Unit 6: The Cell Cycle and Cancer - Subjective Questions

The cell cycle is the ordered sequence of events through which a cell grows, duplicates its genetic material, and divides.

• G1 phase: The cell grows, synthesizes proteins and organelles, and performs normal metabolic functions. It also assesses whether environmental conditions are suitable for division.
• S phase: DNA replication occurs, producing two identical copies of each chromosome. Centrosomes are also duplicated.
• G2 phase: The cell continues to grow, synthesizes proteins required for mitosis, and checks whether DNA replication has been completed accurately.
• M phase: Mitosis separates duplicated chromosomes, followed by cytokinesis, which divides the cytoplasm into two daughter cells.
• G0 phase: Some cells temporarily or permanently leave the cycle and perform specialized functions without dividing.

The cell cycle is regulated by checkpoints that prevent damaged or incompletely replicated DNA from being passed to daughter cells.

Mitosis is the division of a nucleus into two genetically identical nuclei.

• Prophase: Chromatin condenses into visible chromosomes, the nucleolus disappears, and the mitotic spindle begins to form.
• Prometaphase: The nuclear envelope breaks down, and spindle microtubules attach to chromosome kinetochores.
• Metaphase: Chromosomes align at the metaphase plate.
• Anaphase: Sister chromatids separate and move toward opposite poles.
• Telophase: Chromosomes decondense, nuclear envelopes reform, and two nuclei are produced.
• Cytokinesis: The cytoplasm divides, forming two daughter cells.

Mitosis is important for growth, tissue repair, replacement of damaged cells, and asexual reproduction in some organisms. It maintains the chromosome number and produces genetically similar daughter cells.

Mitosis and meiosis are both forms of nuclear division, but they have different outcomes.

Meiosis generates variation through crossing over, independent assortment, and random fertilization, whereas mitosis preserves genetic stability.

Meiosis consists of two nuclear divisions following a single round of DNA replication.

• Meiosis I: Homologous chromosomes pair during prophase I. Crossing over occurs between nonsister chromatids. Homologous pairs align independently at metaphase I and separate during anaphase I. This reduces the chromosome number from diploid to haploid.
• Meiosis II: No additional DNA replication occurs. Chromosomes align at metaphase II, and sister chromatids separate during anaphase II. Four haploid cells are produced.

Genetic variation results from:

• Crossing over, which exchanges DNA between homologous chromosomes.
• Independent assortment, which distributes maternal and paternal chromosomes randomly.
• Random fertilization, which combines genetically different gametes.

Thus, meiosis both reduces chromosome number and creates genetically diverse reproductive cells.

The cell-cycle control system is a network of regulatory proteins that coordinates progression through G1, S, G2, and M phases.

• Cyclins are regulatory proteins whose concentrations rise and fall during the cell cycle.
• Cyclin-dependent kinases (CDKs) are enzymes that become active when bound to specific cyclins.
• Cyclin-CDK complexes phosphorylate target proteins and activate events required for progression to the next phase.
• Different cyclin-CDK complexes regulate different transitions, including the G1/S and G2/M transitions.
• CDK inhibitors can block kinase activity when conditions are unfavorable or DNA is damaged.

The system also includes checkpoints that verify cell size, nutrient availability, DNA integrity, completion of DNA replication, and correct chromosome attachment before division proceeds.

Cell-cycle checkpoints prevent cells from dividing when essential conditions have not been met.

• G1 checkpoint: Determines whether the cell is large enough, has adequate nutrients and growth signals, and contains undamaged DNA. Cells may enter G0 if conditions are unfavorable.
• G2 checkpoint: Confirms that DNA replication is complete and that replicated DNA is not seriously damaged.
• Spindle assembly checkpoint: Ensures that every chromosome is correctly attached to spindle fibers before sister chromatids separate.

If damage is detected, checkpoint proteins may:

• Pause the cell cycle to allow DNA repair.
• Activate pathways that permanently stop proliferation.
• Initiate programmed cell death if damage cannot be repaired.

Failure of these checkpoints can allow mutations, chromosome mis-segregation, and uncontrolled proliferation, thereby contributing to cancer development.

Programmed cell death, especially apoptosis, is a genetically regulated process through which unwanted or damaged cells are eliminated in an orderly manner.

Important features of apoptosis include:

• Cell shrinkage and condensation of the cytoplasm.
• Chromatin condensation and fragmentation of the nucleus.
• Fragmentation of the cell into membrane-bound apoptotic bodies.
• Rapid removal of apoptotic bodies by neighboring cells or phagocytes.
• Usually no significant inflammatory response.

Apoptosis is important for:

• Development, such as removal of cells between developing fingers.
• Maintenance of tissue size and homeostasis.
• Elimination of infected, damaged, or potentially cancerous cells.
• Removal of immune cells that react strongly against self-antigens.

Defective apoptosis can promote cancer, while excessive apoptosis can contribute to degenerative diseases.

