Cancer Biology
Loss of Cell Cycle Control
Understanding how proto-oncogenes, tumor suppressors, and checkpoint failures drive uncontrolled cell proliferation.
MCAT Biological Foundations
What is Cancer?
Cancer is a disease of uncontrolled cell division. Normal cells grow, divide, and die in a tightly regulated cycle. Cancer cells escape this regulation: they proliferate without appropriate signals, ignore stop signals, evade programmed cell death, and can invade distant tissues.
The Normal Cell Cycle
Key Regulators of the Cell Cycle
Cyclins
Regulatory proteins whose concentrations rise and fall throughout the cell cycle, activating specific CDKs at each phase.
CDKs
Cyclin-dependent kinases that phosphorylate target proteins to drive cell cycle progression. Only active when bound to their cyclin partner.
CKIs
CDK inhibitors (e.g., p21, p27) that bind cyclin-CDK complexes and block their kinase activity, halting the cycle at checkpoints.
Proto-Oncogenes vs Tumor Suppressors
| Proto-Oncogene | Tumor Suppressor | |
|---|---|---|
| Normal Function | Promotes cell growth and division | Inhibits cell growth or promotes apoptosis |
| Mutation Effect | Gain-of-function (hyperactive) | Loss-of-function (inactive) |
| Alleles Needed | One mutant allele (dominant) | Both alleles (recessive): "two-hit" |
| Analogy | Stuck accelerator | Broken brakes |
| Examples | RAS, MYC, HER2, BCR-ABL | p53, Rb, APC, BRCA1/2 |
Knudson's Two-Hit Hypothesis
How Oncogenes Are Activated
1
Point mutation: A single nucleotide change makes the protein constitutively active (e.g., RAS stuck in GTP-bound "ON" state).
2
Gene amplification: Extra copies of the gene produce excess protein (e.g., HER2 overexpression in breast cancer).
3
Chromosomal translocation: Gene is fused to a new promoter or creates a fusion protein (e.g., BCR-ABL in chronic myelogenous leukemia).
4
Viral insertion: A retrovirus inserts near a proto-oncogene, placing it under viral promoter control, causing overexpression.
p53: Guardian of the Genome
Rb and the G1/S Checkpoint
Growth Factor Signaling Pathway
Hallmarks of Cancer
Self-Sufficiency
Produce own growth signals (oncogene activation)
Evading Apoptosis
Inactivation of p53 or overexpression of Bcl-2
Limitless Replication
Telomerase reactivation bypasses the Hayflick limit
Angiogenesis
Tumors induce new blood vessel formation via VEGF
Metastasis
Invasion through basement membrane and spread to distant organs
Insensitivity
Ignore anti-growth signals (loss of Rb or TGF-beta response)
Benign vs Malignant Tumors
| Benign | Malignant | |
|---|---|---|
| Growth Rate | Slow, well-defined | Rapid, irregular |
| Borders | Encapsulated, smooth | Invasive, irregular |
| Metastasis | No | Yes |
| Differentiation | Well-differentiated | Poorly differentiated (anaplastic) |
| Danger | Rarely life-threatening | Can be lethal |
| Examples | Lipoma, adenoma | Carcinoma, sarcoma |
Steps of Metastasis
1
Local invasion: Cancer cells break through the basement membrane using matrix metalloproteinases (MMPs).
2
Intravasation: Tumor cells enter blood vessels or lymphatic vessels.
3
Circulation: Cells travel through the bloodstream (most are destroyed, but some survive).
4
Extravasation: Surviving cells exit blood vessels at a distant site.
5
Colonization: Cells proliferate at the new site, forming a secondary tumor (the most rate-limiting step).
How to Approach Cancer Questions
1
Identify the gene type: Is it a proto-oncogene (gain-of-function) or tumor suppressor (loss-of-function)?
2
Determine the mutation type: Point mutation? Deletion? Amplification? Translocation?
3
Predict the phenotype: What checkpoint is bypassed? Which hallmark is acquired?
4
Apply the dominance rule: Oncogenes are dominant (1 allele). Tumor suppressors are recessive (2 alleles needed).
5
Connect to the pathway: Trace the signaling cascade from the mutation to the cellular outcome.
Example: RAS Mutation
Scenario: A researcher discovers a point mutation in the RAS gene of a lung tumor. The mutant RAS protein has reduced GTPase activity. What is the consequence?
1
Normal RAS: Cycles between GTP-bound (active) and GDP-bound (inactive). GTPase activity hydrolyzes GTP to GDP, turning RAS OFF.
2
Mutant RAS: Reduced GTPase activity means RAS cannot hydrolyze GTP. It remains stuck in the active (GTP-bound) state.
3
Result: Constitutive activation of the MAPK signaling cascade, leading to continuous cell proliferation without growth factor signals.
Common Mistakes
✕ Confusing Dominance
Oncogenes are gain-of-function (dominant: 1 allele). Tumor suppressors are loss-of-function (recessive: 2 alleles). Don't mix them up.
✕ p53 is an Oncogene
p53 is a tumor suppressor, not an oncogene. It stops growth and induces apoptosis. Loss of p53 promotes cancer.
✕ Benign = Harmless
Benign tumors don't metastasize, but they can still be dangerous (e.g., compressing the brain). "Benign" does not equal "safe."
✕ One Mutation = Cancer
Cancer requires multiple mutations accumulating over time (multi-hit model). A single mutation rarely causes cancer on its own.
✕ Rb Phosphorylation
Phosphorylated Rb is inactive (releases E2F). Unphosphorylated Rb is active (sequesters E2F). Students often reverse this.
Question 1 of 5
A mutation causes a proto-oncogene to become constitutively active. How many alleles must be mutated for this to promote tumor growth?
Oncogenes act in a dominant fashion. A single gain-of-function mutation in one allele is sufficient to produce a hyperactive protein that drives cell proliferation. The two-hit hypothesis applies only to tumor suppressors.
Question 2 of 5
A patient's tumor cells show no functional p53 protein. Which of the following cellular responses would be most directly impaired?
p53 is the "guardian of the genome." When DNA damage occurs, p53 activates p21 to arrest the cell cycle and can trigger apoptosis via BAX. Without p53, damaged cells continue dividing, accumulating further mutations.
Question 3 of 5
The retinoblastoma protein (Rb) in its hypophosphorylated state prevents cell cycle progression by:
Hypophosphorylated Rb (active Rb) binds and sequesters E2F transcription factors. E2F is needed to transcribe genes for DNA replication (S phase). When Rb is phosphorylated by cyclin-CDK complexes, E2F is released and the cell proceeds to S phase.
Question 4 of 5
The Philadelphia chromosome (BCR-ABL fusion) found in chronic myelogenous leukemia is an example of oncogene activation by:
The Philadelphia chromosome results from a translocation between chromosomes 9 and 22, fusing the BCR and ABL genes. The resulting BCR-ABL fusion protein is a constitutively active tyrosine kinase that drives uncontrolled proliferation of white blood cells.
Question 5 of 5
Which feature distinguishes a malignant tumor from a benign tumor?
The defining feature of malignancy is the ability to invade surrounding tissues and metastasize to distant sites. Benign tumors remain localized and encapsulated. They may still be dangerous but cannot spread through the body.