The biology of cancer

Robert Allan Weinberg. The biology of cancer. Second edition. Garland Science, Taylor & Francis Group, 2014

Weinberg The Biology of Cancer 2nd c2014 - ОБЛОЖКА

Chapter 1: The biology and genetics of cells and organisms »

  • Mendel establishes the basic rules of genetics
  • Mendelian genetics helps to explain Darwinian evolution
  • Mendelian genetics governs how both genes and chromosomes behave
  • Chromosomes are altered in most types of cancer cells
  • Mutations causing cancer occur in both the germ line and the soma
  • Genotype embodied in DNA sequences creates phenotype through proteins
  • Gene expression patterns also control phenotype
  • Histone modification and transcription factors control gene expression
  • Heritable gene expression is controlled through additional mechanisms
  • Unconventional RNA molecules also affect the expression of genes
  • Metazoa are formed from components conserved over vast evolutionary time periods
  • Gene cloning techniques revolutionized the study of normal and malignant cells

Chapter 2: The nature of cancer »

  • Tumors arise from normal tissues
  • Tumors arise from many specialized cell types throughout the body
  • Some types of tumors do not fit into the major classifications
  • Cancers seem to develop progressively
  • Tumors are monoclonal growths
  • Cancer cells exhibit an altered energy metabolism
  • Cancers occur with vastly different frequencies in different human populations
  • The risks of cancers often seem to be increased by assignable influences including lifestyle
  • Specific chemical agents can induce cancer
  • Both physical and chemical carcinogens act as mutagens
  • Mutagens may be responsible for some human cancers
  • Synopsis and prospects
  • Key concepts

Chapter 3: Tumor viruses »

  • Peyton Rous discovers a chicken sarcoma virus
  • Rous sarcoma virus is discovered to transform infected cells in culture
  • The continued presence of RSV is needed to maintain transformation
  • Viruses containing DNA molecules are also able to induce cancer
  • Tumor viruses induce multiple changes in cell phenotype including acquisition of tumorigenicity
  • Tumor virus genomes persist in virus-transformed cells by becoming part of host-cell DNA
  • Retroviral genomes become integrated into the chromosomes of infected cells
  • A version of the src gene carried by RSV is also present in uninfected cells
  • RSV exploits a kidnapped cellular gene to transform cells
  • The vertebrate genome carries a large group of proto-oncogenes
  • Slowly transforming retroviruses activate proto-oncogenes by inserting their genomes adjacent to these cellular genes
  • Some retroviruses naturally carry oncogenes
  • Synopsis and prospects
  • Key concepts

Chapter 4: Cellular oncogenes »

  • Can cancers be triggered by the activation of endogenous retroviruses?
  • Transfection of DNA provides a strategy for detecting nonviral oncogenes
  • Oncogenes discovered in human tumor cell lines are related to those carried by transforming retroviruses
  • Proto-oncogenes can be activated by genetic changes affecting either protein expression or structure
  • Variations on a theme: the myc oncogene can arise via at least three additional distinct mechanisms
  • A diverse array of structural changes in proteins can also lead to oncogene activation
  • Synopsis and prospects
  • Key concepts

Chapter 5: Growth factors, receptors, and cancer »

  • Normal metazoan cells control each other’s lives
  • The Src protein functions as a tyrosine kinase
  • The EGF receptor functions as a tyrosine kinase
  • An altered growth factor receptor can function as an oncoprotein
  • A growth factor gene can become an oncogene: the case of sis
  • Transphosphorylation underlies the operations of receptor tyrosine kinases
  • Yet other types of receptors enable mammalian cells to communicate with their environment
  • Nuclear receptors sense the presence of low–molecular–weight lipophilic ligands
  • Integrin receptors sense association between the cell and the extracellular matrix
  • The Ras protein, an apparent component of the downstream signaling cascade, functions as a G protein
  • Synopsis and prospects
  • Key concepts

Chapter 6: Cytoplasmic signaling circuitry programs »

