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Cell Biology Unit 8: Cell Death and Cancer

This unit explains how cells deliberately die through apoptosis, how that program is controlled, and how mutations in growth, death and repair genes lead to cancer.

Covers: Apoptosis versus necrosis, Caspases, Intrinsic (mitochondrial) pathway and the Bcl-2 family, Extrinsic (death receptor) pathway, Autophagy and clearance of dead cells, Oncogenes and tumor suppressors, Hallmarks of cancer and targeted therapy

Study guide

Cells can die in two main ways. Necrosis is uncontrolled death after injury: cells swell, burst and release contents that cause inflammation. Apoptosis is programmed cell death: the cell shrinks, its chromatin condenses, its DNA is cut into fragments, and it breaks into membrane-bound apoptotic bodies. Phosphatidylserine flips to the outer leaflet as an 'eat me' signal, and macrophages engulf the remains without inflammation. Apoptosis sculpts fingers in embryos, removes self-reactive immune cells, and eliminates damaged or infected cells. Autophagy is a related survival process in which cells wrap parts of their cytoplasm in a double membrane and digest them in lysosomes.

Apoptosis is carried out by caspases, cysteine proteases that cut after aspartate. They are made as inactive procaspases. Initiator caspases (8 and 9) are activated by being brought together on adaptor platforms, and they cleave and activate executioner caspases (3, 6 and 7). Executioners cut hundreds of proteins, including lamins, cytoskeletal proteins and the inhibitor of the DNase that fragments DNA. Inhibitor of apoptosis proteins (IAPs) bind and block active caspases, and mitochondria release Smac/DIABLO to neutralize IAPs.

The intrinsic pathway responds to internal stress such as DNA damage, growth factor withdrawal or ER stress. It is controlled by the Bcl-2 family. BH3-only proteins (Bid, Bim, Puma, Noxa) sense stress and block anti-apoptotic Bcl-2 and Bcl-xL, freeing the effectors Bax and Bak to make pores in the outer mitochondrial membrane. Cytochrome c escapes, binds Apaf-1, and forms the apoptosome, which activates caspase-9. The extrinsic pathway starts when ligands such as Fas ligand or TNF bind death receptors; the adaptor FADD recruits procaspase-8 into a DISC, activating it. Caspase-8 can activate caspase-3 directly or cut Bid to tBid, which amplifies death through mitochondria.

Cancer arises when a cell lineage accumulates mutations that let it grow without normal controls. Proto-oncogenes such as RAS, MYC, HER2 and ABL become oncogenes by point mutation, amplification or translocation; these gain-of-function changes act dominantly. Tumor suppressors such as RB, TP53, APC and PTEN restrain growth or trigger death; usually both alleles must be lost, as in Knudson's two-hit hypothesis. Inherited single mutations, as in familial retinoblastoma or Li–Fraumeni syndrome, greatly raise cancer risk because each cell needs only one more hit. Caretaker genes for DNA repair (BRCA1, mismatch repair) speed up mutation.

Tumors develop over years through multiple steps, such as APC loss, KRAS activation and TP53 loss in colon cancer. The hallmarks of cancer include sustained growth signaling, evading growth suppressors, resisting cell death, unlimited replication through telomerase, inducing angiogenesis (for example via VEGF), invasion and metastasis (often after an epithelial-to-mesenchymal transition), reprogrammed metabolism (the Warburg effect), and evading the immune system. Understanding these pathways guides targeted therapy: imatinib blocks BCR-ABL, HER2 antibodies block amplified receptors, BH3-mimetics such as venetoclax reactivate apoptosis, and combinations such as BRAF plus MEK inhibitors limit resistance.

Key ideas

• Apoptosis is an orderly, caspase-driven death that avoids inflammation, unlike necrosis.
• Initiator caspases activate executioner caspases, which dismantle the cell.
• The Bcl-2 family decides whether mitochondria release cytochrome c in the intrinsic pathway.
• Death receptors activate caspase-8 in the extrinsic pathway, which can be amplified through Bid.
• Oncogenes are dominant gain-of-function mutations; tumor suppressors usually need two hits.
• Cancer develops through multiple mutations accumulating over years.
• Targeted therapies block the specific proteins that drive a tumor.

Formulas and rules

Common mistakes

• Calling Bcl-2 pro-apoptotic; it blocks apoptosis, while Bax and Bak promote it.
• Mixing up caspase-8 (extrinsic) and caspase-9 (intrinsic).
• Thinking one mutant tumor suppressor allele is usually enough to cause loss of function.
• Believing apoptosis causes inflammation; necrosis does.
• Assuming the Warburg effect means tumor cells make more ATP per glucose.

Before the test, make sure you can

• Compare apoptosis, necrosis and autophagy.
• Trace the intrinsic and extrinsic apoptosis pathways to executioner caspases.
• Explain the roles of Bcl-2, Bax/Bak, BH3-only proteins, IAPs and Bid.
• Distinguish oncogenes from tumor suppressors and apply the two-hit hypothesis.
• Explain why cancer is multistep and how p53 loss affects therapy.
• Describe major hallmarks of cancer, including angiogenesis, metastasis and telomerase.
• Calculate tumor doublings, growth time and divisions before senescence.
• Predict how targeted drugs such as imatinib, venetoclax and MEK inhibitors work.

Words to know

Apoptosis

Programmed cell death with shrinkage, chromatin condensation, DNA fragmentation and engulfment without inflammation.

Necrosis

Uncontrolled cell death after injury, with swelling, bursting and inflammation.

Caspase

A cysteine protease that cleaves after aspartate and carries out apoptosis.

Apoptosome

A wheel-shaped complex of Apaf-1 and cytochrome c that activates caspase-9.

Bcl-2

An anti-apoptotic protein that blocks Bax and Bak at mitochondria.

Bax and Bak

Pro-apoptotic Bcl-2 family effectors that permeabilize the outer mitochondrial membrane.

BH3-only proteins

Stress-sensing Bcl-2 family members (Bid, Bim, Puma) that trigger apoptosis.

Death receptor

A cell-surface receptor such as Fas that activates caspase-8 through FADD.

IAP

Inhibitor of apoptosis protein that binds and blocks caspases.

Autophagy

Delivery of cytoplasm or organelles to lysosomes in double-membrane autophagosomes.

Proto-oncogene

A normal gene that promotes growth and can become an oncogene when mutated.

Tumor suppressor

A gene whose product restrains growth or promotes death; loss of both copies contributes to cancer.

Two-hit hypothesis

Knudson's idea that both alleles of a tumor suppressor must be inactivated for a tumor to form.

Telomerase

A reverse transcriptase that adds repeats to chromosome ends; reactivated in most cancers.

Angiogenesis

Growth of new blood vessels, often triggered by tumors secreting VEGF.

Metastasis

Spread of cancer cells from the primary tumor to distant sites.

Warburg effect

Preference of many tumor cells for glycolysis to lactate even when oxygen is present.

Sample practice questions

30 more questions like these, from level 1 to 5, are in the practice set.