Cell Biology Unit 21 ReviewCancer Biology and Cell Cycle Regulation

Key Concepts and Terminology

• Cell cycle consists of a series of events that lead to cell division and duplication (replication)
• Interphase is the longest phase of the cell cycle, where the cell grows and prepares for division
  • Divided into G1, S, and G2 phases
• Mitosis is the process of nuclear division, resulting in the formation of two genetically identical daughter cells
• Cytokinesis is the division of the cytoplasm, which occurs after mitosis and results in the complete separation of the two daughter cells
• Checkpoints are control mechanisms that ensure the proper progression of the cell cycle (G1/S, G2/M, and metaphase checkpoints)
• Cancer is a group of diseases characterized by uncontrolled cell growth and the ability to invade surrounding tissues
• Oncogenes are genes that, when mutated or overexpressed, can contribute to the development of cancer (e.g., Ras, Myc)
• Tumor suppressor genes are genes that normally regulate cell growth and division, and their loss or inactivation can lead to cancer development (e.g., p53, Rb)

The Cell Cycle: Phases and Checkpoints

• The cell cycle is divided into four main phases: G1, S, G2, and M
• G1 phase is the first gap phase, where the cell grows and prepares for DNA replication
  • Restriction point (R point) in G1 is a critical checkpoint that determines whether the cell will proceed to S phase or enter a resting state (G0)
• S phase is the synthesis phase, where DNA replication occurs
• G2 phase is the second gap phase, where the cell continues to grow and prepares for mitosis
• M phase consists of mitosis and cytokinesis, resulting in the division of the nucleus and cytoplasm, respectively
• Checkpoints ensure proper cell cycle progression and maintain genomic stability
  • G1/S checkpoint ensures that the cell is ready for DNA replication
  • G2/M checkpoint ensures that DNA replication is complete and the cell is ready for mitosis
  • Metaphase checkpoint (spindle assembly checkpoint) ensures proper attachment of chromosomes to the mitotic spindle

Molecular Mechanisms of Cell Division

• Cyclins and cyclin-dependent kinases (CDKs) are key regulators of the cell cycle
  • Specific cyclins are expressed at different stages of the cell cycle and bind to their corresponding CDKs to form active complexes
• CDK activity is regulated by phosphorylation and dephosphorylation events, as well as by binding to cyclin partners and CDK inhibitors (CKIs)
• Ubiquitin-mediated proteolysis plays a crucial role in cell cycle progression by targeting specific proteins for degradation (e.g., cyclins, securin)
• The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that regulates the transition from metaphase to anaphase and the exit from mitosis
• Mitotic spindle formation and chromosome segregation are essential for proper cell division
  • Microtubules, centrosomes, and kinetochores play key roles in this process
• Cytoskeletal rearrangements and the formation of the contractile ring are necessary for cytokinesis

Cancer: Definition and Hallmarks

• Cancer is a complex disease characterized by uncontrolled cell growth, invasion, and metastasis
• Hallmarks of cancer include sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, enabling of replicative immortality, induction of angiogenesis, and activation of invasion and metastasis
• Additional emerging hallmarks include deregulation of cellular energetics, avoidance of immune destruction, and tumor-promoting inflammation
• Genome instability and mutation, as well as tumor microenvironment, are enabling characteristics that facilitate the acquisition of the hallmarks of cancer
• Hanahan and Weinberg's "Hallmarks of Cancer" provide a framework for understanding the common features of cancer cells and the mechanisms underlying cancer development and progression

Oncogenes and Tumor Suppressors

• Oncogenes are genes that, when mutated or overexpressed, can drive cancer development
  • Examples include Ras (signal transduction), Myc (transcription factor), and Bcl-2 (apoptosis regulator)
• Oncogenes can be activated by various mechanisms, such as point mutations, gene amplification, and chromosomal translocations
• Tumor suppressor genes are genes that normally regulate cell growth and division, and their loss or inactivation can contribute to cancer development
  • Examples include p53 (cell cycle regulator and "guardian of the genome"), Rb (cell cycle regulator), and PTEN (PI3K/Akt pathway regulator)
• Tumor suppressor genes can be inactivated by mutations, deletions, or epigenetic silencing
• The "two-hit hypothesis" suggests that both alleles of a tumor suppressor gene must be inactivated for cancer to develop (Knudson's hypothesis)
• The interplay between oncogenes and tumor suppressors, along with other genetic and epigenetic alterations, contributes to the development and progression of cancer

