Principles of Oncogenesis Flashcards
What is neoplasia usually the interaction between?
Environmental and genetic factors
List some biologic agents that are oncogenic pathogens
Retroviruses (FeLV) - express oncogenes
Poxviruses (BPV and equine sarcoids)
Others (Helicobacter pylori and gastric carcinoma)
List examples of environmental carcinogens
Chemical
Radionucleic
Radiation
What is a mitogen?
Causes cell proliferation
Define oncogene
contribute to formation of a cancer when inappropriately activated
What does activating/gain of function mutation of proto-oncogenes cause?
promote proliferation, inhibit apoptosis or both
Name 2 tumour suppressor genes
Rb and p53
Normally act to prevent cells proliferating out of control
For function to be lost, both copies of the gene need to be mutated/deleted/silenced
Rb - transduces growth-inhibitory signals that originate largely outside the cell and determines whetherh or not cell cycle progression should proceed.
p53 - receives input from intracellular operating systems, such that if cell viability is suboptimal, it calls a halt to cell cycle progression, until such time as these new conditions have been normalised. Can also trigger apoptosis.
What can increase susceptibility to malignant transformation?
insertion, deletion, chromosomal rearrangement or missense mutation of:
oncogenes or tumour suppressor genes
What is the multi-step carcinogenesis model?
Initiation
Promotion
Progression
These depend on accumulation of several different mutations (usually at least 10-12). Thus, cumulative mutations in several oncogenes and tumour suppressor genes are required before a clinically significant tumour can develop.
What are the Hallmarks of Cancer (Hanahan and Weinberg)? 6
Sustaining proliferative signalling Evading growth suppressors Activating invasion and metastases Enabling replicative immorality Inducing angiogenesis Resisting cell death
What tumours do the sex hormones predispose to?
Oestrogen/progesterone - mammary tumours
Androgens - prostatic carcinoma and perianal adenoma
List some common breed predispositions
Boxers - lymphoma, MCT, others
Flat coated retrievers - STS
Irish Wolfhound - OSA
GSD - HSA
How can sustaining proliferative signalling be achieved by tumour cells? 3
Secretion of endogenous growth factors
Mutation of growth factor receptors
Mutation of intracellular signalling molecules
Outline MCT and KIT mutations.
How does this affect novel treatment?
N.b. KIT is a RTK
Mast cells normally rely on stem cell factor (SCF) to survive and this acts through the KIT pathway. In these tumours, there is a mutation in the juxtamembrane portion of the RTK-R meaning that the KIT pathway is constitutively active.
NOVEL TREATMENT: RTK inhibitors include:
Toceranib and Masitibib
(Secondary effect of also inhibiting angiogenesis)
How can tumour cells resist cell death? 2
EXTRINSIC PATHWAY - receives and processes EC death-inducing signals
INTRINSIC PATHWAY - sensing and integrating variety of singals of intracellular membrane
Each culminates in the activation of the Caspase cascade –> apoptosis.
Many cancer cells downregulate death receptors or upregulate members of the Bcl-2 family to this end. This can also provide some resistance to cytotoxic anti-cancer drugs
Define combination chemotherapy
Modern treatment technique
Attack the cancer on several biological fronts simultaneously
How do tumour cells enable replicative immortality?
Telomerase is upregulated in the vast majority of malignant cells –> immortality. THis is a specialised DNA polymerase that adds telomere repeat segments to the ends of DNA
How do tumours induce angiogenesis?
Many tumours secrete angiogenic factors (VEGF)
How do tumour cells invade tissues and metastasise? 2
Produce MMPs
Alter cell adhesion molecules to detach and migrate (e.g. loss of E-cadherin by carcinoma cells)
Name 2 emerging hallmarks of cancer
Deregulating cellular energetic/reprogramming energy metabolism
Evading immune detection
How do tumour cells alter their energy metabolism?
Re-programme their glucose metabolism (limiting metabolism largely to glycolysis rather than mitochondrial oxidative phosphorylation which is achieved in a number of ways such as upregulating GLUT1 transports for more efficient glucose uptake)
How do tumour cells evade immune destruction?
WHAT?
Avoid immunosurveillance
Downregulate immune effector mechanisms
Induce immunological tolerance
HOW? downregulating immunogenic Ags Kill tumour-infiltrating WBCs Produce immunosuppressive mediators Induce tolerance
What are the 2 new enabling characteristics of cancer?
Genome instability and mutation
Tumour-promoting inflammation
How do tumour cells become genetically unstable? 3
increased sensitivity to mutagenic agents
breakdown in one or several components of the genome maintenance machinery
both
