Table of Contents
Preface
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 Transcription factors control gene expression
1.9 Metazoa are formed from components conserved over vast evolutionary time periods
1.10 Gene cloning techniques revolutionized the study of normal and malignant cells
Chapter 2 The Nature of Cancer
2.1 Tumors are complex 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 Cancers occur with vastly different frequencies in different human populations
2.7 The risks of cancers often seem to be increased by assignable influences including lifestyle
2.8 Specific chemical agents can induce cancer
2.9 Both physical and chemical carcinogens act as mutagens
2.10 Mutagens may be responsible for some human cancers
2.11 Synopsis and prospects
Essential Concepts
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
Essential Concepts
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 retroviruses
4.4 Proto-oncogenes can be activated by genetic changes affecting either protein expression or structure
4.5 Variations on a theme: the myc oncogene can arise via at least three additional distinct mechanisms
4.6 A diverse array of structural changes in proteins can also lead to oncogene activation
4.7 Synopsis and prospects
Essential Concepts
Additional Reading
Chapter 5 Growth factors and their receptors
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 Integrin receptors sense association between the cell and the extracellular matrix
5.9 The Ras protein, an apparent component of the downstream signaling cascade, functions as a G protein
5.10 Synopsis and Prospects
Essential Concepts
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 groups explain how growth factor receptors activate Ras and acquire signaling specificity
6.5 A cascade of kinases forms one of three important signaling pathways downstream of Ras
6.6 A second pathway downstream of Ras controls inositol lipids and the Akt/PKB kinase
6.7 A third Ras-regulated pathway acts through the 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 receptors
6.10 The Wnt-_-catenin pathway contributes to cell proliferation
6.11 G-protein coupled receptors can also drive normal and neoplastic proliferation
6.12 Four other signaling pathways contribute in different fashions to normal and neoplastic proliferation
6.13 Synopsis and prospects
Essential Concepts
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
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
Essential Concepts
Additional reading
Chapter 8 pRb and Control of the Cell Cycle Clock
8.1 External signals influence a cell's decision to enter into the active cell cycle
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 controls the transition 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 oncoprotein perturbs the decision to phosphorylate pRb and thereby deregulates control of cell cycle progression
8.10 TGF-_ prevents phosphorylation of pRb and thereby blocks cell cycle progression
8.11 pRb function and the process 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
Essential Concepts
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 and ARF battle over the fate of p53
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 progression
9.12 Inherited mutant alleles of p53 predispose one to a variety of tumors
9.13 Apoptosis is a complex program that often depends on mitochondria
9.14 Two distinct signaling channels can trigger apoptosis
9.15 Cancer cells invent numerous ways to inactivate some or all of the apoptotic machinery
9.16 Synopsis and Prospects
Essential Concepts
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 ancestors in the early embryo
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 development of human tumors
10.12 Synopsis and Prospects
Essential Concepts
Additional reading
Chapter 11 Multistep tumorigenesis
11.1 Most human cancers develop over many decades of time
11.2 Histopathology provides evidence of multi-step tumor formation
11.3 Colonic growths accumulate genetic alterations as tumor progression proceeds
11.4 Multi-step tumor progression helps to explain familial polyposis
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 progression
11.7 A linear path of clonal succession oversimplifies the reality of cancer
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 mutated gene
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 hyphen 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 many humans tissues
11.18 Synopsis and Prospects
Essential Concepts
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 are the likely targets of the mutagenesis that leads to cancer
12.3 Various strategies 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
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 Stromal cells are active contributors to tumorigenesis
13.5 Macrophages represent important participants in activating the tumor-associated stroma
13.6 Endothelial cells and the vessels that they form ensure tumors adequate access to the circulation
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 Certain anti-angiogenesis therapies hold great promise for treating cancer
13.11 Synopsis and Prospects
Essential Concepts
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 enables carcinoma cells to become invasive
14.4 The epithelial-mesenchymal transition is often induced by stromal signals
14.5 EMTs are programmed by transcription factors that orchestrate key steps of embryogenesis
14.6 Extracellular proteases play key roles in invasiveness
14.7 Small Ras-like GTPases control cellular processes including adhesion, cell shape and cell motility
14.8 Metastasizing cells can use lymphatic vessels to disperse from the primary tumor
14.9 A variety of factors govern the organ sites in which disseminated cancer cells form metastases
14.10 Metastasis to bone requires the subversion of osteoblasts and osteoclasts
14.11 Metastasis suppressor genes contribute to regulating the metastatic phenotype
14.12 Occult micrometastases represent a threat to the long-term survival of cancer patients
14.13 Synopsis and Prospects
Essential Concepts
Additional reading
Chapter 15 Crowd Control: Tumor Immunology and Immunotherapy
15.1 The immune system functions in complex ways to destroy foreign invaders and abnormal cells in the body's tissues
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 distinguish between them
15.11 Immune recognition of tumors may be delayed until relatively late in tumor progression
15.12 Tumor-specific transplantation antigens often provoke a potent immune response
15.13 Tumor-associated transplantation antigens may also evoke anti-tumor immunity
15.14 Cancer cells can evade immune detection by suppressing cell-surface display of tumor antigens
15.15 Cancer cells protect themselves from NK-mediated attack
15.16 Tumor cells launch counterattacks on immunocytes
15.17 Cancer cells become intrinsically resistant to various forms of killing used by the immune system
15.18 Cancer cells attract regulatory T cells to fend off attacks by other lymphocytes
15.19 Passive immunization with Herceptin can be used to kill breast cancer cells
15.20 Passive immunization with antibody can be used to treat B-cell tumors
15.21 Passive immunization can be achieved by transfer of immunocytes from one individual to another
15.22 Patients' immune systems can be mobilized to attack their tumors
15.23 Synopsis and prospects
Essential Concepts
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 disease
16.2 Successful anti-cancer drugs can elicit several responses from tumor cells
16.3 Functional considerations dictate that only a subset of the defective proteins in cancer cells are attractive targets for drug development
16.4 The biochemistry of proteins also determines whether they are attractive targets for intervention
16.5 Pharmaceutical chemists can generate and explore the biochemical properties of a wide array of potential drugs
16.6 Drug candidates must be tested on cell models as an initial measurement of their utility in whole organisms
16.7 Studies of a drug's action in laboratory animals are an essential part of preclinical testing
16.8 Promising candidate drugs must be subjected to rigorous and extensive clinical trials in Phase I trials in humans
16.9 Phase II and III trials provide credible indications of clinical efficacy
16.10 Tumors often develop resistance to initially effective therapy
16.11 Gleevec development has paved the way for the development of many other highly targeted compounds
16.12 EGF receptor antagonists may be useful for treating a wide variety of tumor types
16.13 Proteasome inhibitors yield unexpected therapeutic benefit
16.14 A sheep teratogen may be useful as a highly potent anti-cancer drug
16.15 mTOR, a master regulator of cell physiology, represents an attractive target for anticancer therapy
16.16 Synopsis and Prospects: Challenges and opportunities on the road ahead
Essential Concepts
Additional reading
Glossary
Abbreviations/Acronyms