Cancer 2nd Ed.

Chapter 1 The Biology and Genetics of Cells and Organisms

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

Chapter 2 The Nature of Cancer

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

Chapter 3 Tumor Viruses

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

Chapter 4 Cellular Oncogenes

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

Chapter 5 Growth Factors, Receptors, and Cancer

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

Chapter 6 Cytoplasmic Signaling Circuitry Programs Many of the Traits of Cancer

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

Chapter 7 Tumor Suppressor Genes

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

Chapter 8 pRb and Control of the Cell Cycle Clock

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

Chapter 9 p53 and Apoptosis: Master Guardian and Executioner

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

Chapter 10 Eternal Life: Cell Immortalization and Tumorigenesis

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

Chapter 11 Multi-Step Tumorigenesis

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

Chapter 12 Maintenance of Genomic Integrity and the Development of Cancer

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

Chapter 13 Dialogue Replaces Monologue: Heterotypic Interactions and the Biology of Angiogenesis

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

Chapter 14 Moving Out: Invasion and Metastasis

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

Chapter 15 Crowd Control: Tumor Immunology and Immunotherapy

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

Chapter 16 The Rational Treatment of Cancer

• 16.1 The development and clinical use of effective therapies will depend on accurate diagnosis of di
• 16.2 Surgery, radiotherapy, and chemotherapy are the major pillars on which current cancer therapies
• 16.3 Differentiation, apoptosis, and cell cycle checkpoints can be exploited to kill cancer cells
• 16.4 Functional considerations dictate that only a subset of the defective proteins in cancer cells are attractive targets for drug development
• 16.5 The biochemistry of proteins also determines whether they are attractive targets for interventi
• 16.6 Pharmaceutical chemists can generate and explore the biochemical properties of a wide array of potential drugs
• 16.7 Drug candidates must be tested on cell models as an initial measurement of their utility in whole organisms
• 16.8 Studies of a drug’s action in laboratory animals are an essential part of pre-clinical testin
• 16.9 Promising candidate drugs are subjected to rigorous clinical tests in Phase I trials in humans
• 16.10 Phase II and III trials provide credible indications of clinical efficacy
• 16.11 Tumors often develop resistance to initially effective therapy
• 16.12 Gleevec paved the way for the development of many other highly targeted compounds
• 16.13 EGF receptor antagonists may be useful for treating a wide variety of tumor types
• 16.14 Proteasome inhibitors yield unexpected therapeutic benefit
• 16.15 A sheep teratogen may be useful as a highly potent anti-cancer drug
• 16.16 mTOR, a master regulator of cell physiology, represents an attractive target for anti-cancer t
• 16.17 B-Raf discoveries have led to inroads into the melanoma problem
• 16.18 Synopsis and prospects: challenges and opportunities on the road ahead