Molecular Basis of Cancer
Carcinogenesis & Normal Cell Cycle
●​ Cancer develops due to changes in a subset of 20,000 genes, called Cancer Genes.
●​ Carcinogenesis is a multistep process involving genetic mutations.
Cancer Genes
●​ Genes that are frequently altered in cancers and directly contribute to malignant
behavior.
Causes of Mutation
1.​ Chemical exposure
2.​ Radiation
3.​ Viruses
4.​ Spontaneous mutations
5.​ Inherited mutations (germline mutations)
Categories of Cancer Genes
1. Oncogenes
●​ Mutated versions of proto-oncogenes.
●​ Promote increased cell growth → uncontrolled proliferation.
●​ Encode:
○​ Transcription factors
○​ Pro-growth signaling factors
○​ Cell survival factors
●​ Dominant mutations (only one allele needs to be mutated).
2. Tumor Suppressor Genes
●​ Normally act as brakes to prevent uncontrolled growth.
●​ Both alleles must be damaged to contribute to cancer.
●​ Two types:
○​ Governors: Control cellular proliferation.
○​ Guardians: Detect DNA damage & trigger repair or apoptosis.
○​ Example: TP53 (guardian gene)
Genetic Lesions in Cancer
1. Driver Mutations
●​ Directly contribute to cancer development.
●​ Clustered within cancer genes.
2. Passenger Mutations
●​ Neutral mutations, do not affect cancer progression.
●​ Common in cancers caused by carcinogens (e.g., smoking, UV exposure).
3. Tumor Clonality & Progression
●​ Cancer arises from a single mutated cell.
●​ Continues to evolve via Darwinian selection, becoming:
○​ More aggressive
○​ Less responsive to therapy
Genetic Mechanisms of Cancer Development
1. Point Mutations
●​ Activate oncogenes → Uncontrolled growth.
●​ Inactivate tumor suppressor genes → Loss of cell cycle control.
●​ Example: RAS mutation (oncogene activation), TP53 mutation (tumor suppressor
inactivation).
2. Gene Rearrangements
●​ Chromosomal translocations or inversions can:
○​ Overexpress proto-oncogenes (e.g., MYC in Burkitt lymphoma, BCL2 in
follicular lymphoma).
○​ Create chimeric proteins with oncogenic activity (e.g., BCR-ABL in chronic
myeloid leukemia).
3. Deletions
●​ Loss of tumor suppressor genes.
●​ Example: RB gene deletion (retinoblastoma), TP53 deletion (various cancers).
4. Gene Amplifications
●​ Proto-oncogenes become overactive due to excess copies.
●​ Seen as:
○​ Double minutes (extrachromosomal DNA fragments)
○​ Homogeneously staining regions (chromosomal insertions)
●​ Example:
○​ NMYC amplification → Neuroblastoma
○​ HER2 amplification → Breast cancer (targeted by HER2 antibody therapy).
5. Aneuploidy
●​ Abnormal chromosome number due to mitotic errors.
●​ Leads to:
○​ More oncogene copies
○​ Fewer tumor suppressor genes
6. microRNAs & Cancer
●​ OncomiRs (oncogenic microRNAs) suppress tumor suppressor genes.
●​ Example: Loss of miRNAs leads to BCL2 overexpression (anti-apoptotic effect).
7. Epigenetic Modifications
●​ Histone & DNA methylation changes alter gene expression.
●​ Cancer cells show:
○​ Global DNA hypomethylation (genomic instability).
○​ Promoter hypermethylation (silences tumor suppressor genes).
Hallmarks of Cancer
Cancer cells display eight fundamental changes in cell physiology
1.​ Self-sufficiency in growth signals
2.​ Insensitivity to growth-inhibitory signals
3.​ Altered cellular metabolism
4.​ Evasion of apoptosis
5.​ Limitless replicative potential (immortality)
6.​ Sustained angiogenesis
7.​ Invasion and metastasis
8.​ Evasion of immune surveillance
Additionally, two enabling characteristics facilitate cancer progression:
●​ Genomic instability
●​ Tumor-promoting inflammation
Self-Sufficiency in Growth Signals
●​ Cancer cells do not rely on external growth factors for proliferation.
●​ This occurs due to gain-of-function mutations converting proto-oncogenes into
oncogenes.
●​ Oncogenes encode oncoproteins that promote continuous growth without external
signals.
The Cellular Growth Process
1. Growth Factors
●​ Normal cells do not produce their own growth factors.
●​ Cancer cells bypass this restriction by:
○​ Producing their own growth factors (e.g., glioblastomas secrete PDGF).
○​ Inducing stromal cells to produce growth factors for them.
○​ Stimulating neighboring cells in the tumor microenvironment to support their
growth.