  • Many of the traits of cancer
  • A signaling pathway reaches from the cell surface into the nucleus
  • The Ras protein stands in the middle of a complex signaling cascade
  • Tyrosine phosphorylation controls the location and thereby the actions of many cytoplasmic signaling proteins
  • SH2 and SH3 groups explain how growth factor receptors activate Ras and acquire signaling specificity
  • Ras-regulated signaling pathways: A cascade of kinases forms one of three important signaling pathways downstream of Ras
  • Ras-regulated signaling pathways: a second downstream pathway controls inositol lipids and the Akt/PKB kinase
  • Ras-regulated signaling pathways: a third downstream pathway acts through Ral, a distant cousin of Ras
  • The Jak–STAT pathway allows signals to be transmitted from the plasma membrane directly to the nucleus
  • Cell adhesion receptors emit signals that converge with those released by growth factor receptors
  • The Wnt-β-catenin pathway contributes to cell proliferation
  • G-protein–coupled receptors can also drive normal and neoplastic proliferation
  • Four additional “dual-address” signaling pathways contribute in various ways to normal and neoplastic proliferation
  • Well-designed signaling circuits require both negative and positive feedback controls
  • Synopsis and prospects
  • Key concepts

Chapter 7: Tumor suppressor genes »

  • Cell fusion experiments indicate that the cancer phenotype is recessive
  • The recessive nature of the cancer cell phenotype requires a genetic explanation
  • The retinoblastoma tumor provides a solution to the genetic puzzle of tumor suppressor genes
  • Incipient cancer cells invent ways to eliminate wildtype copies of tumor suppressor genes
  • The Rb gene often undergoes loss of heterozygosity in tumors
  • Loss-of-heterozygosity events can be used to find tumor suppressor genes
  • Many familial cancers can be explained by inheritance of mutant tumor suppressor genes
  • Promoter methylation represents an important mechanism for inactivating tumor suppressor genes
  • Tumor suppressor genes and proteins function in diverse ways
  • The NF1 protein acts as a negative regulator of Ras signaling
  • Apc facilitates egress of cells from colonic crypts
  • Von Hippel–Lindau disease: pVHL modulates the hypoxic response
  • Synopsis and prospects
  • Key concepts

Chapter 8: pRb and control of the cell cycle clock »

  • Cell growth and division is coordinated by a complex array of regulators
  • Cells make decisions about growth and quiescence during a specific period in the G1 phase
  • Cyclins and cyclin-dependent kinases constitute the core components of the cell cycle clock
  • Cyclin–CDK complexes are also regulated by CDK inhibitors
  • Viral oncoproteins reveal how pRb blocks advance through the cell cycle
  • pRb is deployed by the cell cycle clock to serve as a guardian of the restriction-point gate
  • E2F transcription factors enable pRb to implement growth-versus-quiescence decisions
  • A variety of mitogenic signaling pathways control the phosphorylation state of pRb
  • The Myc protein governs decisions to proliferate or differentiate
  • TGF-β prevents phosphorylation of pRb and thereby blocks cell cycle progression
  • pRb function and the controls of differentiation are closely linked
  • Control of pRb function is perturbed in most if not all human cancers
  • Synopsis and prospects
  • Key concepts

Chapter 9: p53 and apoptosis: master guardian and executioner »

  • Papovaviruses lead to the discovery p53
  • p53 is discovered to be a tumor suppressor gene
  • Mutant versions of p53 interfere with normal function
  • p53 protein molecules usually have short lifetimes
  • A variety of signals cause p53 induction
  • DNA damage and deregulated growth signals cause p53 stabilization
  • Mdm2 destroys its own creator
  • ARF and p53-mediated apoptosis protect against cancer by monitoring intracellular signaling
  • p53 functions as a transcription factor that halts cell cycle advance in response to DNA damage and attempts to aid in the repair process
  • p53 often ushers in the apoptotic death program
  • p53 inactivation provides advantage to incipient cancer cells at a number of steps in tumor progression
  • Inherited mutant alleles affecting the p53 pathway predispose one to a variety of tumors
  • Apoptosis is a complex program that often depends on mitochondria
  • Both intrinsic and extrinsic apoptotic programs can lead to cell death
  • Cancer cells invent numerous ways to inactivate some or all of the apoptotic machinery
  • Necrosis and autophagy: two additional forks in the road of tumor progression
  • Synopsis and prospects
  • Key concepts

Chapter 10: Eternal life: cell immortalization and tumorigenesis »

