Cancer Cell Biology¶
Chapter 77 | Part 4: Oncology and Hematology · Part 4 – Oncology: Solid Tumors · Chapter 77
Key Clinical Points¶
- Cancers originate from monoclonal genetic alterations but exhibit heterogeneity due to microenvironment interactions.
- Malignant neoplasms are defined by uncontrolled proliferation, evasion of apoptosis, tissue invasion, and metastasis.
- p53 pathway mutations (in 50% of human cancers) disrupt DNA repair and cell cycle control.
- Tumor growth follows Gompertzian kinetics with declining growth fractions over time.
- Telomerase expression (>90% of cancers) prevents telomere shortening, enabling immortality.
- Targeted therapies (e.g., imatinib for CML, BRAF inhibitors for melanoma) exploit specific genetic lesions.
- Pediatric cancers differ from adult cancers in mutational burden and chemotherapy responsiveness.
- Cancer cells evade immune surveillance via MHC downregulation and regulatory T-cell expansion.
- Warburg effect shifts metabolism to aerobic glycolysis for rapid proliferation.
- Restoring normal cell cycle regulation is challenging; inhibiting oncogenic pathways is more clinically feasible.
1. DEFINITION & OVERVIEW¶
• Definition: Cancer is characterized by unregulated cell division, evasion of apoptosis, tissue invasion, and metastasis. • Classification: ◦ Benign: Non-invasive. ◦ Malignant: Invasive/metastatic. • Histogenesis: ◦ Carcinomas: Origin from epithelial tissues. ◦ Sarcomas: Origin from mesenchymal tissues. ◦ Leukemias/Lymphomas: Origin from hematopoietic cells. • Growth Dynamics: ◦ Monoclonal Origin: Cancers arise from single-cell genetic alterations but develop heterogeneity through clonal evolution and microenvironment interactions. ◦ Gompertzian Kinetics: Initial 100% growth fraction declines to <5% at diagnosis due to microenvironmental constraints.
1.1 Monoclonal Origin and Heterogeneity¶
• Heterogeneity Factors: ◦ Genetic/epigenetic changes. ◦ Extrinsic factors (stroma, oxygen availability) leading to spatially variable microenvironments. • Clinical Impact: Therapeutic resistance often arises from subpopulations with distinct genetic profiles.
1.2 Cancer as an Organ That Ignores Its Niche¶
• Loss of Control: Malignant cells lose responsiveness to growth-inhibiting signals from the tissue niche. ◦ Clinical Detection: Tumor mass reaches clinical detectability at ≈10^9 cells; lethal burden at 10^{12}–10^{13} cells. ◦ Growth Rate: Gompertzian kinetics show a decline in proliferation rates over time.
2. EPIDEMIOLOGY¶
Childhood cancers differ from adult cancers in: • Lower mutational burden (often germline-driven). • Higher chemotherapy responsiveness. • Predominant mesodermal/ectodermal origins (e.g., ALL, brain tumors). • Reduced environmental risk factors compared to adult populations.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Cancer arises through multi-step genetic/epigenetic processes involving oncogenes, tumor suppressors, and DNA repair defects. • Oncogene activation (e.g., BCR-ABL in CML, BRAF V600E in melanoma). • Tumor suppressor inactivation (p53, Rb, BRCA1/2). • Cell cycle checkpoint failure. • Telomerase reactivation. • Immune evasion mechanisms.
3.1 Oncogenes and Tumor-Suppressor Genes¶
• Oncogenes: (e.g., RAS, MYC) drive uncontrolled proliferation when mutated. • Tumor Suppressors: (p53, Rb) normally inhibit cell cycle progression and DNA repair. • p53 Mutation: Found in >50% of human cancers; located on chromosome 17p.
3.2 Cell Cycle Checkpoints¶
• G1/S Checkpoint: Regulated by Rb-E2F and inhibited by p16INK4a/p21Cip1. • G2/M Checkpoint: p53-mediated DNA damage response (ATM/ATR activation). • Spindle Checkpoint: Failure leads to aneuploidy in ≈90% of cancers.
