Neoplasia Flashcards
Define tumor.
- abnormal growth of tissue
Define neoplasm. How do neoplasms use telomerase, angiogenesis, and metastasis to their advantage?
- new tissue growth
- unregulated
- monoclonal
TELOMERASE
- cancers have upregulated telomerase => allows stabilization of telomere length => prevents cell cycle arrest due to short telomeres
ANGIOGENESIS
- necessary for tumor growth, nutrients, oxygen, growth factors
- upregulation of VEGF in tumor cells
- hypoxia-inducible factor (HIF-1a) can upregulate VEGF
- Von-Hippel Lindau (VHL) is a tumor-suppressor gene that inhibits HIF-1a. If VHL mutated => angiogenesis
METASTASIS
- downregulation of e-cadherin epithelial adhesion factor => dissociation of attached cells => cells attach to laminin => destruction of basement membrane via collagenase => attach to fibronectin => invade ECF, vessels, etc.
List and define characteristics used to differentiate between benign and malignant neoplasms.
- differentiation - how well do parenchymal cells resemble normal cells
- anaplasia - loss of structure and function of original cells
- pleomorphism - variation in size and shape of cells, characteristic of anaplastic neoplasms
- Nuclear-to-cytoplasm ratio (N:C Ratio) approaches 1:1 (typically, 1:6)
- dysplasia -
Explain the natural history of dysplasia. Describe clinical examples such as the respiratory tract and female genital tract.
def - disorderly architecture, primarily in epithelium characteristics - pleomorphic - hyperchromatic nuclei - high N:C ratio - disorderly maturation - mitoses above basal layer - do not penetrate basement membrane - may be reversible if stressor is removed
List and define characteristics used to differentiate between benign and malignant neoplasms.
BENIGN
- well-differentiated to dysplastic
- slow growth
- encapsulated
- localized
MALIGNANT
- well-differentiated to anaplastic
- pleomorphic
- hyperchromatic nuclei
- mitoses
- variable, unpredictable rate of growth
- ability to metastasize
- infiltrates locally
Define metastasis. List 3 pathways by which neoplasms metastasize.
- secondary implants of a malignant tumor
- may be in remote tissues
- presence indicates malignancy more than any other characteristics
PATHWAYS OF DISSEMINATION
- seeding within body cavities (ovarian cancer)
- via lymphatic spread (initially carcinomas spread to lymph drainage nodes)
- via blood vessels (hematogenous spread)
=> more typical of sarcomas, renal/hepatic carcinomas
Define proto-oncogene.
NORMAL genes that promote cell proliferation
- mutated or overexpressed versions of proto-oncogenes
- function autonomously
- encode TFs, growth proteins, cell survival proteins
- potent carcinogenic factor
- dominant
- gain of function = cancer
Define tumor suppressor genes.
NORMAL genes that inhibit cell proliferation
- recessive b/c need both to get transformation
- loss of function = cancer
Discuss: “The molecular basis of carcinogenesis is a multi-step process”
4 classes of normal regulatory genes are typical targets of cell damage
- proto oncogenes
- tumor suppressor genes
- apoptosis genes
- DNA repair genes
How does RAS mutations contribute to carcinogenesis?
- most commonly mutated gene in human tumors (30%)
- member of G protein family that transfers signal from membrane to nucleus
- when inactive = GDP, when active = GTP
- mutations interfere with RAS GTPase activity and prevent dephosphorylation of GTP => constantly active
- downstream effectors are proliferation genes => cell is continuously proliferating
How do Rb mutations contribute to carcinogenesis? Contrast between unilateral and bilateral retinoblastomas.
Retinoblastoma gene = first tumor suppressor discovered
- controls G1 to S transition in cell cycle
- when active = hypophosphorylated, bound to E2F transcription factor => prevents transcription of DNA replication genes => cells arrest in G1
- CDK4 (cyclin-dependent kinase) phosphorylates Rb => detaches from E2F
- mutated Rb is always unbound (inactive) => E2F TF is constantly stimulating progression of the cell cycle => uncontrolled growth
UNILATERAL - due to sporadic Rb mutations;
BILATERAL - germline; characteristic of osteosarcomas as well
How do p53 gene mutations contribute to carcinogenesis? Define Li-Fraumeni syndrome.
guardian of the genome - one of most commonly mutated gene
- in response to DNA damage by activating quiescence, senescence, or upregulating DNA repair genes
- if repair is not possible, activates apoptosis
LI-FRAUMENI
- germline + somatic (2 hit)
- 25x greater risk of developing malignancy by age 5
Apoptosis is carried out by caspases, which activate proteases and endonucleases. Describe the key principles of internal and external apoptotic pathways.
INTRINSIC (mitochondrial)
- DNA damage => inactivation of BCL2 => allows cytochrome c to leak from mitochondria => activates caspases => activates apoptosis
- BCL2 is normally anti-apoptotic when active b/c it blocks cytochrome c from damaging the mitochondrial membrane
- carcinogenesis: overexpression of BCL2
EXTRINSIC (receptor ligand)
- FAS ligand binds to FAS death receptor (CD95) on target cell
- activates caspases
- normally used to eliminate self-reactive lymphocytes
- carcinogenesis: disruption of FASL or FAS death receptor
Describe the mechanism of action of chemical carcinogenesis. List some common ones.
- react with RNA/DNA or nuclear proteins EXAMPLES - vinyl chloride => angiosarcoma of liver - nitrosamine in smoked meats => stomach cancer - asbestos - arsenic - napthylamine dyes - aflatoxin B - cigarette smoke
Define direct-acting carcinogenic agents.
- require no metabolic conversion
- ex: chemotherapy
