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The oncogene was the first chromosomal abnormality shown to be associated with a specific human malignancy, the chronic myelogenous leukemia (CML), resulting from a reciprocal t(9;22) translocation characterized by the formation of a shortened chromosome, named Philadelphia chromosome (Ph), in which the tyrosine kinase of c-ABL is constitutively activated. This chromosomal translocation generates fusion genes which can be translated in three different oncoproteins, p210, p190, and p230, associated with three different pathologies in humans, CML, acute lymphoblastic leukemia (ALL), and chronic neutrophilic leukemia, respectively. The molecular mechanisms and downstream pathways of are poorly understood mainly as a result of the lack of a good in vivo model that mimics the human disease. Nevertheless, additional in vitro and in vivo models have led to the design of several novel therapeutic approaches. That is the case of Imatinib mesylate (Gleevec, STI571; Novartis Pharma AG), a drug targeting the tyrosine kinase activity of and an effective therapy for chronic phase CML but not advanced stages of CML and patients with Ph ALL. The resistance mutations in the kinase domain of together with the stem cell origin of the chromosomal translocation and the inability of the imatinib to inhibit the activity in these cells have revealed the limitations of Gleevec, providing new lessons for the development of alternative therapies in oncology.

Angiogenesis, the creation of neovasculatures from pre-existing ones, is required for various physiological processes. However, pathological angiogenesis is a hallmark of malignant tumors, metastasis and various ischemic as well as inflammatory disorders. Angiogenesis is regulated by the balance between proangiogenic factors and antiangiogenic factors, and concentrated effort in this area of research has led to the discovery of a growing number of angiogenesis-associated factors and the complex interactions among these factors. Understanding of the regulatory mechanisms of these factors in mediating the angiogenic process involved in tumor growth prompted the application of antiangiogenic factors on experimental tumor models with successful outcomes. Based on these experimental results, some antiangiogenic agents have been tested in clinical trials. In this review, the process and regulators of angiogenesis, the involvement of angiogenesis in cancer development and the application of antiangiogenic therapies on established tumors would be discussed. Among various antiangiogenic reagents, special emphasis will be given to antiangiogenic reagents derived from vascular basement membranes, a crucial regulator of angiogenesis, rather than a structural tissue component.

Metastasis, the spread of tumor cells from the primary site of growth to a secondary site, is the leading cause of cancer related deaths. The process of metastasis can be conceptually broken down into a series of sequential steps: acquisition of an invasive phenotype, intravasation, travel through the circulatory system, arrest at a secondary site, and extravasation and colonization at that site. The metastatic cell must be able to escape cell death at several steps in this process. Thus, it is not surprising that metastatic cells can be molecularly characterized by altered expression of several apoptosis genes and altered signaling through cell survival and death pathways. In addition, this same acquired resistance to cell death that has allowed metastatic cells to survive and colonize in a secondary organ has also permitted resistance to courses of chemotherapy. Herein, we describe the aberrant apoptotic signaling that metastatic cells have evolved, how this aberrant signaling impedes traditional chemotherapeutic approaches that induce cell death, and potential therapeutic approaches to overcome apoptotic resistance of metastasis.

Numerous molecules and pathways have been identified that control various aspects of apoptosis and survival signaling. A dynamic balance between these opposing activities is required to finetune biological systems under both normal and stressed conditions. In this chapter, pathways leading to apoptosis are briefly summarized. This is followed by a discussion of various survival pathways that are activated by both prosurvival and proapoptotic stimuli. Finally, a model depicting the simultaneous engagement of both pro-survival and pro-death pathways by stress signals is presented.

Mutations in gene products controlling DNA damage checkpoints and repair pathways cause predisposition to a large number of sporadic cancers, hereditary cancer syndromes, and developmental defects. This underscores the vital need for the fidelity of checkpoint control and efficiency for the repair machineries. The checkpoint functions are ensured by multiple, often parallel, pathways and show specificity regarding the nature of the damage, cell-cycle phase, and the subsequent cellular response. The checkpoint control mechanisms also link to other cellular responses such as apoptosis to initiate a death program in the event of unsuccesful repair. It is striking that several checkpoint mutations are associated with developmental abnormalities and cancer syndromes, such as the Nijmegen breakage syndrome and Fanconi anemia, indicating that the maintenance of the genome integrity is essential throughout development. Though several critical DNA maintenance proteins have been identified and their links to tumor progression have been established, alterations of several known checkpoint-associated proteins (e.g., 53BP1, Mdc1, SMC1) in cancer are still undiscovered. Knowledge of the DNA damage checkpoint pathways and pathways sensing the damage and instigating repair will pave the way to improved diagnostics, identification of genetic susceptibility, and, in future, rational therapy of cancer.

