Rapid Review·General Pathology
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NEOPLASIA
T2High yieldHallmarks of Cancer
P217
Focus on
The set of acquired capabilities a cell must collect to become a tumor, each one mapped to a mutated gene class.
Key takeaways
The premise
The premise
cancer is caused by mostly acquired DNA mutations affecting growth, DNA repair, and survival. Each hallmark below is one capability the clone has to acquire.Growing without permission
Growth signal self-sufficiency
mutations anywhere along the growth pathway.- Proto-oncogenes → ↑ growth factors → an autocrine loop (↑ PDGF in brain tumors).
- Growth factor receptors → constitutive signaling (HER2).
- Signaling molecules (RAS), transcription factors (MYC), and cell cycle regulators (cyclins, CDKs).
Anti-growth signal insensitivity
loss of tumor suppressors (Rb), and loss of E-cadherin → loss of contact inhibition (NF2).Refusing to die
Evasion of apoptosis
TP53 loss, or BCL2 overexpression, which produces follicular lymphoma.Limitless replicative potential
reactivation of telomerase keeps telomeres from shortening, so the clone never hits replicative senescence.Feeding the tumor
Sustained angiogenesis
↑ VEGF or ↓ angiogenesis inhibitors.- Neoangiogenesis is sprouting from existing capillaries; vasculogenesis recruits endothelial precursors from marrow.
- Tumor vessels are leaky and dilated, which is why tumors bleed and why contrast pools in them.
Warburg effect
a shift from oxidative phosphorylation to glycolysis even under aerobic conditions, so-called aerobic glycolysis.- Driven by pyruvate kinase M2 and LDH-A.
- Supplies biosynthetic intermediates for nucleotides, lipids, and amino acids, at the cost of ↑ lactate production.
- This is the basis of FDG-PET imaging.
Hiding, invading and spreading
Immune evasion
↓ MHC class I expression so cytotoxic T cells cannot see the tumor, secretion of TGF-β, recruitment of Tregs, and upregulation of immune checkpoint molecules.Tissue invasion
loss of E-cadherin loosens junctions → metalloproteinases degrade basement membrane and ECM → cells attach to laminin and fibronectin → locomotion → vascular dissemination.Metastasis
emboli spread, adhere to endothelium, extravasate, and home.- The target organ is usually the first capillary bed encountered, but some cancers show organ tropism (lung cancer seeding the adrenals).
Hallmarks side by side
| Hallmark | Mechanism | Gene / molecule to name |
|---|---|---|
| Growth self-sufficiency | Constitutive growth signaling | RAS, HER2, MYC, cyclins |
| Anti-growth insensitivity | Brakes cut | Rb, TP53 |
| Apoptosis evasion | Death program blocked | TP53, BCL2 |
| Limitless replication | Telomeres maintained | Telomerase |
| Angiogenesis | Local hypoxia drives new vessels | HIF-1α → VEGF (opposed by VHL) |
| Altered metabolism | Aerobic glycolysis | Warburg effect, PKM2, LDH-A |
| Immune evasion | T cells blinded or braked | ↓ MHC I, PD-L1, CTLA-4, TGF-β |
| Invasion and metastasis | Membrane digested, cells detach | ↓ E-cadherin, matrix metalloproteinases |
Drug resistance
P-glycoprotein (MDR1)
an ATP-dependent efflux pump that some cancer cells express to expel chemotherapeutic agents, producing acquired multidrug resistance over time.Why does an FDG-PET scan light up most tumors?
Tumor cells rely on aerobic glycolysis (the Warburg effect) even when oxygen is available, so they take up far more glucose, and the glucose analog FDG, than normal tissue.
How it's tested
The Warburg effect is the newest favorite: tumor cells burn glucose to lactate via glycolysis even when oxygen is abundant, which is why cancers are avid on FDG-PET and why serum LDH tracks tumor burden.
The other guaranteed mechanism is angiogenesis. As a tumor outgrows its blood supply, local pO₂ falls, which induces HIF-1α → ↑ VEGF → new vessels. This is exactly why VHL, which normally degrades HIF-1α, is a tumor suppressor, and why its loss produces the wildly vascular tumors of von Hippel-Lindau disease.
Separately, a patient whose tumor initially shrank on chemotherapy but is now progressing has upregulated P-glycoprotein (MDR1), an ATP-dependent efflux pump that expels the drug from the cell.
Go deeper
First Aid "Cancer hallmarks"; Pathoma Ch. 3 "Cancer — carcinogenesis"; Boards & Beyond. Anchor the metastasis cascade (E-cadherin loss → matrix metalloproteinase basement-membrane breakdown → intravasation) and the Warburg effect (why FDG-PET lights up tumors).
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