Speaker:郭庭維 戴郁亭 Date:104/05/26

Stem cells http://futurehumanevolution.com/genetic-engineering-and-the-future-of-human-evolution-articles

Figure 1.Examples of Stem Cells Found in Adult Somatic Tissues.

Many studies performed over the past 30 to 40 years, when viewed collectively, have shown that the characteristics of stem-cell systems, the specific stem-cell properties described above, or both, are relevant to some forms of human cancer. The attribute of self-renewal is especially notable, because its subversion is highly relevant to oncogenesis and malignancy. Aberrantly increased self-renewal, in combination with the intrinsic growth potential of stem cells, may account for much of what is considered a malignant phenotype. Nat Rev Cancer 2003;3:895-902 Oncogene 2004;23:7274-82

Figure 2.Stem-Cell Systems

Cancer Stem cells (CSCs) Accordingly, the properties of tumor-initiating cells closely parallel the three features that define normal stem cells. Malignant cells with these functional properties have been termed “cancer stem cells”

CSC can be the source of all the malignant cells in a primary tumor , they can compose the small reservoir of drug-resistant cells that are responsible for relapse after a chemotherapy induced remission, or they can give rise to distant metastases. The biologic features of cancer stem cells in each of these instances may differ, suggesting that the acquisition of features associated with tumor progression, such as genetic instability and drug resistance. 在初階腫瘤中癌症幹細胞可以是所有的惡性細胞的來源，它們可以構成有抗藥性細胞，它們在化療誘導之後又會復發，或者它們可以轉移到其他地方（圖3）。 癌幹細胞的生物特徵可能不同，這表示與腫瘤生成中得到的功能有關，如遺傳不穩定性和耐藥性，也將與癌症幹細胞相關聯。

Figure 3.Scenarios Involving Cancer Stem Cells. 剛剛所說的癌幹細胞有這三種生成方式: A.正常幹細胞或原始細胞接受外在刺激突變後，就會變成新的癌症幹細胞，之後形成原發性腫瘤 B.在化療期間，多數腫瘤細胞會被殺死，但如果其中的癌幹細胞沒被殺到，腫瘤可能又再復發 C.腫瘤中的癌幹細胞則可能直接轉移到身體其他部位 標靶治療特異的癌症幹細胞應比目前只治療整顆腫瘤能更有效根除腫瘤和減少復發和轉移的風險。 Figure 3.Scenarios Involving Cancer Stem Cells.

Cancer Stem Cells in the Hematopoietic System In various types of leukemia, cancer stem cells have been unequivocally identified, and several biologic properties of these stem cells have been found to have direct implications for therapy. Trends Cell Biol 2005;15:494-501 Cancer Control 2004;11:97-104 Oncogene 2004;23: 7178-87 Ann N Y Acad Sci 2005;1044:1-5 Cancer stem cells are readily evident in chronic myelogenous leukemia (CML) acute myelogenous leukemia (AML) acute lymphoblastic leukemia (ALL)

Chronic myelogenous leukemia (CML) Gleevec 干擾素 Imatinib (Glivec)

Chronic myelogenous leukemia (CML) Despite the remarkable clinical responses achieved with imatinib, however, residual disease persists in many patients. In vitro studies indicate that inhibition of the CML translocation product BCR-ABL is sufficient to eradicate most or all leukemia cells, but the drug does not appear to kill CML stem cells. Furthermore, although the newly approved CML agent dasatinib is effective for imatinib resistant disease, recent data suggest that it too may fail to eradicate CML stem cells Leukemia 2002;16:549-58. Blood 2003;101:3142-9 Blood 2001;98:2301-7. Blood 1996;88:1944-50. Blood 1999;94:2056-64.

Acute myelogenous leukemia (AML) Early efforts have demonstrated the usefulness of antibodies against the CD33 antigen in the treatment of AML,and recent reports indicate that CD33 is expressed on some leukemia stem cells.

Unique molecular in AML stem cells For example, there is evidence of constitutive activation of both the nuclear factor-κB (NF-κB) and phosphatidylinositol 3 (PI3) kinase signaling pathways in AML stem cells. A separate study demonstrated that inhibition of PI3 kinase reduced the growth of AML stem cells. Similarly, inhibition of the downstream PI3-kinase mammalian target of rapamycin (mTOR) appears to enhance the activity of the chemotherapeutic agent etoposide against AML stem cells. Inhibition of mTOR also blocks the growth of leukemia-initiating cells in a mouse model of AML. Proc Natl Acad Sci U S A 2002;99:16220-5. Blood 2005;105:4163-9. Blood 2005;106:4261-8. Nature 2006;441:475-82. J Neurosci 1992;12:4565-74 Science 1992;255:1707-10.

