, is currently in Phase 1 clinical trial from patients with recurrent malignant glioma and brain metastasis from melanoma The most clinically advanced Hh targeting therapy is vismodegib , which is approved by the FDA for the treatment of metastatic basal cell carcinoma

41. Targeting surface markers CD44 is the most common CSC marker and plays a major role in enhancing stemness and communication with the microenvironment . However Anti CD 44 is in phase 1 clinical trail. Imatinib is a tyrosine kinase inhibitor that selectively inhibits c-kit, BCR/ABL and PDG F receptors and is approved for the treatment of chronic myelogenous leukemia(CML) and unresectable CD117+ gastrointestinal stromal tumors