Unit 6: The Cell Cycle and Cancer

I. Orientation — Regulated Cell Reproduction and Tissue Homeostasis

The cell cycle is the ordered sequence by which a cell grows, duplicates its genetic material, and divides. Its central principle is that proliferation must be balanced by accurate DNA replication, chromosome segregation, and removal of damaged or unnecessary cells. Cancer develops when genetic changes disrupt this coordination, allowing cells to divide, survive, and spread abnormally.

A. Defining principles

• Continuity of genetic information: DNA is replicated once during S phase and distributed to daughter cells during mitosis.
• Checkpoint dependence: Progression is permitted only when conditions such as adequate cell size, intact DNA, and correct chromosome attachment are satisfied.
• Signal dependence: Growth factors, nutrients, extracellular matrix contacts, and neighboring cells influence whether a cell divides.
• Homeostasis: Tissue size reflects a balance among cell proliferation, differentiation, quiescence, and programmed cell death.
• Cancer as an evolutionary process: Mutations that enhance proliferation or survival are selected within a population of abnormal cells.
• Terminology: Diploid cells contain two chromosome sets, represented as 2n; haploid gametes contain one set, represented as n.

II. Overview of cell cycle — Phases and cellular duplication

The cell cycle consists of interphase, when the cell grows and copies DNA, followed by M phase, when the nucleus and cell divide.

A. Overview of cell cycle

• G1 phase: The cell grows, synthesizes RNA and proteins, and assesses environmental conditions. A cell may leave G1 and enter G0, a quiescent state.
• S phase: Each chromosome is duplicated to form two sister chromatids joined at the centromere. DNA content doubles from approximately 2C to 4C, although chromosome number remains 2n.
• G2 phase: The cell checks replicated DNA, produces mitotic proteins, and prepares the cytoskeleton for division.
• M phase: Mitosis separates sister chromatids, and cytokinesis divides the cytoplasm into two daughter cells.
• Duration: Human cell-cycle timing varies by cell type; cultured mammalian cells often complete a cycle in roughly 18–24 hours.
• Restriction point: In late G1, cells become committed to DNA replication if growth signals and internal conditions are sufficient.

III. Mitosis and meiosis — Nuclear division and genetic variation

Mitosis produces genetically similar body cells, whereas meiosis produces haploid cells and generates genetic diversity for sexual reproduction.

A. Mitosis and meiosis

• Mitosis: One nuclear division produces two genetically similar diploid cells.
  • Prophase and prometaphase: Chromosomes condense, the mitotic spindle forms, and the nuclear envelope breaks down.
  • Metaphase: Chromosomes align at the metaphase plate.
  • Anaphase: Cohesin is cleaved, allowing sister chromatids to move to opposite poles.
  • Telophase and cytokinesis: Nuclear envelopes reform and a contractile actin–myosin ring separates the cells.
• Meiosis: Two successive divisions follow one round of DNA replication, producing four genetically different haploid cells.
  • Meiosis I: Homologous chromosomes pair and separate; sister chromatids remain together.
  • Meiosis II: Sister chromatids separate, resembling mitosis.
  • Crossing over: Exchange between homologous chromosomes during prophase I creates new allele combinations.
• Comparison: Mitosis maintains chromosome number, whereas meiosis reduces 2n to n. A failure of chromosome separation, or nondisjunction, can produce aneuploid gametes such as those contributing to trisomy 21.

IV. Cell cycle control system — Molecular timing and checkpoints

The cell cycle control system is a network of cyclin-dependent kinases, regulatory proteins, and checkpoints that coordinates progression with cellular readiness.

