Wright Cancer Flashcards by Rebecca Joynt

What are the 2 types of cnacer growth?

Hyperplastic: too many cells
Dysplastic: mutant cells

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What variation can observed in dysplastic growths?

Changes to nuclear size, shape, dye uptake, cytoplasmic ratio
Increased mitosis
Lack of cytoplasmic features

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Which cells are most cancers derived from?

90% epithelial

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How can primary tumours spread?

Via intravasation and dispersion of cells through blood and lymph systems

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What are the 2 types of epithelial cancer?

Squamous cell carinomas

Adenocarcinoma

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What are the main types of cancer?

Epithelial carcinomas
Connective tissue sarcomas
Haematopoetic leukaemias and lymphomas
CNS

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How does cancer arise?

Somatic driver mutations aquired over a period of time

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What are passenger mutations?

Mutations aquired during tumour development, contributing to genomic instability

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What features do cancer cells have in culture?

No contact inhibition
limitless replication
Less growth factor dependance
Refractile
Disarrayed actin

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What are the 6 hallmarks of cancer?

Evasion of apoptosis
Invasion and metastases
Sustained angiogenesis
Deregulated proliferation
Block of differentiation
Limitless replication
Evasion of immune system

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What test measures mutagenicity?

Ames

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How does the Ames test work?

Mutations disrupt histidine degrading gene so cells die in excess-histidine medium

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What is the relationship between mutagenicity and carcinogenicity?

Linear correlation

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What was the first oncogenic virus to be studied?

Rous Sarcome Virus

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How did RSV aquire v-Src?

Reterovirus inserts as provirus adjacent to c-Src gene

Uptaken during replication

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How does RSV cause cancer?

Acutely transforming with v-Src under control of consitutive strong 5’LTR

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How can c-Src be detected?

Hybridisation of v-Src probe to uninfected tissues

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How do slowly transforming reteroviruses cause cancer?

Insertational mutagenesis upregulates oncogene

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How can oncogenes be upregulated?

Amplification
Point mutations
Chromosome translocations

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What are Her2 related cancers caused by?

Gene amplification and overexpression of RTK

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What cancers are caused by chromosome translocations?

BCR-Abl in chronic myleogenous lymphoma

c-myc BCL in Burkitt’s lymphoma

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Where does ALV insert?

upstream of the c-myc oncogene

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How can point mutations be detected?

Inserting gene into mouse cell results in fibroblast formation
Southern blot to detect gene
Detect critical region of fragment by recombinant techniques to reduce size
sequence

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What is an example of an activating point mutation in an oncogene?

Ras oncogene mutated and activated in codon 12

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What are the main oncogene functions?

``` RTK Cytoplasmic TK Ser/Thr Kinase Steroid growth factor receptors nuclear TFs GTP-binding proteins ```

What kind of mutation is found in src?

Absence of phosphorylation of RTK C-terminal regulator so no autoinhibiton

What kind of mutation is v-ErbB?

Truncated ectodomain has ligand independant, constitutive activation

What function does c-Src have?

Tyrosine kinase adapter protein with SH2/SH3 domains for PDGFr

How is v-src constituitvely activate?

Phosphorylation of Y416 exposes kinase domain | No autoinhibition

What are the main ways RTKs are mutated in cancer?

Overexpression Autocrine signalling Ligand independance Lack of autoinhibition

How is Ras signalling upregulated in cancer?

Overactivation of receptors Loss of GTPase function Loss of GAPs

What cellular responses does Ras cause?

PI3K for PKB for proliferation PI3K for Rho for cell shape and motility MAPK for cell proliferation RAL for motility

What type of mutations are required to activate oncogenes?

Dominant

What type of mutations are required to knock-out tumour suppressors?

Recessive (both alleles)

How can tumour suppressor function be removed?

Deleting entire gene or critical region | Upregulation of inhibitor

How can tumour suppressor genes be studied in culture?

Fusion of cancer cell with normal cell will halt tumour growth

Which type of cancer gene can be inherited?

tumour suppressors

What are the 2 types of Retinoblastoma?

``` Sporadic mutations cause tumours in one eye Inherited form (40%) cause multiple tumours, both eyes and malignancy ```

What function is the Rb gene shown to have by fusion with tumour cells?

Halts cell cycle in G1 phase

What mutation causes retinoblastoma?

Chromosome 13 q14 deletion

What functions do tumour supressors have?

Restrain cell proliferation | Promote apoptosis

What are the targets of tumour suppressor genes?

Oncogene products | Signalling pathways

What does NF1 encode?

Neurofibromin for 1000x increase in Ras GTPase

What mutation does neurofibromatosis have?

Knock-out of tumour suppressor NF1 in schwann cells for consitutive activation of Ras

How is p53 tumour suppressor function lost?

Mutations affect folding of DNA binding domain | Loss of ARF inhibitor of MDM2 causing degradation of p53

What proportion of cancers shown p53 mutations?

50%

What function does p53 have in normal cells?

DNA repair Apoptosis Cell cycle arrest Block of angiogenesis

What proportion of cancer is encoded epigentically?

50% of all germline cancers

How do epigenetic changes cause cancer?

Methylation of CpG silences tumour suppressor genes

When are epigenetic changes developed?

Early in tumour formation

How is DNA methylation observed?

Stained dark

What are examples of genes that can be methylated to cause cancer?

RASSF1A | P16INK4A

How can cancer be detected without sequencing?

Measuring expression ratios of protein using mRNA/cDNA with microarray probes Ratios can be compared to "normal" Ratios/signatures determine prognosis

How many genes can be compared in a gene expression assay?

20,000

What are the 2 main classes of rational cancer treatment?

Antibodies | Low molecular weight compounds

What type of mutations do rational protein treatments target?

Oncogenes

How can antibodies be used in cancer treatment?

Neutralise overexpression of RTK by preventing ligand binding or dimerisation

What is an example of antibody treatment of cancer?

Herceptin for Neu/Her2 Epidermal Growth factor receptor overexpression

What are the advantages of Low Mw compounds to treat cancer?

Easier to produce | Penetrate tumour

How do low Mw compounds block signalling mutations?

Target ligand independant RTKs to block ATP binding in kinase domain

What is an example of the use of low Mw compounds to treat cancer?

Gleevec blocks Abl kinase domain in BCR-Abl translocations to prevent activation and TF activity

What is the main problem with cancer therapy using low Mw compounds?

Resistance develops

How are low Mw compounds developed?

Using structure based design