Molecular Basis of Cancer

Molecular Basis of Cancer

• Cancer development is a multi-step process involving multiple genetic alterations
• Nonlethal genetic damages (mutations) initiate carcinogenesis
• Mutations may be environmental, inherited, or spontaneous
• A tumor arises from the clonal expansion of a single precursor cell with genetic damage
• Key targets of cancer-causing mutations include growth-promoting proto-oncogenes, growth-inhibiting tumor suppressor genes, apoptosis regulators, and DNA repair genes
• Cancer progression involves stepwise acquisition of complementary mutations
• Eight fundamental changes in cell physiology define cancer hallmarks

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 Damage Agents

• Chemicals
• Radiation
• Viruses

Normal Cell Cycle

• The cell cycle progression is tightly regulated by cyclins and cyclin-dependent kinases (CDKs), and their inhibitors
• Checkpoints at G1/S and G2/M transitions monitor DNA damage and ensure proper progression
• The G1/S checkpoint prevents replication of cells with DNA damage, ensuring accurate copying is performed
• The G2/M checkpoint prevents cell division if DNA is damaged or incompletely replicated

Cell Cycle Checkpoints

• The cell cycle has internal controls called checkpoints at G1/S and G2/M transitions
• DNA damage sensors, signal transducers and effector molecules are required for proper checkpoint function

G1/S Checkpoint

• The S phase is the point of no return in the cell cycle, where cells commit to DNA replication
• A G1/S checkpoint checks for DNA damage before proceeding
• If DNA damage is detected, DNA repair mechanisms are activated. If repair fails, apoptosis is triggered
• DNA damage that arises after replication can also be repaired as long as chromatids haven't separated

Oncogenes and Proto-oncogenes

• Oncogenes promote autonomous cell growth in cancer
• Proto-oncogenes are their normal counterparts that encode proteins for normal cell function
• Mutations or overexpression of proto-oncogenes leads to oncogenic forms which are constitutively active, driving cell growth independently of external cues

Functional Category of Oncogenes

• Growth factors
• Growth factor receptors
• proteins involved in signal transduction
• Nuclear regulatory proteins
• Cell cycle regulators

Downstream Components of Receptor Tyrosine Kinase Pathway

• RAS mutations are common events in human cancers
• RAS proteins are involved in signal transduction pathways
• Mutant RAS proteins lose their ability to hydrolyze GTP, causing constitutive activation and downstream signaling

Oncogenic BRAF and PI3K Mutations

• BRAF and PI3K are serine/threonine protein kinases involved in signal pathways
• Mutations in these genes either increase an enzyme's activity leading to uncontrolled signal activation, or inactivate inhibitory proteins

Alterations in Nonreceptor Tyrosine Kinases

• ABL (nonreceptor tyrosine kinase) translocations frequently occur in leukemias
• The resultant chimeric BCR-ABL gene encodes for constitutively active oncogenic tyrosine kinase

Transcription Factors

• Signal transduction pathways converge on the nucleus, where expression of target genes take place
• Transcription factors, such as MYC, MYB, JUN, FOS, and REL proto-oncogenes, play essential roles in regulating gene expression
• MYC is frequently involved in human tumors

Oncogenes, Oncoproteins

• MYC is one of the handful of transcription factors that can reprogram somatic cells into pluripotent stem cells
• MYC is commonly mutated in various cancers, resulting in constitutive expression and uncontrolled cell proliferation

Cyclins and CDKs

• Progression of cells through cell cycle is orchestrated by cyclin-dependent kinases(CDKs) activated through binding to cyclins
• Cyclins drive cells forward through the cell cycle by phosphorylating crucial target proteins
• Two major checkpoints exist at G1/S and G2/M transitions, regulated by growth-promoting and suppressing factors

Tumor Suppressor Genes

• Tumor suppressor genes apply brakes to cell proliferation
• Abnormalities in these genes lead to uncontrolled growth
• Tumor suppressor proteins function as check points, preventing uncontrolled growth

TP53: Guardian of the Genome

• TP53 is a tumor suppressor gene that regulates cell cycle progression, DNA repair, senescence, and apoptosis
• Loss-of-function mutations in TP53 are found in more than 50% of cancers
• TP53 encodes for the protein p53 that is tightly regulated on several levels
• MDM2 and related proteins are frequently overexpressed in malignancies with normal TP53 alleles
• p53 activation is stimulated by DNA damage and hypoxia, prompting either cell-cycle arrest, senescence or apoptosis

APC: Gatekeeper of Colonic Neoplasia

• APC is a tumor suppressor gene that downregulates growth-promoting signaling pathways
• Mutations in APC are associated with familial adenomatous polyposis, leading to an increased risk of colorectal cancer