Lecture 4 Flashcards
Proliferation of normal cells regulation
Regulated by:
1. Genetic program of each cell
2. Signals from one cell to another through direct contact
3. Soluble substances that have growth promoting or inhibiting effects
Differentiation: selective activation of genes and depression of other gene
Proliferation of neoplastic cells
Neoplasia (new growth): Unregulated growth of cells
Proliferation:
1. Autonomous: independent of growth factors and stimuli that promote normal cells
2. Excessive: unceasing in response to normal regulators of cellular proliferation
3. Disorganized: do not follow rules governing formation of normal tissues
Classification of tumours
Histological Classification
• Macroscopic features (gross, naked-eye examinations)
• Microscopic features (histological cell features)
• Chromosomal differences
• Biological features
Clinical Classification
•Clinical presentation and outcome
Macroscopic features of benign vs malignant cells
Benign: slow, limited expansion; no metastases; smooth external surface; capsule; no necrosis; no hemorrhage
Malignant: Fast, uncontrollable expansion; metastases; irregular external surface; no capsule; necrosis; hemorrhage
Microscopic features of benign vs malignant cells
Benign: resembles normal cells of the tissue of origin, cells are well differentiated; uniform nuclei of a normal size and shape; few cells doing mitosis
Malignant: does not resemble normal tissue of origin; poorly differentiated; pleomorphic nuclei with a high nuclei:cytoplasm ratio; many irregular mitoses
Chromosomes of tumour cells
Benign: usually normal chromosome number
• Diploid (46): 44 autosomes and 2 sex chromosomes (XX, or XY)
Malignant:
•Aneuploid (abnormal number)
•Structurally abnormal
•Deletions
•Translocations
—> Due to disorderly mitosis
Metastasis
Tumour cells move from one site to another
Only malignant tumour cells
3 pathways:
1. Lymphatics
2. Blood (hematogenous spread)
3. Seeding of the surface of body cavities
Biochemistry of cancer cells
• Less differentiated, more adapted to survive under unfavorable conditions; require less oxygen to survive
• Fewer mitochondria, RER, specialized enzymes, underdeveloped cytoplasm
• Simplified metabolism and function
• Anaplasia – atypical features, nuclear irregularities
• Can regress to assume some fetal features
• Liver cells secrete alpha-fetoprotein
Teratoma tumour
• Derived from germ cells
• Embryonic cells that differentiate into embryonic germ layers
• Contains tissues formed from all three germ layers:
1. Ectoderm (nervous system, epidermis)
2. Mesoderm (bone, muscle, connective)
3. Endoderm (GI, respiratory, urinary)
Blastoma
• Malignant tumours composed of embryonic cells originating from embryonic primordia
• Retinoblastoma: eye
• Neuroblastoma: adrenal medulla or immature neural cells
• Hepatoblastoma: liver
• Nephroblastoma: kidney
Tumour staging
Staging (extent of tumour spread): based on clinical assessment during gross examination, surgery, x-ray examinations
•TNM system: size of tumor (T), presence of lymph node metastases (N), distant metastases (M)
TMN system T (for tumour size)
T1: 0-2 cm
T2: 2-5 cm
T3: >5 cm
T4: tumour has broken through skin or attached to chest wall
TMN system N (for lymph node status)
N0: surgeon cannot feel any nodes
N1: surgeon can feel swollen nodes
N2: Nodes feel swollen and lumpy
N3: Swollen nodes loaded near collarbone (in case of breast cancer)
TMN system M (for metastasis)
M0: Tested nodes are cancer free
M1: Tested nodes show cancer cells or micrometastasis
Tumour grading
Grading: based on histological examination (differentiation based)
•Grade I: tumours are well differentiated
•Grade II: moderately differentiated
•Grade III: undifferentiated
Causes of cancer
Exogenous (carcinogens)
•Chemical
•Physical
•Biological (eg oncogenic virus)
Endogenous
•Resides in the genome and cells, heritable
•Causes changes in the genome of the target cells
•Oncogenes (human cancer genes)
•Tumour suppressor genes (p53
Where chemical carcinogens may act
- Locally - skin carcinogens at the site of contact
- Site of digestion in the intestines – mediated by intestinal bacteria
- Site of metabolic activation in the liver
- Site of excretion in urine
Chemical carcinogenesis
- Initiation: irreversible genetic changes in exposed cells
- Promotion: cellular proliferation
- Conversion: new cell type
- Progression: new genetic features and expansion of cell clones
Physical carcinogens
Radiation:
•Ultraviolet light (most common cause of skin cancers)
•X-rays
•Radioactive material
Physical carcinogenesis
- UV light causes DNA damage
- Damage initiates repair process
- Individuals who are constantly exposed to UV or lack proper DNA repair mechanisms develop cancers
•Point mutations
•Cross-linkage
Physical carcinogens: atomic bomb
•Atomic bomb in Hiroshima and Nagasaki 1945
•Large release of ionizing radiation
•Breaks molecular bonds = DNA damage
•Significant increases in leukemia 2-years after the bomb
•Attributable risk of leukemia spiked to 46% for bomb survivors
•10 years after the bomb led to a spike in solid tumours
•Attributable risk increased to ~12%
Human oncogenes
•Homologous to viral oncogenes
•Cellular oncogenes = mutated normal cellular genes called proto-oncogenes
•Proto-oncogenes transformed to oncogenes via 4 mechanisms:
1. Amino acid substitution
2. Increased number of copies
3. Translocation or deletion of chromosomal fragment
4. Gene insertion
Burkitt’s lymphoma
• Characterized by activation of MYC Oncogene
• Chromosomal translocation leads to increase of MYC activation
• Leads to tumour formation
• High-grade non-Hodgkin lymphoma
• Develops from B-lymphocytes
• One of the fastest growing lymphoma
Tumour suppressor genes
Protects cells against activated or newly acquired oncogenes
Best known tumour suppressor genes:
• P53 (numerous cancers – breast, colon)
• RB1 (retinoblastoma gene)
• BRCA1 and BRCA2 (breast and ovarian carcinoma)
Prevent excessive cell growth by inhibiting cell cycle progression
