21 Neoplasia 2 Flashcards
Define carcinogenesis
The initiation of cancer formation
What are the four basic principles of carcinogenesis?
- Non-lethal damage is KEY
- A tumor is formed by the clonal expression of a single precursor cell that has incurred damage (ie monoclonal)
- 4 classes of normal regulatory genes
- Carcinogenesis is a multi-step process
Understand concept of Multistep carcinogenesis
- cancers result from the accumulation of multiple mutations
- Average of 90 mutant genes per tumor
- Some (11/90) are mutated at high frequency
- Some true tansformers, others passengers
- NO SINGLE MUTATION IS ENOUGH
Multistep carcinogenesis:
- First hit?
- Second Hit?
- Followed by?
- First hit: germ-line (inherited) or somatic (acquired) mutations of cancer suppressor genes
- Second hit: methylation abnormalities; invasion of normal alleles
- Proto-oncogene mutations
- Homozygous loss of add’n cancer suppressor genes // overexpression of COX-2
- Oncogene-induced senescence OR add’n mutations // gross chromosomal alterations
Compare and contrast behavioural characteristics of normal cells and malignant tumor cells
7 important characteristics:
1. Response to Growth signals
2. Response to growth inhibitory signals
3. Response to apoptotic signals
4. Ability to repair DNA
5. Angiogenesis
6. Ability to invade and spread
7. Replicative potential
Normal Cell // Malignant Cell
1. Controlled // Self-sufficient
2. Yes // No
3. Yes // No
4. Yes // No
5. Limited // Induced
6. No // Yes
7. Telomeres and 53 activation // Limitless replicative potential via telomerase reactivation
Understand concept of proto-oncogenes, oncogenes, and tumor suppressor genes and their relation ot genetic abnormalites in tumor cells
examples?
Tumor Suppressor Genes: products apply the brakes to cell proliferation
- Eg RB and p53 - important genes that recognize genotoxic stress and shut down proliferation
RB = retinoblastoma protein
Understand concept of proto-oncogenes, oncogenes, and tumor suppressor genes and their relation ot genetic abnormalites in tumor cells
Oncogenes: genes that promote the autonomous growth of cancer cells
- Autosomal dominant
- Provides tumor self-sufficiency in growth signals
- eg HER2 ;
Understand concept of proto-oncogenes, oncogenes, and tumor suppressor genes and their relation ot genetic abnormalites in tumor cells
Proto-oncogenes: the unmutated cellular counterpart of the oncogene
- Typically drive the normal cell through the cell cycle
- Growth factors or their receptors
- Signal transducers
- Transcription factors
- Cell cycle components
eg Ras proteins are proto-oncogenes that are frequently mutated in human cancers
What is an oncoprotein?
Oncoprotein: product of an oncogene that is similar to the product of the proto-oncogene but lacks regulatory elements
- production independent on growth factors and external signals = autonomous growth
understand the role of chemical agents in causing cell transformation
Chemical Carcinogenesis:
Initiation: exposure of cells to a ? of carcinogenic agent (?) to cause a ?
- Cell capable of ? but ? alone no enough
- Permanent and irreversible ?
Promoters: induce tumors in ? but are ? on their own
- -Do not directly affect ?
- - Do not work on ?
- Are ?
Chemical Carcinogenesis:
Initiation: exposure of cells to a sufficient dose of carcinogenic agent (initiator) to cause a permanently altered cell
- Cell capable of giving rise to a tumor but initiation alone no enough
- Permanent and irreversible DNA damage
Promoters: induce tumors in initiated cells but are non-tumorigenic on their own
- -Do not directly affect DNA
- - Do not work on non-initiated cells
- Are reversible
Expain the mechanisms of the body’s immunologic defenses against tumors
- Tumor antigens: ?
- Antitumor Effector Mechanisms: ?
- Immunodeficiency: ?
- A normal function of immune system is to survey body for emergy malignant cells and destroy them
- Tumor antigens: **tumor products that elicit an immune response
- eg lymphocytic infiltrate around rumors**
- Antitumor Effector Mechanisms: Cell-mediated immunity (cytotoxic T-cells, NKC, Macrophages
- Antibodies produced but not protective
- Anti-CD20 (b-cell surface antigen) used to treat lymphoma
- Immunodeficiency: strongest argument for the existence of immune surveillance
- Congenital immunodeficiencies, immunosuppressed transplant patients, AIDS
Explain the proposed mechanisms of late recurrence
- Variably defined: >10 years after primary tx
- Unclear which tumors will have late recurrence and why
- Tumor dormancy Theory: prolonged survival of micrometastases without progression
- Millions of tumor cells shed daily even from small tumors
- Detected in blood and bone arrow, even in patients who never delop grossly metastatic lesions
- Remain dormant until right background milieu makes metastatic site habitable
What is RB?
Which checkpoint is it important?
Retinoblastoma - First and prototypic tumor suppressor gene
- Active (Hypophosphorylated) in quiescent cells
- Inhibits transcription of genes for G1-S checkpoint
- If mutated, cell cycle is released
- - 1st mutation inherited, second is acquired
What is the “Two-hit hypothesis”?
Two mutations, involving both alleles, are required (Growth inhibititory signals)
= Loss of heterozygosity
Exception: Haploinsufficiency
What is p53 and what happens if p53 is inactivated?
Activated by?
TP53 gene -> tumor protein p53 (or p53).
p53 = tumor suppressor, regulates cell division by keeping cells from growing and dividing too fast or in an uncontrolled way
- Activated by Cell stress -> quiescence -> if dna is repaired cell cycle continues otherwise apoptosis
- If inactivated, cell proceeds to divide even with damaged DNA/ shortened telomeres/ hypoxia
What is the result of Mitotic catastrophe?
Massive cell death (loss of telomerase)
The defining features of a malignant cell:
Invasion and metastasis:
- Invade extracellular matrix
- Vascular dissemination
- Extravasation and metastatic growth
Role of viral agents in causing cell transformation:
- HPV: ?
- HepB/C: ?
- HHV-8: ?
Role of viral agents in causing cell transformation:
- HPV: Human papilloma Viruscervical cancer through carcinogenic proteins
- HepB/C: liver cancer through chronic inflammation, cirrhosis, and re-generation
- HHV-8: Keposi sarcoma
