Chapter 080. Cancer Cell Biology and Angiogenesis (Part 13) pdf

Chapter 080. Cancer Cell Biology and Angiogenesis (Part 13) New Concepts in the Development of Cancer Therapeutics Cancer Stem Cells It has long been recognized that only a small proportion of the cells within a tumor are capable of initiating colonies in vitro or of forming tumors at high efficiency when injected into immunocompromised NOD/SCID mice. Current work indicates that human acute and chronic myeloid leukemias (AML and CML) have a small population of cells (<1%) that have properties of stem cells, such as unlimited self-renewal and the capacity to cause leukemia when serially transplanted in mice. These cells have an undifferentiated phenotype (Thy1 – CD34 + CD38 – , and negative for other differentiation markers) and resemble normal stem cells in many ways, but are no longer under homeostatic control (Fig. 80-7). Solid tumors may also contain a population of stem cells. Cancer stem cells, like their normal counterparts, have unlimited proliferative capacity and paradoxically traverse the cell cycle at a very slow rate; cancer growth occurs largely due to expansion of the stem cell pool, the unregulated proliferation of the transit amplifying population, and failure of apoptosis pathways (Fig. 80-7). Slow cell cycle progression, plus high levels of expression of anti-apoptotic Bcl-2 family members and drug efflux pumps of the MDR family, render cancer stem cells less vulnerable to cancer chemotherapy or radiation therapy. Implicit in the cancer stem cell hypothesis is the idea that failure to cure most human cancers is due to the fact that current therapeutic agents do not kill the stem cells. If cancer stem cells can be identified and isolated, then aberrant signaling pathways that distinguish these cells from normal tissue stem cells can be identified and targeted. Oncologists eagerly await a new class of agent that may directly attack the cells that drive tumor growth. Figure 80-7 Cancer stem cells play a critic al role in the initiation, progression, and resistance to therapy of malignant neoplasms. In normal tissues (left ), homeostasis is maintained by asymmetric division of stem cells leading to one progeny cell that will differentiate, and one cell that will m aintain the stem cell pool. This occurs within highly specific niches unique to each tissue, such as in close apposition to osteoblasts in bone marrow, or at the base of crypts in the colon. Here, paracrine signals from stromal cells, such as sonic hedgeho g or Notch-ligands, as well as upregulation of β- catenin and telomerase, help to maintain stem cell features of unlimited self- renewal while preventing differentiation or cell death. This occurs in part through upregulation of the transcriptional repressor Bmi-1 and inhibition of the p16 Ink4a /Arf and p53 pathways. Daughter cells leave the stem cells niche and enter a proliferative phase (referred to as transit-amplifying cells ) for a specified number of cell divisions, during which time a developmental prog ram is activated, eventually giving rise to fully differentiated cells that have lost proliferative potential. Cell renewal equals cell death and homeostasis is maintained. In this hierarchal system, only stem cells are long-lived. Recent evidence has led to the hypothesis that cancers harbor stem cells that make up a small fraction (i.e., 0.001– 1%) of all cancer cells. These cells share several features with normal stem cells, including an undifferentiated phenotype, unlimited self-renewal potential, a cap acity for some degree of differentiation; however, due to initiating mutations (mutations are indicated by lightning bolts), they are no longer regulated by environmental cues. The cancer stem cell pool is expanded, and rapidly proliferating progeny, throu gh additional mutations, may attain stem cell properties, although most of this population is thought to have a limited proliferative capacity. Differentiation programs are dysfunctional due to reprogramming of the pattern of gene transcription by oncogenic signaling pathways. Within the cancer transit- amplifying population, genomic instability generates aneuploidy and clonal heterogeneity as cells attain a fully malignant phenotype with metastatic potential. The cancer stem cell hypothesis has led to the id ea that current cancer therapies may be effective at killing the bulk of tumor cells, but do not kill tumor stem cells, leading to a regrowth of tumors that is manifested as tumor recurrence or disease progression. Research is in progress to identify uniqu e molecular features of cancer stem cells that can lead to their direct targeting by novel therapeutic agents. . Chapter 080. Cancer Cell Biology and Angiogenesis (Part 13) New Concepts in the Development of Cancer Therapeutics Cancer Stem Cells It has long been recognized. population of stem cells. Cancer stem cells, like their normal counterparts, have unlimited proliferative capacity and paradoxically traverse the cell cycle at a very slow rate; cancer growth occurs. Bcl-2 family members and drug efflux pumps of the MDR family, render cancer stem cells less vulnerable to cancer chemotherapy or radiation therapy. Implicit in the cancer stem cell hypothesis is