DNA Damage and Repair Mechanisms

• DNA damage can occur due to various factors, including endogenous sources (e.g., replication errors, reactive oxygen species) and exogenous sources (e.g., UV radiation, chemical mutagens)
• Different types of DNA damage include base modifications, single-strand breaks, double-strand breaks, and interstrand crosslinks
• Cells have evolved several DNA repair mechanisms to maintain genomic integrity
  • Base excision repair (BER) corrects small base modifications and single-strand breaks
  • Nucleotide excision repair (NER) removes bulky DNA lesions, such as those caused by UV radiation
  • Mismatch repair (MMR) corrects replication errors and base mismatches
  • Double-strand break repair occurs through homologous recombination (HR) or non-homologous end joining (NHEJ)
• DNA damage response (DDR) pathways detect DNA damage, signal its presence, and promote repair or cell death if the damage is irreparable
  • Key players in the DDR include ATM, ATR, Chk1, Chk2, and p53
• Defects in DNA repair mechanisms can lead to genomic instability and predispose individuals to cancer development (e.g., hereditary breast and ovarian cancer syndrome caused by BRCA1/2 mutations)

Cell Death: Apoptosis and Necrosis

• Cell death is a fundamental biological process that maintains tissue homeostasis and eliminates damaged or unwanted cells
• Apoptosis is a highly regulated form of programmed cell death characterized by distinct morphological and biochemical features
  • Morphological features include cell shrinkage, chromatin condensation, and the formation of apoptotic bodies
  • Biochemical features include caspase activation, DNA fragmentation, and exposure of phosphatidylserine on the cell surface
• Apoptosis can be triggered by extrinsic (death receptor-mediated) or intrinsic (mitochondrial-mediated) pathways
  • The extrinsic pathway is initiated by the binding of death ligands (e.g., FasL, TNF-α) to their corresponding death receptors (e.g., Fas, TNFR1)
  • The intrinsic pathway is regulated by the balance between pro-apoptotic (e.g., Bax, Bak) and anti-apoptotic (e.g., Bcl-2, Bcl-xL) proteins of the Bcl-2 family
• Necrosis is a form of cell death characterized by cell swelling, organelle dysfunction, and plasma membrane rupture
  • Necrosis is often associated with inflammation and tissue damage
• Dysregulation of cell death pathways can contribute to various diseases, including cancer, autoimmune disorders, and neurodegenerative diseases

Cancer Therapies and Future Directions

• Traditional cancer therapies include surgery, radiation therapy, and chemotherapy
  • Surgery aims to remove the primary tumor and, in some cases, nearby lymph nodes
  • Radiation therapy uses high-energy radiation to kill cancer cells and shrink tumors
  • Chemotherapy employs cytotoxic drugs to kill rapidly dividing cells, including cancer cells
• Targeted therapies are designed to specifically target molecules or pathways that are crucial for cancer cell growth and survival
  • Examples include small molecule inhibitors (e.g., tyrosine kinase inhibitors) and monoclonal antibodies (e.g., trastuzumab for HER2-positive breast cancer)
• Immunotherapy harnesses the power of the immune system to fight cancer
  • Approaches include immune checkpoint inhibitors (e.g., anti-CTLA-4, anti-PD-1/PD-L1), adoptive cell therapy (e.g., CAR T-cell therapy), and cancer vaccines
• Personalized medicine aims to tailor cancer treatment based on the molecular characteristics of an individual patient's tumor
  • Genomic profiling and biomarker identification are key aspects of personalized medicine
• Combination therapies that target multiple pathways or combine different treatment modalities (e.g., chemotherapy and immunotherapy) are being explored to improve treatment efficacy and overcome resistance
• Future directions in cancer research include further understanding of the tumor microenvironment, exploiting synthetic lethality, and developing novel drug delivery systems (e.g., nanoparticles)