Lecture 32 and 33 Flashcards
Neoplasia
abnormal growth of cells or tissues
Differences between malignant tumors and benign tumors
cancers are less differentiated
cancers are invasive
cancers are metastatic
Grading
estimate of aggressiveness of malignancy based on microscopic examination of tumor cell
grading is based on the differentiation state and the number of mitoses of the tumor
Staging
is the estimate of aggressiveness of level of malignancy based on size of the primary lesion, extent of spread to lymph nodes, and the presence of absence of metastases
staging is largely quantitative in nature
staging is of greater clinical value
Three fundamental principles of carcinogenesis
- Genetic changes lie at the heart of carcinogenesis
- Two major classes of genes are the targets of this damage
- Oncogenes: genes that are targets for this damage
- Tumor suppressor genes: genes that inhibit cancer - Carcinogenesis is often a multistep process with multiple genes involved
Two-hit hypothesis for tumor suppressor genes
Alfred Knudsen-1971: Used mathematics to develop this hypothesis
needs a mutation in both alleles to show the phenotype of the mutation
Some cancers are a result of mutation or deletion of a single gene and these cancers tend to run in families
Assumption that hereditary retinoblastoma results from a single, recessive inherited genetic mutation
Most tumor suppressors are recessive and need homozygous deletion/mutation. Families show increased susceptibility to cancers
Oncogenes
drives cancer
can result from a translocation to make a protein with new function
can result from a mutation that makes more active version of a protein
alterations are dominant and often occur at a single allele
How does cancer risk increase with age?
Two common causes:
1. accumulation of somatic mutations
2. decline in immune function
How do environmental factors increase DNA damage?
Increased incidence of lung cancer in smokers is an example of environmental factor that may contribute to cancer incidence
NSCLC in non-smokers slow mutation rate
NSCLC in smokers increase mutation rate
Chemical carcinogens function by reacting with DNA which leads to DNA damage
How do inherited mutations in DNA repair genes contributes to increased cancer risk?
loss of DNA repair causes increased mutation rate and increased tumor occurrence
BRCA 1/2 repair of a double stranded DNA breaks. Inherited mutations lead to breast and ovarian cancer
Xeroderma pigmentosum mutations in XP genes is high risk for skin cancer
Ataxia telangiectasia mutation in the ATM involved in repairing double stranded DNA breaks. Neurodegeneration disorder with increased lymphoma and leukemia incidence
Radiation
radiation causes genetic lesions by inducing DNA strand breaks which causes overexpression of oncogenes or reduced expression of tumor suppressor genes
UV light causes genetic lesions by cross-linking DNA bases which can cause LOF mutations in tumor suppressor genes and GOF mutations in oncogenes genes
Hallmark 1
Self-sufficiency in growth signals
activation of kinase signal transduction pathways that respond to mitogenic signaling
Essentially active RAS pathways will result in uncontrolled cell growth
Hallmark 2
Resistance to growth inhibitory signals
cancer may arise through loss of expression of growth inhibitory proteins
When RB is mutated, it allows E2F to initiate gene transcription without regulation
Hallmark 3
Evade apoptosis: disruption of apoptotic pathways prevents cell death upon DNA damage or cell cycle activation
Loss of p53 expression or function
Loss of p51 (cell cycle checkpoint)
Loss of BAX pro-apoptotic proteins
Hallmark 4
Limitless relative potential
Tumor cells overexpress telomerase, leading to cell immortalization
Telomere shortening leads to chromosomal abnormalities and cell death