3.3 Telomeres and Telomerase¶
• Senescence: Telomere shortening triggers p53-dependent senescence. • Immortalization: >90% of cancers express telomerase (hTERT) to maintain telomere length. • Clinical Correlation: Telomerase deficiency causes dyskeratosis congenita with bone marrow failure.
3.4 Signal Transduction Pathways¶
• RAS/MAPK: Activation in ≈30% of cancers (e.g., KRAS mutations). • PI3K/AKT/mTOR: Dysregulation in 20–30% of tumors. • JAK/STAT: Signaling aberrations in hematologic malignancies.
4. CLINICAL FEATURES¶
• Pediatric Cancers: More responsive to chemotherapy, lower mut1ational burden. • Adult Cancers: Higher genetic complexity, more resistance to therapy. • Metastatic Potential: Correlates with EMT markers (vimentin, N-cadherin upregulation).
4.1 Pediatric vs. Adult Cancer Differences¶
• Genetics: Germ100% germline mutations common in pediatric cancers (e.g., Li-Fraumeni syndrome). • Outcome: Higher cure rates with intensive chemotherapy regimens. • Risk Factors: Less frequent environmental risk factors in children.
5. DIFFERENTIAL DIAGNOSIS¶
• Benign vs. Malignant: Distinguished by invasive growth, metastasis, and genetic instability. • Tumor Type: Differentiation based on histogenesis (carcinoma vs. sarcoma). • Mimics: Immune-related disorders mimicking cancer (e.g., sarcoidosis with lymphadenopathy).
6. INVESTIGATIONS & DIAGNOSIS¶
• Molecular profiling: Targeted therapies (NGS, FISH). • Immunohistochemistry: Biomarkers (p53, Ki-67 proliferation index). • Tumor mutation burden assessment: For immunotherapy eligibility.
6.1 Diagnostic Algorithms¶
- Clinical suspicion based on symptoms/signs.
- Imaging (CT/MRI for localization).
- Biopsy with histopathology and molecular testing.
- Genetic counseling for hereditary cancer syndromes.
7. MANAGEMENT & TREATMENT¶
• Targeted therapies: Imatinib (CML), BRAF inhibitors (melanoma), Osimertinib (EGFR-mutant NSCLC). • Immunotherapy: PD-1/PD-L1 inhibitors, CAR-T cells for hematologic malignancies. • Chemotherapy: Tailored to tumor type and molecular profile.
7.1 Targeted Therapies¶
• EGFR TKIs: Target exon 19/21 mutations. • ALK Inhibitors: Crizotinib, alectinib for NSCLC with rearrangements. • PARP Inhibitors: Olaparib for BRCA-mutant cancers.
7.2 Future Directions¶
• Liquid biopsy for real-time monitoring. • CRISPR-based gene editing for tumor suppression. • Combination immunotherapy with oncolytic viruses.
8. PROGNOSIS & COMPLICATIONS¶
• Prognosis Factors: Stage, molecular profile, and treatment response. • Complications: Tumor lysis syndrome, cachexia, immune-related adverse events (e.g., pneumonitis from checkpoint inhibitors). • Long-term Risks: Secondary malignancies (e.g., leukemia after alkylating agents).
9. SPECIAL CONSIDERATIONS¶
• Germline cancer syndromes: BRCA1/2, Lynch syndrome, Li-Fraumeni. • Pediatric oncology: Unique toxicities from anthracyclines (cardiotoxicity). • Palliative care integration for advanced disease.
10. KEY PEARLS & CLINICAL TRAPS¶
• p53 Prevalence: Mutations are the most common in human cancers (50% of tumors). • Telomerase Expression: Expressed in >90% of cancers but absent in normal somatic cells. • Warburg Effect: A metabolic hallmark, not a cause, of cancer. • Immune Checkpoints: Inhibitors require PD-1/PD-L1 expression for optimal response.