  • Normal cell populations register the number of cell generations separating them from their ancestors in the early embryo
  • Cancer cells need to become immortal in order to form tumors
  • Cell-physiologic stresses impose a limitation on replication
  • The proliferation of cultured cells is also limited by the telomeres of their chromosomes
  • Telomeres are complex molecular structures that are not easily replicated
  • Incipient cancer cells can escape crisis by expressing telomerase
  • Telomerase plays a key role in the proliferation of human cancer cells
  • Some immortalized cells can maintain telomeres without telomerase
  • Telomeres play different roles in the cells of laboratory mice and in human cells
  • Telomerase-negative mice show both decreased and increased cancer susceptibility
  • The mechanisms underlying cancer pathogenesis in telomerase-negative mice may also operate during the development of human tumors
  • Synopsis and prospects
  • Key concepts

Chapter 11: Multi-step tumorigenesis »

  • Most human cancers develop over many decades of time
  • Histopathology provides evidence of multi-step tumor formation
  • Cells accumulate genetic and epigenetic alterations as tumor progression proceeds
  • Multi-step tumor progression helps to explain familial polyposis and field cancerization =
  • Cancer development seems to follow the rules of Darwinian evolution
  • Tumor stem cells further complicate the Darwinian model of clonal succession and tumor progression
  • A linear path of clonal succession oversimplifies the reality of cancer: intra-tumor heterogeneity
  • The Darwinian model of tumor development is difficult to validate experimentally
  • Multiple lines of evidence reveal that normal cells are resistant to transformation by a single mutated gene
  • Transformation usually requires collaboration between two or more mutant genes
  • Transgenic mice provide models of oncogene collaboration and multi-step cell transformation
  • Human cells are constructed to be highly resistant to immortalization and transformation
  • Nonmutagenic agents, including those favoring cell proliferation, make important contributions to tumorigenesis
  • Toxic and mitogenic agents can act as human tumor promoters
  • Chronic inflammation often serves to promote tumor progression in mice and humans
  • Inflammation-dependent tumor promotion operates through defined signaling pathways
  • Tumor promotion is likely to be a critical determinant of the rate of tumor progression in many human tissues
  • Synopsis and prospects
  • Key concepts

Chapter 12: Maintenance of genomic integrity and the development of cancer »

  • Tissues are organized to minimize the progressive accumulation of mutations
  • Stem cells may or may not be targets of the mutagenesis that leads to cancer
  • Apoptosis, drug pumps, and DNA replication mechanisms offer tissues a way to minimize the accumulation of mutant stem cells
  • Cell genomes are threatened by errors made during DNA replication
  • Cell genomes are under constant attack from endogenous biochemical processes
  • Cell genomes are under occasional attack from exogenous mutagens and their metabolites
  • Cells deploy a variety of defenses to protect DNA molecules from attack by mutagens
  • Repair enzymes fix DNA that has been altered by mutagens
  • Inherited defects in nucleotide-excision repair, base-excision repair, and mismatch repair lead to specific cancer susceptibility syndromes
  • A variety of other DNA repair defects confer increased cancer susceptibility through poorly understood mechanisms
  • The karyotype of cancer cells is often changed through alterations in chromosome structure
  • The karyotype of cancer cells is often changed through alterations in chromosome number
  • Synopsis and prospects
  • Key concepts

Chapter 13 Dialogue replaces monologue: heterotypic interactions and the biology of angiogenesis »

  • Normal and neoplastic epithelial tissues are formed from interdependent cell types
  • The cells forming cancer cell lines develop without heterotypic interactions and deviate from the behavior of cells within human tumors
  • Tumors resemble wounded tissues that do not heal
  • Experiments directly demonstrate that stromal cells are active contributors to tumorigenesis
  • Macrophages and myeloid cells play important roles in activating the tumor-associated stroma
  • Endothelial cells and the vessels that they form ensure tumors adequate access to the circulation
  • Tripping the angiogenic switch is essential for tumor expansion
  • The angiogenic switch initiates a highly complex process
  • Angiogenesis is normally suppressed by physiologic inhibitors
  • Anti-angiogenesis therapies can be employed to treat cancer
  • Synopsis and prospects
  • Key concepts

Chapter 14: Moving out: invasion and metastasis »

