General Cancer Information and Molecular Basis

General Cancer Information

• Cancer develops from nonlethal genetic damage (mutation)
• Environmental exposures, inherited germline mutations, and spontaneous random mutations can cause cancer
• A tumor is formed by the clonal expansion of a single precursor cell with genetic damage
• Tumors are clonal

Molecular Basis of Cancer

• Sustaining proliferative signaling
• Avoiding immune destruction
• Evading growth suppressors
• Enabling replicative immortality
• Deregulating cellular energetics
• Resisting cell death
• Inducing angiogenesis
• Activating invasion and metastasis
• Tumor-promoting inflammation
• Genomic instability (mutator phenotype)

Principal Cancer Targets

• Growth-promoting proto-oncogenes
• Growth-inhibiting tumor suppressor genes
• Genes regulating programmed cell death (apoptosis)
• Genes involved in DNA repair

Cancer Development

• Cancer develops through a stepwise acquisition of complementary mutations
• Accumulation of driver and passenger mutations
• Normal cell
• Carcinogen-induced mutation
• Mutation affecting genomic integrity
• Initiated precursor with stem cell-like properties
• Precursor with mutator phenotype
• Additional driver mutations
• Founding cancer cell
• Additional mutations
• Emergence of subclones
• Acquisition of genomic instability
• Acquisition of cancer hallmarks
• Further genetic evolution
• Genetically heterogeneous cancer
• Diagnosis

Cellular and Molecular Hallmarks of Cancer

• Self-sufficiency in growth signals
• Insensitivity to growth-inhibitory signals
• Altered cellular metabolism
• Evasion of apoptosis
• Limitless replicative potential (immortality)
• Sustained angiogenesis
• Ability to invade and metastasize
• Ability to evade the host immune response

Acquired DNA Damaging Agents

• Chemicals
• Radiation
• Viruses
• Normal cell
• Successful DNA repair
• DNA Damage
• Failure of DNA repair
• Mutations in the genome of somatic cells
• Inherited mutations
• Activation of growth-promoting oncogenes
• Inactivation of tumor suppressor genes
• Unregulated cell proliferation
• Alterations in genes regulating apoptosis
• Decreased apoptosis
• Clonal expansion
• Additional mutations
• Angiogenesis
• Escape from immunity
• Tumor progression
• Malignant neoplasm
• Invasion and metastasis

Normal Cell Cycle

• Molecular regulation of cell cycle is critical in understanding cancer growth
• Progression of cells through phases is orchestrated by cyclins and cyclin-dependent kinases (CDKs) and their inhibitors
• Cell cycle checkpoints ensure accurate progression
• G1/S transition and G2/M checkpoints are essential checkpoints regulating progression

Main Cell-Cycle Components and Inhibitors

• Cyclin-Dependent Kinases (CDKs)
• CDK Inhibitors
• Checkpoint Components

Cell-Cycle Inhibitors

• Activity of cyclin-CDK complexes is tightly regulated by inhibitors
• Two main classes of CDK inhibitors: the Cip/Kip and INK4/ARF families, frequently altered in tumors
• Cip/Kip-p21, p27, p57
• INK4/ARF- p16INK4a, p14ARF

Cell-Cycle Checkpoints

• Cell cycle has internal controls called checkpoints
• Two main checkpoints: One at the G1/S transition and another at the G2/M
• Checkpoints require DNA damage sensors, signal transducers, and effector molecules

G1/S Checkpoint

• S phase is the point of no return in the cell cycle
• Checkpoint checks for DNA damage before committing to replication
• DNA repair is initiated
• Apoptotic pathways are triggered if damage is unrepairable

Normal Cell Cycle Diagrams

• Charts illustrating the different stages of the cell cycle, showing checkpoints, and growth regulation pathways

Functional Category of Oncogenes

• Growth Factors
• Growth Factor Receptors
• Proteins Involved in Signal Transduction
• Nuclear Regulatory Proteins
• Cell-Cycle Regulators

Selected Oncogenes, Their Mode of Activation, and Associated Human Tumors

• Various oncogenes, their proto-oncogenes, mode of activation, and associated human tumors are provided in charts

Oncogenic BRAF and PI3K Mutations

• BRAF is a serine/threonine protein kinase
• Activating BRAF mutations stimulate downstream kinases
• Mutations in BRAF have been detected frequently in certain cancers
• PI3K mutations affect catalytic subunits and increase enzyme activity

Alterations in Nonreceptor Tyrosine Kinases

• Chronic myelogenous leukemia (CML)
• Acute lymphoblastic leukemias(ALL)
• ABL gene translocation from chromosome 9 to chromosome 22, fusing with BCR gene
• BCR-ABL tyrosine kinase results in chronically active oncogenic protein

Transcription Factors

• Signal transduction pathways converge on the nucleus
• Include products of various proto-oncogenes like MYC, MYB,JUN, FOS, and REL, with MYC being commonly involved in human tumors

Oncogenes, Oncoproteins, and Transcription Factors

• MYC is among the most frequently mutated transcription factors in human tumors

Cyclins and Cyclin-Dependent Kinases (CDKs)

• Progression of cells through cell cycle through cyclin-dependent kinases (CDKs)
• CDKs are activated by binding to cyclins
• CDKs-cyclin complexes phosphorylate proteins
• G1/S and G2/M checkpoints are critical
• Regulation by growth-promoting/suppressing factors and DNA damage sensors

Oncogenes, Oncoproteins, and Unregulated Cell Proliferation

• Proto-oncogenes are normal cellular genes that promote cell proliferation
• Oncogenes are mutated/overexpressed proto-oncogenes that act independently of growth promoters
• Oncoproteins are encoded by oncogenes and drive cell proliferation
• Constitutive expression of oncogenes promotes unregulated cell growth (cancer)

Additional Notes

• Multiple mechanisms involved in cancer development and progression
• Mutations, deregulation, alterations in pathways, and gene rearrangements are among the factors
• Multiple types of cancers, their characteristics, and molecular drivers are listed
• Tumors are heterogeneous and have complex pathways leading to them
• Detailed examples of molecular processes behind specific cancers are also provided.
• Charts and diagrams help illustrate the processes and pathway relationships