A. Cell cycle control system

• Cyclin–CDK complexes: Cyclins activate cyclin-dependent kinases, or CDKs, whose kinase activity phosphorylates target proteins.
  • G1/S transition: Cyclin D–CDK4/6 and cyclin E–CDK2 promote passage through the restriction point.
  • G2/M transition: Cyclin B–CDK1 triggers entry into mitosis.
• Cyclin destruction: Ubiquitin ligases remove cyclins at appropriate stages. The anaphase-promoting complex/cyclosome, or APC/C, promotes securin and cyclin B degradation.
• DNA-damage checkpoint: ATM and ATR kinases respond to DNA lesions and replication stress. They activate checkpoint kinases, which inhibit CDKs.
• p53 pathway: DNA damage stabilizes p53, which induces p21. p21 inhibits CDKs and can halt the cycle for repair.
• Spindle checkpoint: Unattached or incorrectly attached kinetochores inhibit APC/C, preventing anaphase until chromosomes are properly aligned.
• Checkpoint failure: Mutations in TP53, RB1, or checkpoint regulators permit replication or division despite DNA damage, increasing genomic instability.

V. Programmed cell death — Controlled removal of cells

Programmed cell death eliminates cells in a regulated manner, preserving tissue organization and preventing damaged cells from becoming harmful.

A. Programmed cell death

• Apoptosis: A regulated, generally non-inflammatory form of cell death involving cell shrinkage, chromatin condensation, membrane blebbing, and apoptotic-body formation.
• Intrinsic pathway: Internal stress such as DNA damage or growth-factor withdrawal alters mitochondrial permeability.
  • Mitochondria: Cytochrome c enters the cytosol and binds Apaf-1 to form the apoptosome.
  • Caspase cascade: Initiator caspase-9 activates executioner caspases-3 and -7.
• Extrinsic pathway: Death receptors such as Fas and TNF receptor bind extracellular ligands and form a death-inducing signaling complex, activating caspase-8 or caspase-10.
• Cell clearance: Phosphatidylserine becomes exposed on the outer membrane leaflet, signaling phagocytes to remove the dying cell without major inflammation.
• Other regulated deaths: Necroptosis can produce membrane rupture and inflammation; pyroptosis is an inflammatory death associated with inflammasomes and gasdermin pores.
• Physiological role: Apoptosis shapes developing tissues, removes autoreactive lymphocytes, and eliminates cells carrying irreparable mutations.

VI. Cancer and cellular basis of cancer — Abnormal proliferation and survival

Cancer is a collection of diseases in which cells acquire heritable alterations that disrupt proliferation, differentiation, tissue organization, and survival.

A. Cancer and cellular basis of cancer

• Oncogenes: Mutated or overexpressed proto-oncogenes stimulate growth independently of normal signals. Examples include mutant RAS, BCR-ABL, and amplified HER2.
• Tumor-suppressor genes: Loss-of-function mutations remove inhibitory controls. RB normally restrains E2F-dependent S-phase genes, while p53 promotes arrest, repair, or apoptosis.
• Hallmarks of cancer: Common capabilities include sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, replicative immortality, angiogenesis, invasion, and metastasis.
• Genomic instability: Defective DNA repair, abnormal centrosomes, and chromosome mis-segregation produce mutations and aneuploidy that accelerate tumor evolution.
• Tumor microenvironment: Fibroblasts, immune cells, extracellular matrix, and blood vessels can supply growth signals, inflammatory mediators, and protection from therapy.
• Clonal selection: A primary tumor contains subclones; treatment or nutrient limitation may select resistant cells already carrying advantageous mutations.

VII. Key proteins regulating cell death — Molecular decision points

Key proteins regulating cell death determine whether mitochondrial integrity is maintained, caspases are activated, or a damaged cell survives.

A. Key proteins regulating cell death

• Bcl-2 family: These proteins regulate mitochondrial outer-membrane permeabilization.
  • Anti-apoptotic proteins: Bcl-2, Bcl-xL, and Mcl-1 bind and inhibit pro-apoptotic factors.
  • Pro-apoptotic proteins: Bax and Bak form membrane pores; BH3-only proteins such as Bim, Puma, and Noxa activate them or inhibit anti-apoptotic members.
• Cytochrome c: Released cytochrome c activates Apaf-1 and caspase-9; its escape is a major commitment step in intrinsic apoptosis.
• Caspases: Initiator caspases start the cascade, while executioner caspases cleave proteins such as lamins and cytoskeletal components.
• p53: p53 can induce p21-mediated arrest or transcription of pro-apoptotic genes such as PUMA and NOXA. TP53 is mutated in about half of human cancers.
• IAP proteins: Inhibitor-of-apoptosis proteins, including XIAP, suppress caspases; mitochondrial Smac/DIABLO can neutralize IAP activity.
• Death receptors: Fas and TRAIL receptors connect extracellular death signals to caspase-8 activation.