Apoptosis and necrosis are different forms of cell death.

Apoptosis is generally a beneficial homeostatic process, whereas necrosis is usually an uncontrolled response to acute cellular injury.

Apoptosis can be initiated through intrinsic or extrinsic pathways.

• Intrinsic pathway: Internal stress, such as DNA damage, growth-factor withdrawal, or severe oxidative stress, affects the mitochondria. Pro-apoptotic Bcl-2 family proteins increase mitochondrial outer-membrane permeability, allowing cytochrome to enter the cytosol. Cytochrome combines with Apaf-1 and procaspase-9 to form the apoptosome, which activates caspase-9.
• Extrinsic pathway: Death ligands such as Fas ligand or tumor necrosis factor bind death receptors on the cell surface. The receptors recruit adaptor proteins and procaspase-8 or procaspase-10 into a death-inducing signaling complex.
• Convergence: Initiator caspases activate executioner caspases, particularly caspases-3, -6, and -7. These enzymes cleave structural and regulatory proteins, producing the characteristic changes of apoptosis.

Caspase activity is tightly controlled to prevent inappropriate cell death.

Bcl-2 family proteins regulate the mitochondrial pathway of apoptosis.

• Anti-apoptotic proteins, such as Bcl-2 and Bcl-xL, preserve mitochondrial membrane integrity.
• Pro-apoptotic effector proteins, such as Bax and Bak, promote mitochondrial membrane permeabilization.
• BH3-only proteins sense cellular stress and either inhibit anti-apoptotic proteins or activate Bax and Bak.

p53 is a tumor-suppressor protein activated by DNA damage and other cellular stresses. It can:

• Induce expression of CDK inhibitors, causing cell-cycle arrest.
• Activate genes involved in DNA repair.
• Stimulate expression of pro-apoptotic proteins when damage is irreparable.
• Promote senescence or apoptosis.

Loss or mutation of p53 allows cells with damaged DNA to continue dividing, increasing the risk of malignant transformation.

Cancer is a group of diseases characterized by abnormal, uncontrolled cell proliferation and the ability of cells to invade tissues or spread to distant sites.

The cellular basis of cancer involves the accumulation of genetic and epigenetic alterations that affect:

• Growth-promoting genes, which may become oncogenes.
• Growth-inhibitory genes, such as tumor-suppressor genes.
• Genes responsible for DNA repair.
• Regulators of apoptosis and cellular senescence.
• Mechanisms controlling cell adhesion, migration, and angiogenesis.

As mutations accumulate, cells may acquire autonomy from growth signals, resistance to inhibitory signals, avoidance of apoptosis, unlimited replicative potential, and invasive behavior. Cancer is therefore a disease of abnormal regulation of cell division, survival, and tissue organization.

Proto-oncogenes are normal genes that promote cell growth, division, or survival when appropriately regulated. Examples include genes encoding growth-factor receptors, Ras proteins, and Myc proteins.

An oncogene is a mutated, amplified, or abnormally expressed proto-oncogene that promotes excessive cell proliferation or survival. Oncogenes commonly act through a gain-of-function mechanism and may require alteration of only one gene copy. Examples include mutated RAS, amplified HER2, and translocated BCR-ABL.

Tumor-suppressor genes normally inhibit cell proliferation, promote DNA repair, maintain genomic stability, or induce apoptosis. Examples include TP53, RB1, and APC. Their inactivation is generally a loss-of-function event and often requires loss of both functional gene copies.

The balance between growth-promoting and growth-inhibitory pathways is disrupted in cancer.

The hallmarks of cancer are acquired properties that enable tumor cells to survive and expand.

• Sustained proliferative signaling: Cells continuously stimulate their own growth pathways.
• Evading growth suppressors: Cells become insensitive to inhibitors such as p53- and RB-mediated controls.
• Resisting cell death: Alterations in apoptotic pathways allow damaged cells to survive.
• Replicative immortality: Reactivation of telomerase allows repeated division.
• Inducing angiogenesis: Tumors stimulate formation of blood vessels to obtain oxygen and nutrients.
• Activating invasion and metastasis: Cells lose adhesion, migrate, and colonize distant tissues.
• Deregulating cellular energetics: Cancer cells alter metabolism to support rapid growth.
• Avoiding immune destruction: Tumor cells may suppress or evade immune responses.

These characteristics develop progressively through the accumulation of genetic and epigenetic changes.

Several proteins coordinate cell-cycle progression and help prevent uncontrolled proliferation.

• Cyclins and CDKs: Drive cells through specific phases of the cycle. Overexpression of cyclins or excessive CDK activity can cause inappropriate division.
• p53: Detects stress and DNA damage and induces arrest, repair, senescence, or apoptosis. Its loss permits survival of genetically damaged cells.
• RB protein: Restrains the G1/S transition by inhibiting E2F transcription factors. RB inactivation releases E2F and promotes uncontrolled entry into S phase.
• p21: A CDK inhibitor induced by p53; it can stop the cycle after DNA damage.
• APC: Helps regulate beta-catenin signaling and intestinal cell proliferation. Its loss can contribute to colorectal cancer.
• Ras: Transmits growth signals from membrane receptors. Mutated Ras can remain permanently active.