2. Growth Factor Receptors
●​ Mutated or overexpressed receptors act as oncoproteins, constantly driving growth.
●​ Examples:
○​ ERBB1 (EGF receptor) → Overexpressed in lung squamous cell carcinoma,
glioblastoma, and epithelial head & neck tumors.
○​ HER2 (ERBB2) → Amplified in 20% of breast cancers and some lung, ovarian,
gastric, and salivary gland cancers.
3. Downstream Signal-Transducing Proteins
●​ Cancer cells mutate signaling molecules, leading to uncontrolled growth.
●​ Two key oncoproteins:
○​ RAS: Most frequently mutated oncogene in human tumors.
■​ Normally switches between active/inactive states.
■​ Mutations lock it in an active, growth-promoting state.
○​ ABL:
■​ In chronic myeloid leukemia (CML), ABL gene translocates from
chromosome 9 to 22 → BCR-ABL fusion gene.
■​ This fusion protein continuously stimulates cell proliferation.
4. Nuclear Transcription Factors
●​ RAS and ABL mutations lead to constant activation of nuclear transcription factors,
which drive growth.
●​ Key oncogenes encoding transcription factors: MYC, MYB, JUN, FOS, REL.
●​ MYC is the most commonly involved in human cancers.
○​ Promotes cell cycle progression and alters metabolism to support rapid growth.
5. Cyclins and Cyclin-Dependent Kinases (CDKs)
●​ Cell cycle progression is controlled by CDKs (activated by cyclins).
●​ CDK inhibitors (CDKIs) suppress CDK activity, preventing uncontrolled division.
●​ Cancer cells disable the G1/S checkpoint, causing continuous division.
Insensitivity to Growth Inhibitory Signals
●​ Tumor suppressor genes prevent uncontrolled division.
●​ When inactivated, cells ignore inhibitory signals and continue proliferating.
RB: The Governor of the Cell Cycle
●​ Retinoblastoma (RB) protein controls the G1/S checkpoint.
●​ Inactivation of RB leads to unchecked cell division.
●​ Two-hit hypothesis (Knudson, 1974):
○​ Sporadic form: Both RB gene copies must be mutated.
○​ Familial form: One inherited mutation + one acquired mutation → Cancer
develops.
●​ HPV (Human Papillomavirus) produces E7 protein, which inactivates RB, leading to
cancer.
TP53: The Guardian of the Genome
●​ p53 protein functions as a tumor suppressor, preventing malignant transformation
via:
1.​ Quiescence (temporary cell cycle arrest)
2.​ Senescence (permanent cell cycle arrest)
3.​ Apoptosis (programmed cell death)
Altered Cellular Metabolism (Warburg Effect)
●​ Even with oxygen, cancer cells prefer glycolysis over oxidative phosphorylation.
●​ This supports rapid growth by producing metabolic intermediates needed for
biosynthesis.
●​ Used in PET scans, where 18F-fluorodeoxyglucose uptake highlights tumor cells.
Evasion of Cell Death (Apoptosis)
●​ Cancer cells acquire mutations preventing apoptosis.
●​ This is mainly due to changes in the intrinsic apoptosis pathway.
Limitless Replicative Potential (Immortality)
●​ Normal cells have a division limit (~70 cycles) due to telomere shortening.
●​ Cancer cells activate telomerase, allowing unlimited replication.
●​ Telomerase is active in 85-95% of cancers.
Sustained Angiogenesis
●​ Tumors require blood supply for growth.
●​ Cancer cells induce neo-angiogenesis, leading to:
○​ New capillary growth for oxygen/nutrient delivery.
○​ Secretion of growth factors (e.g., PDGF, IGFs) by endothelial cells.
●​ Tumor blood vessels are abnormal (leaky, disorganized).
●​ Angiogenesis also helps tumor cells enter the bloodstream → metastasis.
Invasion and Metastasis
Cancer spreads through four steps:
1.​ Loss of cell adhesion: Inactivation of E-cadherin.
2.​ Degradation of ECM: Proteolytic enzymes like MMPs and cathepsins break down
barriers.
3.​ Attachment to new ECM components: Tumor cells bind to novel ECM proteins.
4.​ Migration & spread: Tumor cells travel via blood/lymph.
Metastatic Patterns
●​ Tumor spread depends on:
○​ Anatomic location & vascular drainage of the primary tumor.
○​ Organ tropism (certain tumors prefer specific organs).
Evasion of Immune Surveillance
●​ Immune system identifies tumor cells via MHC class I molecules.
●​ Tumors evade immunity by:
○​ Reducing MHC I expression.
○​ Suppressing immune responses.
○​ Selecting for antigen-negative variants that avoid detection.