Cellular & molecular biology of cancer Flashcards
what is the difference between malignant and benign tumours
- Benign = Locally confined in non-vital organ, Differentiated
- Malignant = Invades other tissues, Spreads to distinct organ via the blood and lymphatic system, Loss of differentiated morphology
What is the evidence for the genetic basis of cancer
- loss of growth control is heritable (somatic)
- DNA damaging agents are generally carcinogenic
- DNA repair deficiency syndromes are associated with an increased susceptibility to carcinogens
- Genetic predisposition to some cancers is hereditary
What evidence shows loss of growth control is heritable
In vitro growth of tumour cells and transplantable tumour lines suggest genetic alteration are involved
what evidence shows that DNA repair deficiency syndromes are associated with an increased susceptibility to carcinogens
Ataxia telangiectasia
Xeroderma pigmentosum
HNPCC (hereditary non-polyposis coli) - DNA mismatch repair defect
what evidence shows that DNA damaging agents are generally carcinogenic
Experimental and Epidemiological evidence
Occupation and lifestyle:
□ Ionising radiation – leukaemia and osteosarcoma
□ Ultra violet light – skin cancers, including melanoma
□ Cigarette smoking – lung cancer, bladder cance
What is the evidence shows that genetic predisposition to some cancers is hereditary
Retinoblastoma, Wilm’s tumour, familial adenomatous polyposis, HNPCC, multiple endocrine neoplasia (MEN), Li Fraumeni, BRCA1&2, acoustic neuroma, etc.
what is the clonal origin of tumours
○ X-linked G6PD markers A and B, distinguishable by electrophoretic mobility
○ Random X-inactivation post fertilisation in females generates a mosaic in normal tissues
○ Tumours are found to express only one of the alleles whereas the surrounding normal tissue is a mosaic
Animals leukaemia, lymphomas and sarcomas can be caused be
Viruses
Rare transmissible
Cancer is not normally infectious though
What are the three main groups that tumours causesing viruses can be classified
- DNA viruses
- Long latency retroviruses
- Acutely transforming retroviruses
what provided the first evidence for the existence of specific cancer causing genes
Acutely transforming retroviruses
The majority of common sporadic cancers in humans includes. These do not have a pattern of _
- Most leukaemias, lung, colorectal, breast, & bladder cancer
- incidence that would suggest a transmissible viral cause
Describe the different types of tumour viruses
DNA - viruses with a DNA genome (Sarcoma)
RNA - Viruses with an RNA genome, also known as retroviruses because their RNA has to be copied into DNA before the protein encoded by the viral genes can be expressed in the host (cervical cancer)
ATR - Acutely transforming retroviruses are so called because the cancers arising from them manifest themselves particularly rapidly (only in animals)
How do in vitro transformation assays aid in identifying cancer biology
- Characteristics of in vitro transformation: Disordered colony morphology, Loss of contact inhibition, Anchorage independent cell growth
- Speed and efficiency suggested direct action of a viral gene
- The viruses found to encode only 3 or 4 genes
- This brought the genetic mechanisms of cancer within reach and laid the foundations of our current concepts of the molecular genetic basis of cancer
Describe how the rous sarcoma virus lead to the discovery of the src oncogene
- A single gene encoding a small protein found to profoundly alter the growth pattern of infected cells and render them cancerous
- Because of the association with sarcomas the gene was called src (pronounced “sark”)
- Term oncogene coined to categorise genes such as src that can transform cells and cause cancer
What implied that there is many alternative ways in which the growth of a cell can be deregulated to give rise to cancers
Different viruses were found to carry different oncogenes, with products located in different parts of the transformed host cell and exhibiting a range of different biochemical functions
What are the origin of the viral oncogenes
- Homologous (~80% ) to host genomic sequences = suggests transduced from normal cellular genes
- Absence of intronic sequences = picked up as reverse transcripts of cellular mRNA that become co-integrated with viral cDNA and provide a growth or survival advantage
- Normal cellular counterparts: “proto-oncogenes” = capacity to be activated to an oncogene on being incorporated into the retrovirus
Long latency retroviruses cause _
tumours that take a longer time to develop
Long latency transforming retroviruses do not
carry oncogenes
But the tumours they generate are stable and clonal suggesting the viruses produce genetic alterations in the host cells
long latency retroviruses activates
cellular proto-oncogenes and insertional mutagenesis
what can the availability of cloned oncogene probes form acutely transforming retroviruses show that
the long latency viruses integrated close to cellular counterparts (proto-oncogenes) of the viral oncogenes
what is an example of activation of proto-oncogenes by long latency retroviruses
c-MYC & avian leukosis viruses
what is the NIH3T3 transfection system
Used to identify and isolate human tumour oncogenes
- DNA isolated directly from human tumours shown to transform cells in culture
How does NIH3T3 work
- Because human DNA was transferred into mouse cells it was possible to identify and clone the specific human oncogenic DNA involved
- DNA sequencing revealed human counterparts (homologues) of oncogenes previously found in acutely transforming retroviruses
= Also led to the discovery of new members the RAS and MYC oncogene familie
How can chromosomes activate proto-oncogenes
- rearrangement
○ Tumour cell chromosomes show frequent abnormalities in number and structure
○ Cytogenetic clues to the location of oncogenes and a route to their discovery = Gene amplification, Chromosomal translocation
How does gene amplification cause cancer
- The gain of multiple copies of a chromosomal region
- Overexpression of genes in that region confer a selective growth advantage to tumour cells
- Manifested as either: ll extrachromosomal staining bodies referred to as double minutes (DM’s)
Explain the philadelphia chromosome
○ t(9;22)(q34,q11) reciprocal translocation frequently found in chronic myeloid leukaemia (CML)
○ Results in the fusion of two genes, BCR and ABL1, activating the ABL1 proto-oncogene
○ This activated tyrosine kinase successfully targeted by imatinib
How do oncogenes and proto-oncogenes differ
○ Point mutations = RAS gene family, FMS, BRAF
○ Deletions, rearrangements and fusions = v-erbB (truncated homologue of the EGF-receptor), BCR + c-ABL fusion (Philadelphia chromosome t(9,22))
○ Over-expression of the normal gene = Chromosomal rearrangements, Viral promoter insertions, Gene amplification
what are oncogene products and what do they do
- Growth factors (extracellular) = sis (PDGF), Int1(WINT1), int2(FGF3), hst(FGF4)
- Growth factor receptors (transmembrane) = erbB family, Other tyrosine kinase receptors
- Signal transducers (inner membrane associated and cytoplasmic) = ras GTP-binding proteins, src, Braf
- Signal effectors (nuclear) = myc, jun and fos, Cell cycle control genes – cyclins & cyclin –dependent kinases
