Premed · Premed · Cell Biology
Lecture 26: Cancer: The Cell Biology of Disease
Cell Biology
Learning Objectives
By the end of this lecture, students will be able to:
- Describe the hallmarks of cancer as defined by Hanahan and Weinberg
- Explain the roles of oncogenes and tumor suppressor genes in cancer development
- Describe the multi-step model of carcinogenesis
- Explain the cell biological basis of invasion and metastasis
- Discuss the principles of targeted cancer therapy based on cell biology knowledge
Lecture Content
I. The Hallmarks of Cancer
Cancer is a disease of uncontrolled cell proliferation arising from accumulation of genetic and epigenetic alterations. Hallmarks of cancer (Hanahan and Weinberg, 2000; updated 2011, 2022): Sustaining proliferative signaling: constitutive growth factor signaling (autocrine loops, activating mutations in RTKs/Ras/MAPK) Evading growth suppressors: inactivation of Rb, p53, APC, and other tumor suppressors. Resisting cell death: overexpression of Bcl-2, loss of p53, upregulation of IAPs. Enabling replicative immortality: telomerase reactivation (TERT) or ALT (alternative lengthening of telomeres); bypass of senescence. Inducing angiogenesis: VEGF secretion to build new blood vessels that supply the tumor. Activating invasion and metastasis: EMT, protease secretion, loss of E-cadherin. Deregulating cellular energetics: Warburg effect (aerobic glycolysis — preference for glycolysis even in the presence of O2) Avoiding immune destruction: downregulation of MHC-I, PD-L1 expression to suppress T cell killing. Genome instability and mutation: defects in DNA repair, chromosomal instability. Tumor-promoting inflammation: chronic inflammation fuels tumor growth (cytokines, growth factors, ROS from immune cells) Additional emerging hallmarks: unlocking phenotypic plasticity, non-mutational epigenetic reprogramming, polymorphic microbiomes, senescent cells in the tumor microenvironment.
II. Oncogenes
Proto-oncogenes: normal genes that promote cell growth/division. Become oncogenes through gain-of-function mutations. Dominant at the cellular level: mutation of one allele is sufficient. Mechanisms of oncogene activation: Point mutation: e.g., Ras (G12V — glycine to valine at position 12 locks Ras in GTP-bound active state) KRAS mutations found in ~25% of all human cancers (pancreatic, colorectal, lung) Gene amplification: extra copies of gene -> overexpression. HER2 (ERBB2) amplification in ~20% of breast cancers. MYC amplification in many cancers. Chromosomal translocation: places gene under a strong promoter or creates a fusion protein; t(9;22) BCR-ABL in chronic myeloid leukemia (CML): constitutively active tyrosine kinase; t(14;18) Bcl-2 in follicular lymphoma: Bcl-2 overexpression under IgH enhancer; t(8;14) MYC in Burkitt lymphoma: MYC under IgH enhancer. Viral insertion: retroviral promoter/enhancer activates nearby proto-oncogene. Categories of oncogene products: Growth factors: PDGF (Sis) Growth factor receptors: EGFR, HER2, Kit, RET. Signal transducers: Ras, Raf, PI3K, Src, Abl. Transcription factors: Myc, Jun, Fos. Cell cycle regulators: cyclin D1, CDK4. Anti-apoptotic: Bcl-2.
III. Tumor Suppressor Genes
Normal function: restrain cell growth, promote apoptosis, maintain genome integrity. Loss-of-function mutations lead to cancer; typically requires both alleles to be lost (Knudson's two-hit hypothesis) First hit: inherited mutation (familial) or somatic mutation. Second hit: loss of heterozygosity (LOH), deletion, mutation, or epigenetic silencing. Key tumor suppressors: p53 (TP53): "guardian of the genome". Mutated in >50% of all cancers. Functions: G1 arrest (p21), DNA repair, apoptosis (PUMA, NOXA, Bax), senescence. Many missense mutations are dominant negative (mutant p53 tetramerizes with wild-type p53 and inactivates it) Li-Fraumeni syndrome: germline TP53 mutations -> predisposition to many cancer types. Rb (RB1): master regulator of G1/S checkpoint. Retinoblastoma: childhood eye tumor; familial (one inherited hit) or sporadic (two somatic hits) Functionally inactivated in most cancers (directly or via the CDK4-cyclin D-Rb pathway) APC: Wnt pathway negative regulator (component of beta-catenin destruction complex) Familial adenomatous polyposis (FAP): germline APC mutation -> thousands of colon polyps -> colorectal cancer. APC loss -> constitutive Wnt activation -> stem cell expansion in crypts. BRCA1, BRCA2: DNA double-strand break repair (homologous recombination) Germline mutations -> hereditary breast and ovarian cancer. Loss of HR repair -> genome instability -> sensitivity to PARP inhibitors (synthetic lethality) PTEN: phosphatase that degrades PIP3 -> antagonizes PI3K/Akt pathway. One of the most commonly lost tumor suppressors.