Deregulated expression of is present in most, if not all, human cancers and is associated with a poor prognosis. The proto-oncogene is essential for both cellular growth and proliferation, but paradoxically may also promote cell death. The study of this “dual potential” of c-Myc over the past two decades has provided a paradigm for exploring the role of other mitogenic proteins, such as E2F, many of which have now also been shown to have such intrinsic “tumor suppressor” properties. In fact, it may be a general feature of proteins that promote cell cycle that the oncogenic potential of deregulated expression is restrained by concurrent activation of processes, such as apoptosis or senescence, which effectively prevent propagation of the “damaged” cell. By implication, these in-built “failsafe” mechanisms must be overcome during tumorigenesis. However, once prevented, for instance by inactivation of the p53 or Rb pathways or upregulation of antiapoptotic proteins, the potentially devastating oncogenic potential of proteins such as c-Myc is unmasked. It is also likely that highly conserved proteins such as c-Myc, situated upstream of signaling pathways regulating both cellular replication/growth on the one hand and apoptosis/growth arrest, act as key integrators of processes determining cell numbers and tissue size during normal development and adult tissue homeostasis. Therefore, maybe not surprisingly, c-Myc may also contribute to disease by way of stimulating apoptotic pathways, the very process that also restrains their oncogenic potential; an expanding body of recent evidence implicates c-Myc as a contributor to the death of insulin-secreting β-cells in diabetes.

Lysophospholipids are not only metabolites in membrane phospholipid synthesis, but also extracellular bioactive mediators of multiple biological processes. The best characterized of these are lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), which have both emerged as important regulators of cell growth and survival. Identification of LPA and S1P receptors in the past several years has led to the accumulation of evidence that most cellular responses to LPA and S1P are mediated through activation of their cognate G protein-coupled receptors (GPCR). There are at least three high-affinity receptors for LPA—named LPA, LPA and LPA—and five receptor subtypes for S1P, designated S1P. The widespread expression of these receptors and their downstream G proteins of various classes allow activation of a variety of signal transduction pathways that are integrated to trigger diverse cellular responses to LPA or S1P.

βGBP is an antiproliferative cytokine produced by activated T-cells and endogenously released by somatic cells. In normal cells, βGBP negatively regulates the cell cycle; in cancer cells βGBP induces apoptosis. Mechanisms of action involve downregulation of PI3 kinase via p110 targeting. Downregulation of PI3 kinase by βGBP reflects on Ras-ERK signaling and Akt mediated signaling resulting in the delay of S/G2 transition in normal cells and activation of programmed cell death in cancer cells. The apoptotic response of cancer cells to βGBP takes place according to the molecular context of the cells. Where βGBP induces cell-cycle arrest, apoptosis relates to E2F-1 deregulation. In cancer cells characterized by strong mitogenic input and elevated Akt/PKB expression, loss of Akt protein deprives the cells of survival signaling. βGBP is an immunomolecule which can perform therapeutically what the native, endogenous protein would naturally perform in a surveillance role.

Depending on the nature of extracellular stimuli and the ensuing intracellular signal transduction pathways, certain transcription factors are activated and subsequently determine the extent of expression of genes involved in cell proliferation, survival, and death. These factors are referred to as transcriptional control nodes because they permit the coordination of cell-cycle progression and the apoptosis program. This coordination is made possible by the existence of feedback loops in the regulatory networks of the entire system. A review of these networks for the following transcription factors is provided in this chapter: E2F, Myc, p53, and NF-κB.

Nuclear factor-κB (NF-κB) is a family of transcription factors instrumental in a variety of physiological as well as pathophysiological conditions. Aberrant activation of NF-κB is responsible for the overexpression of different genes resulting in unregulated cell proliferation, survival, angiogenesis, cell adhesion, migration, and invasion that had been linked to cancer metastasis. Because the constitutively activated NF-κB had been demonstrated in a wide variety of cancers, its inhibition is a natural target for the development of new anticancer drugs. The activity of NF-κB is regulated by proteasome degradation, phosphorylation of NF-κB, and acetylation/deacetylation of histones. Therefore, compounds specifically suppressing proteasome activity, activities of kinases responsible for the phosphorylation of p65 subunit of NF-κB, and acetylation/deacetylation associated with NF-κB activation may be effective in the treatment in a wide variety of cancers.