Cancer may result when growth-promoting proteins are activated and growth-inhibitory proteins are lost.

Malignancy refers to the ability of a tumor to invade surrounding tissues and potentially spread to distant organs.

Malignant cells show abnormal nuclei, altered cell adhesion, loss of tissue organization, increased mitotic activity, and the ability to survive in inappropriate environments. Malignancy is therefore defined not only by rapid growth but especially by invasion and metastatic potential.

Metastasis is the formation of a secondary tumor at a site distant from the primary tumor.

The process generally involves:

• Local invasion: Tumor cells reduce adhesion to neighboring cells and degrade the extracellular matrix using enzymes such as matrix metalloproteinases.
• Intravasation: Cells enter nearby blood vessels or lymphatic vessels.
• Survival in circulation: Tumor cells resist shear forces and immune attack, sometimes by associating with platelets.
• Extravasation: Cells attach to the vessel wall and pass into surrounding tissue at a distant site.
• Colonization: Cells adapt to the new microenvironment, establish survival signals, induce angiogenesis, and proliferate into a secondary tumor.

Most disseminated tumor cells do not form successful metastases because they fail to survive or grow in the new tissue environment. Metastasis is a major cause of cancer-related mortality.

Normal epithelial cells are attached to neighboring cells and to the extracellular matrix. Cancer cells acquire changes that enable them to detach and migrate.

• Reduced expression or abnormal function of E-cadherin weakens cell-to-cell adhesion.
• Altered integrins change how tumor cells attach to the extracellular matrix and blood-vessel walls.
• Tumor cells release matrix metalloproteinases and other proteases that degrade the basement membrane and extracellular matrix.
• Cytoskeletal rearrangements increase cell motility.
• Epithelial-to-mesenchymal transition may produce cells with reduced epithelial characteristics and increased migratory ability.
• Tumor-associated stromal cells can remodel the matrix and release growth factors that support invasion.

Together, these changes allow tumor cells to leave the primary mass, enter circulation, and establish secondary tumors.

Anticancer agents act by selectively damaging or inhibiting rapidly dividing or cancer-specific cells.

• Alkylating agents: Add chemical groups to DNA, causing cross-links and blocking replication and transcription.
• Antimetabolites: Resemble nucleotides or metabolic substrates and inhibit DNA or RNA synthesis.
• Antitumor antibiotics: Intercalate into DNA, generate free radicals, or inhibit enzymes involved in DNA replication.
• Microtubule-targeting drugs: Vinca alkaloids inhibit microtubule assembly, whereas taxanes stabilize microtubules and prevent proper spindle function.
• Topoisomerase inhibitors: Prevent release of DNA strain and produce DNA breaks.
• Hormone therapies: Block hormones or their receptors in hormone-dependent cancers.
• Targeted therapies: Inhibit specific proteins such as mutant kinases or growth-factor receptors.
• Immunotherapies: Enhance immune recognition and destruction of tumor cells.

Many agents ultimately cause cell-cycle arrest, DNA damage, senescence, or apoptosis.

Many anticancer drugs cause DNA damage, replication stress, mitotic failure, or inhibition of essential survival pathways. These effects can activate p53 and other stress-response proteins, increase pro-apoptotic Bcl-2 family activity, promote mitochondrial cytochrome release, and activate initiator and executioner caspases.

Resistance may develop through:

• Mutation or loss of p53.
• Overexpression of anti-apoptotic proteins such as Bcl-2.
• Increased drug efflux by ATP-binding cassette transporters.
• Enhanced DNA repair.
• Alteration of the drug target.
• Failure to activate caspases.
• Changes in the tumor microenvironment.
• Presence of slowly dividing cancer stem-like cells.

Because resistance can involve multiple mechanisms, combination therapy is often used to target different pathways and reduce the likelihood of treatment failure.

DNA repair systems correct damage caused by replication errors, radiation, chemicals, and normal metabolism. When repair genes are defective, mutations accumulate more rapidly.

• Defects in mismatch repair allow replication errors to persist.
• Defects in homologous recombination repair impair accurate repair of double-strand breaks.
• Defects in nucleotide-excision repair prevent removal of bulky DNA lesions.
• Defects in checkpoint proteins allow cells with damaged DNA to continue dividing.

The resulting genomic instability may include point mutations, chromosomal rearrangements, gene amplification, aneuploidy, and loss of heterozygosity. These changes can activate oncogenes, inactivate tumor-suppressor genes, and alter apoptosis or cell adhesion. Genomic instability therefore increases tumor heterogeneity and supports cancer progression, treatment resistance, and metastasis.