Molecular oncogenesis Flashcards
Name a couple ways of how malignant cells thrive or grow
Evade apoptosis Self-sufficiency in growth signals Insensitivity to anti-growth signals Tissue invasion and metastasis Limitless replicative potential Sustained angiogenesis
What is the molecular basis of cancer?
Non-lethal genetic alterations – key to carcinogenesis
What are some of the regulatory gene targets for cancer?
Protooncogenes Tumor suppressor genes Antiapoptosis genes Apoptosis genes DNA repair genes
Describe protooncogenes.
Normal regulatory genes, involved in regulating normal cell growth, expression is under tight control
Describe oncogenes
Cancer genes, involved in autonomous, unregulated cell proliferation in cancer cells, expression is constitutive, only one mutant allele required (gain of function).
Protooncogene + alteration = oncogene
How do tumors learn to respond to growth factors?
They acquire the ability to produce GF to which they are responsive. They may develop GF receptors.
What growth factor does the SIS gene produce and what does it lead to?
beta-PDGF –> overexpression and drives proliferation of astrocytomas/osteosarcomas
How do growth factors normally responds and how does that differ from when they become cancer growth factors?
Normally they are on when a growth factor binds and off when it does not. Cancer leads to abnormal constitutive activation. (ERB B2 gene – HER2/Neu and c-KIT gene)
What does amplification of the ERB B2 (Her-2-Neu) growth factor mean?
Poor prognostic sign in breast cancer and predicts unresponsiveness to estrogen therapy. Patients will be receptive to Trastuzumab (Herceptin).
What drug targets the c-KIT mutation in GISTs and what does it do?
Imatinib mesylate (Gleevec) – tyrosine kinase inhibitor
What are the functions of signal transducing proteins?
They normally receive signals from receptor-ligand complexes and transiently transduce signal into organelles.
Signal transducing protein that contains point mutations in 15-20% of all tumors. GTP binding proteins with reduced GTPase activity. Potential chemotherapy target.
RAS oncogene family
K-RAS in pancreas and colon CA
H-RAS in bladder and kidney CA
Signal transducing protein that has transient tyrosine kinase activity. Cancer results from a translocation between 9th & 22nd Philedelphia chromosome.
c-ABL gene
Translocation creates a bcr-abl fusion product. Present in chronic myelogenous leukemia and acute lymphoblastic leukemia. Detected by cytogenetics and PCR. Results in a loss of regulatory control = constitutively active.
What is the role of transcription factors?
They bind to DNA and control transcription of genes (activation or inhibition).
Transcription factor that activates a wide range of genes. Usually under tight regulation – transient increase in expression following a signal to replicate and then rapid return.
MYC oncogene
C-MYC: mutated form that leads to continued expression
N-MYC: mutated form that leads to amplification
Increased expression in Burkitt Lymphoma
Results from t(8;14) –> becomes under regulation of IgG heavy chain and loses tight regulation
c-MYC gene
Amplification in neuroblastoma with poor prognosis
n-MYC gene
Name two main cell cycle regulators.
Cyclins: transient expression, activate CDKs
CDKs (cyclin-dependent kinases): constitutively expressed, phosphorylate target proteins
What is the function of cyclin D?
Activates CDK4 and that complex phosphorylates Rb protein
How does cyclin D1 become oncogenic?
t(11;14) –> cyclin D1-IgH fusion, over expression of cyclin D1. Detected by cytogenetics and immunohistochemistry. Present in mantle cell lymphoma, minor pop in plasma cell myeloma and hairy cell leukemias.
