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

New Concepts in the Development of Cancer TherapeuticsCancer Stem CellsIt 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 (
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Chapter 080. Cancer Cell Biology and Angiogenesis (Part 13) 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 withina tumor are capable of initiating colonies in vitro or of forming tumors at highefficiency when injected into immunocompromised NOD/SCID mice. Currentwork indicates that human acute and chronic myeloid leukemias (AML and CML)have a small population of cells (Solid tumors may also contain a population of stem cells. Cancer stem cells, liketheir normal counterparts, have unlimited proliferative capacity and paradoxicallytraverse the cell cycle at a very slow rate; cancer growth occurs largely due toexpansion of the stem cell pool, the unregulated proliferation of the transitamplifying population, and failure of apoptosis pathways (Fig. 80-7). Slow cellcycle progression, plus high levels of expression of anti-apoptotic Bcl-2 familymembers and drug efflux pumps of the MDR family, render cancer stem cells lessvulnerable to cancer chemotherapy or radiation therapy. Implicit in the cancerstem cell hypothesis is the idea that failure to cure most human cancers is due tothe fact that current therapeutic agents do not kill the stem cells. If cancer stemcells can be identified and isolated, then aberrant signaling pathways thatdistinguish 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 cellsthat drive tumor growth. Figure 80-7 Cancer stem cells play a critical role in the initiation, progression, andresistance to therapy of malignant neoplasms. In normal tissues (left),homeostasis is maintained by asymmetric division of stem cells leading to oneprogeny cell that will differentiate, and one cell that will maintain the stem cellpool. This occurs within highly specific niches unique to each tissue, such as inclose apposition to osteoblasts in bone marrow, or at the base of crypts in thecolon. Here, paracrine signals from stromal cells, such as sonic hedgehog orNotch-ligands, as well as upregulation of β-catenin and telomerase, help tomaintain stem cell features of unlimited self-renewal while preventingdifferentiation or cell death. This occurs in part through upregulation of thetranscriptional repressor Bmi-1 and inhibition of the p16Ink4a/Arf and p53pathways. 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 program is activated, eventually giving rise tofully differentiated cells that have lost proliferative potential. Cell renewal equalscell death and homeostasis is maintained. In this hierarchal system, only stem cellsare long-lived. Recent evidence has led to the hypothesis that cancers harbor stemcells that make up a small fraction (i.e., 0.001–1%) of all cancer cells. These cellsshare several features with normal stem cells, including an undifferentiatedphenotype, unlimited self-renewal potential, a capacity for some degree ofdifferentiation; however, due to initiating mutations (mutations are indicated bylightning bolts), they are no longer regulated by environmental cues. The cancerstem cell pool is expanded, and rapidly proliferating progeny, through additionalmutations, may attain stem cell properties, although most of this population isthought to have a limited proliferative capacity. Differentiation programs aredysfunctional due to reprogramming of the pattern of gene transcription byoncogenic signaling pathways. Within the cancer transit-amplifying population,genomic instability generates aneuploidy and clonal heterogeneity as cells attain afully malignant phenotype with metastatic potential. The cancer stem cellhypothesis has led to the idea that current cancer therapies may be effective atkilling the bulk of tumor cells, but do not kill tumor stem cells, leading to aregrowth of tumors that is manifested as tumor recurrence or disease progression.Research is in progress to identify unique molecular features of cancer stem cellsthat can lead to their direct targeting by novel therapeutic agents.