Reference Tables¶
TABLE 77-1 Phenotypic Characteristics of Malignant Cells Deregulated cell proliferation: Loss of function of negative…¶
Harrison's 22e, p.529
- Deregulated cell proliferation: Loss of function of negative growth regulators
(tumor suppressor genes, i.e., Rb, p53) and increased action of positive growth
regulators (oncogenes, i.e., Ras, Myc). Leads to aberrant cell cycle control and
includes loss of normal checkpoint responses. - Failure to differentiate: Arrest at a stage before terminal differentiation.
May retain stem cell properties. (Frequently observed in leukemias due to
transcriptional repression of developmental programs by the gene products of
chromosomal translocations.) - Loss of normal apoptosis pathways: Inactivation of p53, increases in Bcl-2
(antiapoptotic) family members. This defect enhances the survival of cells with
oncogenic mutations and genetic instability and allows clonal expansion and
diversification within the tumor without activation of physiologic cell death
pathways. - Genetic instability: Defects in DNA repair pathways leading to either single
nucleotide or oligonucleotide mutations (as in microsatellite instability, MIN) or,
more commonly, chromosomal instability (CIN) leading to aneuploidy (abnormal
number of chromosomes in a cell). Caused by loss of function of a number of
proteins including p53, BRCA1/2, mismatch repair genes, DNA repair enzymes,
and the spindle checkpoint. Leads to accumulation of a variety of mutations in
different cells within the tumor and heterogeneity. - Loss of replicative senescence: Normal cells stop dividing in vitro after 25–50
population doublings. Arrest is mediated by the Rb, p16INK4a, and p53 pathways.
While most cells remain arrested, genetic and epigenetic changes in a subset
of cells allow further replication, leading to telomere loss, with crisis leading
to death of many cells. Cells that survive often harbor gross chromosomal
abnormalities and the ability to continue to proliferate. These cells express
telomerase, which maintains telomeres and is important for ongoing growth of
these cells. Relevance to human in vivo cancer remains uncertain. Many human
cancers express telomerase. - Nonresponsiveness to external growth-inhibiting signals: Cancer cells have
lost responsiveness to signals normally present to stop proliferating when they
have overgrown the niche normally occupied by the organ from which they are
derived. Our understanding about this mechanism of growth regulation remains
limited. - Increased angiogenesis: Due to increased gene expression of proangiogenic
factors (VEGF, FGF, IL-8, angiopoietin) by tumor or stromal cells, or loss of
negative regulators (endostatin, tumstatin, thrombospondin). - Invasion: Cell mobility and ability to move through extracellular matrix and into
other tissues or organs. Loss of cell-cell contacts (gap junctions, cadherins) and
increased production of matrix metalloproteinases (MMPs). Can take the form
of epithelial-to-mesenchymal transition (EMT), with anchored epithelial cells
becoming more like motile fibroblasts. - Metastasis: Spread of tumor cells to lymph nodes or distant tissue sites. Limited
by the ability of tumor cells to migrate out of initial site and to survive in a foreign
environment, including evading the immune system (see below). - Evasion of the immune system: Downregulation of MHC class I and II molecules;
induction of T-cell tolerance; inhibition of normal dendritic cell and/or T-cell
function; antigenic loss variants and clonal heterogeneity; increase in regulatory
T cells. - Shift in cell metabolism: Complex changes including alterations due to
tumor stress such as hypoxia and energy generation shifts from oxidative
phosphorylation to aerobic glycolysis generate building blocks for malignant cell
production and proliferation. - Complex interactions with the extracellular environment around the
cancer cells: Induction of changes as well as complex interactions with the
extracellular environment around cancer cells, including modifications to the
extracellular matrix, vasculature, chemokines, mesenchymal stromal cells,
fibroblasts, immune cells, other hematopoietic cells, platelets, nerves, and
potentially infectious agents impacting many of the above processes.