Cancer Stem Cells in the Central Nervous System Isolation of cancer stem cells of the central nervous system (CNS) has been achieved by means of antigenic markers and by exploiting in vitro culture conditions developed for normal neural stem cells. As was first observed in 1992 CNS cells grown on nonadherent surfaces give rise to balls of cells (neurospheres) that have the capacity for self-renewal and can generate all of the principal cell types of the brain (i.e., neurons, astrocytes, and oligodendrocytes). Neurosphere

Cancer Stem Cells in the Central Nervous System Nature 432, 281-282(18 November 2004 Transplantation of as few as 100 CD133-positive human glioma cells into the brains of immunodeficient mice initiates the development of a glioma, whereas no tumors result from transplantation of 10 CD133-negative cells from the same tumors.

Cancer Stem Cells in the Central Nervous System For example, expression of the ras and myc oncogenes in oligodendrocyte progenitors yields cells that readily form tumors when transplanted in vivo. http://en.wikipedia.org/wiki/Oncogene

Cancer Stem Cells in the Breast Studies by Al-Hajj of specimens from patients with advanced stages of metastatic breast cancer demonstrated that cells with a specific cell-surface antigen profile (CD44-positive and CD24-negative) could successfully establish themselves as tumor xenografts. Furthermore, the purified CD44-positive and CD24-negative cells could differentiate and give rise to cells similar to those found in the bulk tumor population. With the experimental tools developed for characterization of normal mammary stem cells, further elucidation of the biologic properties of breast-cancer stem cells should be forthcoming

Summary Cancer Stem Cells target Hematopoietic System chronic myelogenous leukemia (CML) BCR-ABL fusion tyrosine kinase acute myelogenous leukemia (AML) CD33+ activation of NF-κB and PI3k mTOR Central Nervous System CD133 + ras and myc oncogene Breast CD44 + and CD24 -

Challenges for Therapy Targeted against Cancer Stem Cells Design treatments that selectively eradicate cancer stem cells, it is useful to have the cognate normal stem cell or progenitor cell. (i.e., cell-surface antigen markers) Need similar ways to describe cancer stem cells and appropriate functional assays must be validated. How cancer stem cells differ from normal stem cells, particularly with regard to mechanisms controlling cell survival and responses to injury. 1.化驗的發展來表徵正常幹細胞的功能，並訂定物理特徵（例如，細胞表面抗原標記物）2.需要類似的方式來描述癌症幹細胞和適當的功能測定。 3.了解正常幹細胞與癌症幹不同處，特別是在控制細胞存活和損傷的機制。

How therapies that effectively target the bulk of tumor cells fail to eradicate cancer stem cells. How the properties of stem cells make them particularly difficult to kill in targeting cancer stem cells . Stem cells is expression of proteins associated with the efflux of xenobiotic toxins. Particularly during relapse, express such proteins, thus providing resistance to many chemotherapeutic agents. 1.要了解療法為何針對大部分腫瘤細胞有效，但無法根除癌症幹細胞。 2.在靶向癌症幹細胞的另一項挑戰是要了解幹細胞難以殺滅的特性。 3.幹細胞的另一個共同特徵是有異生毒素（EX多藥耐藥蛋白和ATP結合盒[ABC]轉運蛋白家族的相關成員）的外排相關蛋白的表達。 多種癌細胞，特別是在復發，表達這樣的蛋白質，從而提供抵抗許多化學治療劑。

Conclusion How existing chemotherapy agents affect the evolution of cancer stem cells during conventional treatment regimens. Therefore, the development of assays that measure the survival of cancer stem cells will be important for assessing the potential of new targeted regimens. 目前，我們必須確定在何種程度幹細胞生物學是人類所有主要的癌症型態。 1.調查的另一個重要問題是現有的化療藥物如何影響現在治療癌症幹細胞的演變方式。這個問題涉及到正常幹細胞，和抗藥性可能出現的機制進行比較。 2.因此，測量腫瘤幹細胞的存活測定法的發展將是用於評估新的靶向療法。

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Embryonic stem cell（胚胎幹細胞）： Also called hES (human Embryonic Stem Cells) Undifferentiated cells from the embryo that have the potential to become a variety of specialized cell types. Embryonic stem cells are cells derived from the inner cell mass of a developing blastocysts. A hES is self-renewing (can replicate itself) and is pluripotent (can form into all 220 different cell types found in the human body.)