VIII. Anticancer-agents — Targeting proliferation and survival

Anticancer agents exploit differences between rapidly dividing, genetically stressed tumor cells and normal tissues, although many also damage healthy proliferating cells.

A. Anticancer-agents

• DNA-damaging agents: Cisplatin forms DNA cross-links, while alkylating agents modify DNA bases. Damage activates checkpoints and may trigger p53-dependent apoptosis.
• Antimetabolites: Methotrexate inhibits dihydrofolate reductase; 5-fluorouracil inhibits thymidylate synthase. Both interfere with nucleotide synthesis and S phase.
• Microtubule drugs: Taxanes stabilize microtubules; vinca alkaloids prevent microtubule polymerization. Both disrupt spindle function and arrest cells in mitosis.
• Topoisomerase inhibitors: These stabilize DNA–topoisomerase cleavage complexes, producing lethal DNA breaks during replication.
• Targeted therapies: Imatinib inhibits BCR-ABL in chronic myeloid leukemia; trastuzumab targets HER2-positive breast cancers.
• Apoptosis-directed agents: BH3 mimetics such as venetoclax inhibit Bcl-2 and promote mitochondrial apoptosis, particularly in selected leukemias.
• Limitations: Resistance can arise through drug efflux, target mutation, DNA repair, pathway bypass, or altered apoptosis. Bone-marrow suppression, gastrointestinal injury, and hair loss reflect damage to normal rapidly dividing cells.

IX. Concept of malignancy — Features distinguishing dangerous tumors

Malignancy describes the capacity of a neoplasm to invade surrounding tissues and establish growth at distant sites, rather than merely forming a localized mass.

A. Concept of malignancy

• Benign versus malignant: Benign tumors usually remain localized and resemble their tissue of origin; malignant tumors invade, destroy tissue, and may metastasize.
• Anaplasia: Poor differentiation, irregular nuclei, high nuclear-to-cytoplasmic ratio, and abnormal mitoses indicate loss of normal cellular specialization.
• Invasion: Malignant cells reduce adhesion, degrade basement membranes, and migrate through extracellular matrix.
• Angiogenesis: Tumors release vascular endothelial growth factor, or VEGF, to recruit blood vessels when diffusion alone cannot supply oxygen and nutrients.
• Replicative immortality: Many cancers activate telomerase, preventing progressive telomere shortening and allowing extended proliferation.
• Grading and staging: Grade describes microscopic aggressiveness; stage describes anatomical spread. Stage commonly has greater prognostic value because distant disease is difficult to eradicate.
• Clinical consequence: Malignancy is not defined solely by rapid growth; a slowly growing carcinoma can be dangerous if it invades critical organs or spreads.

X. Metastasis — Dissemination of cancer cells

Metastasis is the multistep spread of malignant cells from a primary tumor to a nonadjacent organ, where they establish a secondary tumor.

A. Metastasis

• Local invasion: Cells detach from neighbors, often through reduced E-cadherin-mediated adhesion, and secrete matrix metalloproteinases that digest extracellular matrix.
• Intravasation: Tumor cells enter blood or lymphatic vessels, aided by interactions with endothelial cells, stromal cells, and inflammatory signals.
• Survival in circulation: Platelets can coat circulating tumor cells, shielding them from shear stress and immune attack.
• Extravasation: Cells adhere to distant endothelium and pass through the vessel wall into a new tissue.
• Colonization: Successful metastasis requires adaptation to the new microenvironment, including formation of a supportive niche and often new blood supply.
• Organ preference: Metastases are influenced by blood flow, adhesion molecules, chemokine receptors, and tissue compatibility; common sites include liver, lung, bone, and brain.
• Clinical significance: Metastatic disease is often the major cause of cancer mortality because disseminated cells are genetically diverse and difficult to remove completely by local surgery or radiotherapy.