Lecture 27: Cancer Cells: Excessive Birth Rate Flashcards
What are cancer cells (in terms of chromosomes?)
Aneuploid
What is euploid?
Abnormal number of chromosomes (humans= 46)
What is aneuploid?
An abnormal number of chromaomes
Cancer cells may also have what kind of altered chromosomes?
Structurally altered
Describe the nature of abnormalities in cancer cells
Many abnormalities are random but some are characteristic of a particular type of tumour
Cancer cells containing excess copies of certain genes can increase what?
Gene copy number (amplification)
What can amplification arise from the accumulation of?
Extra chromosomes in which the gene is found,
Multiple small “double minute” chromosomes each composed of a segment of chromosomal DNA (an amplicon) containing the relevant gene.
Multiple copies of the gene arranged in head to tail tandem configuration in a chromosomes which appears as a homogenously staining region
Which gene is often amplified in cancer?
The gene containing the epidermal growth factor receptor EGFR
How does EGFR bind to growth factors like EGF and TGFα?
Epidermal growth factor receptor has an extracellular ligand binding domain which binds growth factors,
And a transmembrane domain and a cytoplasmic tyrosine kinase domain which phosphorylates protein substrates in tyrosine
What may happen to the EGFR gene in advanced cancers?
It may undergo a deletion where the ligand binding domain is removed from the EGFR protein .
What happens in a normal EGFR receptor?
The ligand binding domain in the absence of the ligands (EGF and TGFα) suppress tyrosine kinase activity
What happens in the truncated protein?
It has deregulated tyrosine kinase activity
What kind of chromosome translocations do many cancers have?
Characteristic chromosome translocations
Due to exchange of genetic material between non homologous chromosomes
What is the effect of the exchange of genetic material between non homologous chromosomes?
They place genes into novel genetic environments and deregulate their expression.
What are mantle cell tumours?
Tumours of b lymphocytes
What break points do mantle cell lymphomas have?
Chromosome (c) 11 near the B cell lymphoma-1 gene and
C-14 within the immunoglobulin heavy chain gene (IgH)
What does the translocated BCL-1 gene become controlled by and why?
IgH gene transcriptional enhances as the translocated BCL-1 gene is placed near it
How can the mutant cancer causing genes in cancer cell DNA be assayed?
Transferring (transfecting) the DNA from cancer cells into partially transformed mouse cells and observing phenotypic change in the latter
What are the effects of transfecting DNA from partially transformed cells (which are immortalised, as they have no limits to proliferation)
They become fully transformed cells and have
Reduced dependence on growth factors Reduced density dependent inhibition of proliferation producing multiple layers of cells Reduced adherence to substrate Anchorage - independent proliferation Tumor formation in mice
What type of genes was discovered by transfecting?
One of the RAS genes which causes 25% of human cancers
What do the oncogenic versions of the RAS genes contain?
Mutations at 1 of 3 amino acid positions (codons 12, 13 or 61)
What is retinoblastoma?
Rare childhood cancer of the eye
How can the tumour be predisposed?
It can either be inherited or it can occur sporadically
What is the difference between hereditary and sporadic retinoblasomas?
Hereditary retinoblastomas develop with single hit kinetics
Sporadic retinoblastomas show two-hit kinetics
What did Knudson propose?
That two genetic mutations are required for cancer development
Hit1: inheritance or mutation of one allele of the RB1 gene
Hit2: loss of the remaining (normal wild type) allele due to nondisjunctionvloss of chromosome 13 at mitosis, mitotic crossing over, deletion