Chapter 080. Cancer Cell Biology and Angiogenesis (Part 4)

Telomerase DNA polymerase is unable to replicate the tips of chromosomes, resulting in the loss of DNA at the specialized ends of chromosomes (called telomeres) with each replication cycle. At birth, human telomeres are 15- to 20-kb pairs long and are composed of tandem repeats of a six-nucleotide sequence (TTAGGG) that associate with specialized telomere-binding proteins to form a T-loop structure that protects the ends of chromosomes from being mistakenly recognized as damaged. The loss of telomeric repeats with each cell division cycle causes gradual telomere shortening, leading to growth arrest (called replicative senescence) when one or more critically...
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Chapter 080. Cancer Cell Biology and Angiogenesis (Part 4) Chapter 080. Cancer Cell Biology and Angiogenesis (Part 4) Telomerase DNA polymerase is unable to replicate the tips of chromosomes, resultingin the loss of DNA at the specialized ends of chromosomes (called telomeres) witheach replication cycle. At birth, human telomeres are 15- to 20-kb pairs long andare composed of tandem repeats of a six-nucleotide sequence (TTAGGG) thatassociate with specialized telomere-binding proteins to form a T-loop structurethat protects the ends of chromosomes from being mistakenly recognized asdamaged. The loss of telomeric repeats with each cell division cycle causesgradual telomere shortening, leading to growth arrest (called replicativesenescence) when one or more critically short telomeres triggers a p53-regulatedDNA-damage checkpoint response. Cells can bypass this growth arrest if pRB andp53 are nonfunctional, but cell death ensues when the unprotected ends ofchromosomes precipitate chromosome fusions or other catastrophic DNArearrangements (termed crisis). The ability to bypass telomere-based growthlimitations is thought to be a critical step in the evolution of most malignancies.This occurs by the reactivation of telomerase expression in cancer cells.Telomerase is an enzyme that adds TTAGGG repeats onto the 3 ends ofchromosomes. It contains a catalytic subunit with reverse transcriptase activity(hTERT) and an RNA component that provides the template for telomereextension. Most normal somatic cells do not express sufficient telomerase toprevent telomere attrition with each cell division. Exceptions include stem cells(such as those found in hematopoietic tissues, gut and skin epithelium, and germcells) that require extensive cell division to maintain tissue homeostasis. Morethan 90% of human cancers express high levels of telomerase that preventtelomere exhaustion and allow indefinite cell proliferation. In vitro experimentsindicate that inhibition of telomerase activity leads to tumor cell apoptosis. Majorefforts are underway to develop methods to inhibit telomerase activity in cancercells. The reverse transcriptase activity of telomerase is a prime target for small-molecule pharmaceuticals. The protein component of telomerase (hTERT) can actas a tumor-associated antigen recognized by antigen-specific cytotoxic Tlymphocytes (CTL) that lyse human melanoma, prostate, lung, breast, and coloncancer cells in vitro. Clinical trials of telomerase vaccines are underway. Signal Transduction Pathways as Therapeutic Targets in Cancer Cells Since the discovery that the v-src oncogene has protein tyrosine kinaseactivity, the central role of tyrosine phosphorylation in cellular responses togrowth factors has become apparent. Many tyrosine kinases act at the apex ofsignaling pathways and are transmembrane proteins (receptor tyrosine kinases,RTK) or are associated with structures at the plasma membrane (Src-, Janus-, andFak-family kinases). RTKs are transmembrane glycoproteins that undergodimerization upon ligand binding, with activation of their cytoplasmic tyrosinekinase domains by proximity-induced trans-phosphorylation of the activation loop.Tyrosine residues of the receptor or adaptor proteins (such as IRS-1 or Shc) arephosphorylated and act as docking sites for proteins containing SH2 (Src-homology 2) or PTB (phosphotyrosine binding) domains, thus initiating multiplesignal transduction pathways (Fig. 80-2). Normally, tyrosine kinase activity isshort-lived and reversed by protein tyrosine phosphatases (PTP). However, inmany human cancers, tyrosine kinases or components of their downstreampathways are activated by mutation, gene amplification, or chromosomaltranslocations. Because these pathways regulate proliferation, survival, migration,and angiogenesis, they have been identified as important targets for cancertherapeutics. Figure 80-2 Therapeutic targeting of signal transduction pathways in cancer cells.Three major signal transduction pathways are activated by receptor tyrosinekinases (RTK). 1. The protooncogene Ras is activated by the Grb2/mSOS guaninenucleotide exchange factor, which induces an association with Raf and activationof downstream kinases (MEK and ERK1/2). 2. Activated PI3K phosphorylates themembrane lipid PIP2 to generate PIP3, which acts as a membrane-docking site fora number of cellular proteins including the serine/threonine kinases PDK1 andAkt. PDK1 has numerous cellular targets including Akt and mTOR. Aktphosphorylates target proteins that promote resistance to apoptosis and enhancecell cycle progression, while mTOR and its target p70S6K upregulate proteinsynthesis to potentiate cell growth. 3. Activation of PLC-γ leads the formation of ...