TABLE 77-2 Some FDA-Approved Molecularly Targeted Agents for the Treatment of Cancer DRUG Ivosidenib, olutasidenib…¶
Harrison's 22e, p.534
| DRUG | MOLECULAR TARGET | DISEASE | MECHANISM OF ACTION |
|---|---|---|---|
| Ivosidenib, olutasidenib | IDH1 | AML, MDS, cholangiocarcinoma | IDH1 inhibitor |
| FLT3 | AML | ||
| Idelalisib | PI3K-delta | CLL | Inhibits PI3k-delta, preventing proliferation and inducing apoptosis |
| PIK3CA | Breast cancer with a PIK3CA mutation | ||
| Belzutifan | Hif-2α | HIF-1α-associated RCC, pancreatic neuroendocrine, CNS hemangioblastoma |
Inhibits Hif-2α |
| AKT | Breast cancer | ||
| Umbralisib | PI3K-delta, CK1-epsilon | MZL, FL | Inhibits PI3K-delta and CK1-epsilon |
| Exportin-1 | MM, DLBCL | ||
| Tazemetostat | EZH2 | FL, epithelioid sarcoma | Inhibits EZH2 |
| Monoclonal Antibodies | |||
| HER2/neu (ERBB2) | Breast cancer, gastric or GEJ cancer | ||
| Pertuzumab | HER2/neu (ERBB2) | Breast cancer | Binds HER2 on tumor cell surface at distinct site from trastuzumab and prevents binding to other receptors |
| EGFR | Colon cancer, squamous cell carcinoma of the head and neck |
||
| Panitumumab | EGFR | Colon cancer | Similar to cetuximab but fully humanized rather than chimeric |
| EGFR | Squamous NSCLC | ||
| Rituximab | CD20 | B-cell lymphomas and leukemias that express CD20 |
Multiple potential mechanisms, including direct induction of tumor cell apoptosis and immune mechanisms |
| CD52 | Chronic lymphocytic leukemia and CD52- expressing lymphoid tumors |
||
| Bevacizumab | VEGF | Colorectal, lung cancers, RCC, glioblastoma | Inhibits angiogenesis by high-affinity binding to VEGF |
| VEGFA, VEGFB, PLGF | Colorectal cancers | ||
| Ramucirumab | VEGFR | Gastric, colorectal, lung cancers | Inhibits angiogenesis by binding to VEGFR |
| CTLA-4 | Melanoma, HCC, MSI-high colorectal cancer | ||
| Nivolumab, pembrolizumab, dostarlimab-gxly, toripalimab, retifanlimab-dlwr, cemiplimab-rwlc |
PD-1 | Melanoma, head and neck cancer, NSCLC, SCLC, Hodgkin’s disease, urothelial cancer, RCC, HCC, gastric cancer, esophageal cancer, cholangiocarcinoma, MSI-high cancers, endometrial cancer, cervical cancer, cutaneous squamous cell carcinoma, basal cell carcinoma, breast cancer, nasopharyngeal cancer, Merkel cell tumor |
Blocks PD-1, preventing interaction with PD-L1 and T-cell inhibition |
| PD-L1 | NSCLC, urothelial cancer, SCLC (durvalumab), HCC (atezolizumab), Merkel cell cancer (avelumab) |
||
| Relatlimab | LAG3 | Melanoma (combined with nivolumab) | Blocks LAG3 interaction with MHCII and other ligands inhibiting immune activation |
| Rank ligand | Breast, prostate | ||
| Dinutuximab | Glycolipid GD2 | Neuroblastoma (pediatric) | Immune-mediated attack on GD2-expressing cells |
| CD38 | MM | ||
| Elotuzumab | SLAMF7 | MM | Activating NK cells to kill MM cells |
| PDGFRα | Soft tissue sarcomas | ||
| Naxitamab | GD2 | Neuroblastoma | Immune-mediated antitumor effect |
| Bispecific Antibodies | |||
| CD19 and CD3 | Ph-relapsed precursor B-cell ALL | ||
| Glofitamab-gxbm, epcoritamab- bysp, mosunetuzumab-axgb |
CD20 and CD3 | DLBCL, FL | Binds CD20 on DLBCL or FL and CD3 on T cells, immune attack on CD20-expressing cells |
| B-cell maturation antigen (BCMA) and CD3 |
MM | ||
| Talquetamab | CD3 and GPRC5D | MM | Binds CD3 T cells and GPRC5D-expressing MM cells |