  • Travel of cancer cells from a primary tumor to a site of potential metastasis depends on a series of complex biological steps
  • Colonization represents the most complex and challenging step of the invasion–metastasis cascade
  • The epithelial–mesenchymal transition and associated loss of E-cadherin expression enable carcinoma cells to become invasive
  • Epithelial–mesenchymal transitions are often induced by contextual signals
  • Stromal cells contribute to the induction of invasiveness
  • EMTs are programmed by transcription factors that orchestrate key steps of embryogenesis
  • EMT-inducing transcription factors also enable entrance into the stem cell state
  • EMT-inducing TFs help drive malignant progression
  • Extracellular proteases play key roles in invasiveness
  • Small Ras-like GTPases control cellular processes such as adhesion, cell shape, and cell motility
  • Metastasizing cells can use lymphatic vessels to disperse from the primary tumor
  • A variety of factors govern the organ sites in which disseminated cancer cells form metastases
  • Metastasis to bone requires the subversion of osteoblasts and osteoclasts
  • Metastasis suppressor genes contribute to regulating the metastatic phenotype
  • Occult micrometastases threaten the long-term survival of cancer patients
  • Synopsis and prospects
  • Key concepts

Chapter 15: Crowd control: tumor immunology and immunotherapy »

  • The immune system functions to destroy foreign invaders and abnormal cells in the body’s tissues
  • The adaptive immune response leads to antibody production
  • Another adaptive immune response leads to the formation of cytotoxic cells
  • The innate immune response does not require prior sensitization
  • The need to distinguish self from non-self results in immune tolerance
  • Regulatory T cells are able to suppress major components of the adaptive immune response
  • The immunosurveillance theory is born and then suffers major setbacks
  • Use of genetically altered mice leads to a resurrection of the immunosurveillance theory
  • The human immune system plays a critical role in warding off various types of human cancer
  • Subtle differences between normal and neoplastic tissues may allow the immune system to distinguish between them
  • Tumor transplantation antigens often provoke potent immune responses
  • Tumor-associated transplantation antigens may also evoke anti-tumor immunity
  • Cancer cells can evade immune detection by suppressing cell-surface display of tumor antigens
  • Cancer cells protect themselves from destruction by NK cells and macrophages
  • Tumor cells launch counterattacks on immunocytes
  • Cancer cells become intrinsically resistant to various forms of killing used by the immune system
  • Cancer cells attract regulatory T cells to fend off attacks by other lymphocytes
  • Passive immunization with monoclonal antibodies can be used to kill breast cancer cells
  • Passive immunization with antibody can also be used to treat B-cell tumors
  • Transfer of foreign immunocytes can lead to cures of certain hematopoietic malignancies
  • Patients’ immune systems can be mobilized to attack their tumors
  • Synopsis and prospects
  • Key concepts

Chapter 16: The rational treatment of cancer »

  • The development and clinical use of effective therapies will depend on accurate diagnosis of disease
  • Surgery, radiotherapy, and chemotherapy are the major pillars on which current cancer therapies rest
  • Differentiation, apoptosis, and cell cycle checkpoints can be exploited to kill cancer cells
  • Functional considerations dictate that only a subset of the defective proteins in cancer cells are attractive targets for drug development
  • The biochemistry of proteins also determines whether they are attractive targets for intervention
  • Pharmaceutical chemists can generate and explore the biochemical properties of a wide array of potential drugs
  • Drug candidates must be tested on cell models as an initial measurement of their utility in whole organisms
  • Studies of a drug’s action in laboratory animals are an essential part of pre-clinical testing
  • Promising candidate drugs are subjected to rigorous clinical tests in Phase I trials in humans
  • Phase II and III trials provide credible indications of clinical efficacy
  • Tumors often develop resistance to initially effective therapy
  • Gleevec paved the way for the development of many other highly targeted compounds
  • EGF receptor antagonists may be useful for treating a wide variety of tumor types
  • Proteasome inhibitors yield unexpected therapeutic benefit
  • A sheep teratogen may be useful as a highly potent anti-cancer drug
  • mTOR, a master regulator of cell physiology, represents an attractive target for anti-cancer therapy
  • B-Raf discoveries have led to inroads into the melanoma problem
  • Synopsis and prospects: challenges and opportunities on the road ahead
  • Key concepts

 

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