CANCER- 6 October 2010
PATHOLOGY
Outline for the day
Introduction
Oncogenes
Tumour suppressor genes (antioncogenes)
Oncogenes, growth factors, hormones and their receptors
Introduction
-current dogma is that cancer is the accumulation of a series of genetic insults (alterations to the gene sequence)
-review of gene sequence
-base sequence adenine, thymidine, guanidine, cytidine
-importance of base sequence-
this is important in-transcription -copying of DNA to make RNA
-translation-interpreting the RNA sequence to make proteins
-genes that are altered in terms of their sequence are those that are involved in the normal cellular processes such as cell cycle regulation, differentiation and signalling
-cell cycle-cellular reproduction
-differentiation- when cells change into different types of cells
-cells start out as stem cells
-as cells differentiate they send out various chemical messengers (signalling messengers) that promote further differentiation of cells
-as cells are under the control of DNA, certain alterations in that DNA can alter the cell cycle, differentiation and chemical messenging resulting in cells that are out of control- these out of control cells continue to reproduce uncontrollably and disrupt the structure and integrity of other cells resulting in loss of function of cells
-alterations to gene sequence-due to insults such as radiation, viruses, chemicals and diet
-there are DNA repair mechanisms but if these mechanisms fail to work then one is left with a permanently altered DNA- it is possible to pass these permanently altered genes to ones offspring
-consequently it is possible to carry out pass damaged or pro-cancerous genes from one generation to the next
-for example the BRCA-1 gene has been identified and linked to breast cancer in current and succeeding generations of women who have the BRCA-1 gene
-once a gene has been modified to a pro-cancerous form and transmitted to future generations there are some cases where it is difficult to undo or overcome the damaging effects of the pro-cancer gene
Protooncogenes and Antioncogenes
Proto-oncogenes-genes that can be converted to oncogenes –oncogenes favour the loss of cellular control
-liken this to an accelerator on a car
Anti-oncogenes-genes that favours the maintenance or regaining of control
-liken this to a brake on a car
-consequently- maintenance of cellular control depends on a constant balance between protooncogenes and the antioncogenes
-indeed in a normal well-controlled cell both protooncogenes and the antioncogenes are active
-protooncogenes-favour cell reproduction
-antioncogenes-prevention of cell reproduction
-if protooncogenes and the antioncogenes activities are not in the correct balance then cancer develops
-examples of protooncogenes and the antioncogenes
-protooncogenes-growth factors and growth factor receptors
-protein kinases
-mediators of cell transduction
-DNA binding proteins
-antioncogenes
-induce cellular apoptosis
-gating genes- will not allow a cell to pass beyond a certain point unless all the correct signals are in place-viewed as earlywarning system
Messages normally go out are those meant to keep the body cancer free
THE RED CAT ATE THE OLD RAT
Conversion of proto-oncogenes to oncogenes via
-point mutations/transversions
-single base change in codon
-frequently result from carcinogens and radiation
-single base change results in sense or nonsense mutations of message
-sense- message is still understandable
THE RED CAR ATE THE OLD RAT
-nonsense-message is unintelligible
THE RED CAX ATE THE OLD RAT
Nonsense message results in stop codon and truncated protein whose signal inunintelligible
-frameshift mutation
result from insertions or deletions of a single nucleotide or of large amounts of DNA
-frequently results in unreadable sequence
THE REC ATA TET HEO LDR ATZ
-amplification
-instead of 2 copies of a gene have at least 10 to hundreds of copies of a protooncogene-push to cell replication cannot beovercome by compensatory cellular mechanisms
-translocations
-fusion of 2 genes resulting in a novel protein
gene A-THE RED CAT ATE THE OLD RAT
gene B-THE DOG SAW THE NEW FLY
after fusion
gene A-THE RED CAT SAW THE NEW FLY
gene B-THE DOG ATE THE OLD RAT
-results in message that may promote cancer
Tumour suppressor genes
-alterations in these reduce braking mechanism and control is lost
Oncogenes, growth factors, growth hormones and their receptors
-all of these are abnormally expressed in malignant cells
-overexpression of oncogenes, growth factors, growth hormones and their receptors in malignant (out of control cancerous) cellsresulting in unfettered cell growth