<image>Oncogenes and tumor suppressors in cancer signaling. Panel A: Normal cell signaling — growth factor binds RTK -> Ras-MAPK and PI3K-Akt pathways (controlled by PTEN) -> transcription factors (Myc) -> cell cycle entry. Checkpoints: Rb (blocks E2F in G1), p53 (responds to DNA damage with arrest or apoptosis), APC (controls Wnt/beta-catenin). Panel B: Cancer cell — multiple alterations shown simultaneously: activating mutation in Ras (star, constitutively active), HER2 amplification (multiple receptors on the surface), loss of PTEN (crossed out), p53 mutated (crossed out), Rb inactivated, Bcl-2 overexpressed (blocking apoptosis), telomerase reactivated. Arrows emphasize uncontrolled proliferative signaling and blocked growth arrest/apoptosis pathways. Panel C: Knudson two-hit model — inherited retinoblastoma (one RB1 allele mutated at birth, second hit in somatic cell -> tumor) versus sporadic retinoblastoma (both hits occur somatically in the same cell -> much rarer).</image>
IV. Multi-Step Carcinogenesis
Cancer develops through the gradual accumulation of mutations over time (usually decades) Colorectal cancer progression (Vogelstein model): Normal epithelium -> APC loss -> small adenoma -> KRAS activation -> large adenoma -> SMAD4/p53 loss -> carcinoma -> additional mutations -> metastasis. Each step provides a selective growth advantage (clonal evolution) Clonal evolution: cancer progresses by Darwinian natural selection at the cellular level. Mutations that provide a proliferative/survival advantage are positively selected. Tumor heterogeneity: different subclones within a tumor carry different mutations. Branching evolution: subclones diverge -> intra-tumor heterogeneity -> therapy resistance. Mutational burden: most cancers have 40-80 protein-altering mutations (only 2-8 are "driver" mutations; the rest are "passenger" mutations) Genome instability accelerates mutation accumulation: Defects in DNA mismatch repair (MLH1, MSH2): microsatellite instability (MSI) -> Lynch syndrome (hereditary nonpolyposis colorectal cancer) Chromosomal instability (CIN): whole chromosome gains/losses; aneuploidy. Chromothripsis: catastrophic shattering and reassembly of chromosome segments.
V. Invasion and Metastasis
Metastasis is the major cause of cancer death (~90% of cancer mortality) Metastatic cascade: Local invasion: tumor cells breach the basement membrane (MMPs, especially MMP-2, MMP-9, MT1-MMP) Intravasation: entry into blood vessels or lymphatics. Survival in circulation: anoikis resistance, platelet cloaking, immune evasion. Extravasation: arrest at distant site, exit from vessels. Colonization: survival and proliferation at the metastatic site (often rate-limiting) Epithelial-to-mesenchymal transition (EMT): E-cadherin downregulation (Snail, Slug, Twist, ZEB1/2 transcription factors) Gain of mesenchymal markers (N-cadherin, vimentin, fibronectin) Increased motility, invasiveness, and resistance to apoptosis. Partial EMT (hybrid states) may be more metastatic than full EMT. Seed and soil hypothesis (Paget, 1889): metastasis depends on compatibility between the tumor cell (seed) and the distant organ microenvironment (soil) Pre-metastatic niche: tumor-secreted factors (exosomes, cytokines) prepare distant sites before tumor cells arrive. Organ tropism: breast cancer -> bone, lung, brain, liver; prostate cancer -> bone; colorectal cancer -> liver. Tumor microenvironment: cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), immune cells, blood vessels, and ECM all support tumor growth and metastasis.
VI. Targeted Therapy: Cell Biology Applied
Imatinib (Gleevec): BCR-ABL tyrosine kinase inhibitor for CML. First molecularly targeted cancer therapy; transformed CML from fatal to chronic disease. Paradigm for targeted therapy based on understanding the driving oncogene. Trastuzumab (Herceptin): anti-HER2 monoclonal antibody for HER2+ breast cancer. EGFR inhibitors: erlotinib, gefitinib, osimertinib for EGFR-mutant non-small cell lung cancer. KRAS G12C inhibitors: sotorasib, adagrasib — first drugs to directly target mutant KRAS (previously considered "undruggable") PARP inhibitors (olaparib): exploit synthetic lethality in BRCA1/2-mutant cancers. BRCA-deficient cells cannot repair DSBs by HR; PARP inhibition blocks backup repair -> cell death. Immune checkpoint inhibitors: Anti-PD-1 (pembrolizumab, nivolumab), anti-PD-L1, anti-CTLA-4 (ipilimumab) Block inhibitory checkpoints -> reactivate T cell killing of tumor cells. Remarkable responses in melanoma, lung cancer, renal cell carcinoma, and others. Venetoclax: Bcl-2 inhibitor (BH3 mimetic) for CLL and AML — directly restores apoptosis. CAR-T cell therapy: T cells engineered to express chimeric antigen receptors targeting tumor antigens (CD19 for B-cell lymphomas/leukemias) Resistance: nearly universal problem; pre-existing resistant subclones or acquired mutations under therapy selection pressure; drives combination therapy approaches.
<image>The metastatic cascade and therapeutic targets. Panel A: Steps of metastasis — primary tumor (1) invading through the basement membrane, (2) intravasation into a blood vessel, (3) survival in circulation (tumor cells surrounded by platelets), (4) extravasation at a distant organ, (5) colonization and formation of a micrometastasis that grows into a secondary tumor. EMT transcription factors (Snail, Twist) indicated at the invasion step. Panel B: Targeted therapy map — a cancer cell with labeled molecular targets and their corresponding drugs: HER2 (trastuzumab), EGFR (erlotinib), BCR-ABL (imatinib), KRAS G12C (sotorasib), BRAF V600E (vemurafenib), Bcl-2 (venetoclax), PARP (olaparib in BRCA-mutant context), PD-L1 on tumor surface (anti-PD-L1 antibody blocking interaction with PD-1 on a T cell).</image>
