Lecture 30: From tumor biology to clinical care Flashcards
List factors 1-3 of the hallmarks of cancer and their therapeutic potential examples
1) Sustaining proliferative signalling i.e EGFR inhibitors
2) Evading growth suppressors i.e cyclin-dependant kinase inhibitors
3) Avoiding immune destruction i.e Immune activating anti-CTLA4 mAb
List factors 4-6 of the hallmarks of cancer and their therapeutic potential examples
4) Enabling replicative immortality i.e telomermase inhibitors
5) Tumor promoting inflammation i.e selective anti-inflammatory drugs
6) Activating invasion and metastasis i.e Inhibitors of HGF/c-met
List factors 7-10 of the hallmarks of cancer and their therapeutic potential examples
7) Inducing angiogenesis i.e inhibitors of VEGF signalling
8) Genome instability and mutation i.e PARP inhibitors
9) Resisting cell death i.e Proapoptotic BH3 mimetics
10) Deregulating cellular energetics i.e aerobic glycolysis inhibitors
What is neoplasm/neoplasia/”tumour”
Abnormal and excessive growth that is uncoordinated with that of the normal surrounding tissue
What is benign vs. malignant?
Does not spread vs has the potential to metastasize
linked to stage
What is adenoma vs adenocaricinoma?
Benign tumour of the epithelial cells vs malignant tumour of the epithelial cells
What is dysplasia?
(lack of control)
- Abnormal cell growth, often associated with microscopic appearance of variability between cells, reduced cellular differentiation and maturation
What is anaplasia?
(Cant differentiate)
- Reduced differentiation
What is metaplasia?
- Replacement of one type of mature differentiated cells with another
What is proliferation?
Division of cells, controlled by signalling pathways, often becomes uncontrolled in cancer
What is tumour evolution?
Mutations and epi-genetics accumulate in the somatic cells of a tumour, these changes are retained by tumour cells if they provide a competitive advantage in terms of survival, proliferation, migration, resistance to immune response or treatment
What is tumour heterogeneity?
Genetic, epi-genetic, and gene expression differences between distinct regions of a tumour, which may possibly result from tumour evolution
What is invasion?
Local spread of tumour
What is metastasis?
Spread of tumour to distinct sites i.e lymph nodes
What is grade?
How aggressive and unlike the originating cell type the cancer looks like under the microscope, especially in terms of proliferation and anaplasia.
What is stage?
How far a cancer developed and spread, in terms of primary tumour growth and invasion, and in terms of distant metastasis
What is tumour stroma?
Non-tumour cells within and around a tumour that support the tumours survival and growth
How is the regeneration of the colon mucosa achieved?
Genetically programmed signalling pathways control cellular proliferation and differentiation
i.e its very complex and requires many factors
How can DNA be influenced by cell signalling?
Many receptors and signals to impact the nucleus but hormones can freely diffuse in
What are some microscopic cellular features of dysplasia?
- Pleomorphism: Variation in size and shape between cells
- Hyperchromatic nuclei and increase in the nucleus/cytoplasm ratio
- loss of tissue architecture
What do anaplasia and dysplasia represent?
Failure of normal signalling pathways in cells due to genetic or epi-genetic changes, you can think of this as a loss of cellular social responsibility.
What are the two sets of genes help generate out of control cells?
Changes to tumour suppressor genes - inactivating proteins ‘not enough break’
Changes to proto-oncogenes - overactive proteins ‘too much throttle’
What are some examples of tumour suppressor genes?
RB1, TP53, BRCA1/2, APC
What are some examples of proto-oncogenes?
EGFR, RAS, BRAF, CCND1
Describe how cancer is initiated?
- Cancer is initiated and progresses through the accumulation of genetic changes that disrupt the signalling pathways that regulate cells
- (Somatic changes)
- 5-10% sig inheritance component
What is one of the hallmarks of cancer and why?
Evading the immune system
- Required for cancer cells to survive and proliferate
Summarise of key molecules and cells involved in cancer elimination by the immune system;
- Antigen presentation (MHC class 1, display tumour antigens from within cancer cells)
- NK cells
- CD4
- CD8
Describe 1-4 mechanisms of tumour immune resistance?
1) Reduced HLA class 1 expression
2) Antigen loss
3) Antigen processing system loss
4) Increase resistance to immune attack
Describe 5-8 mechanisms of tumour immune resistance?
5) Release immune inhibitors
6) Amino acid depletion
7) Activate immune inhibitory T cell types
8) Express immune inhibitors on cancer cell surface i.e CD80
How does trastuzumab act?
- Causing Her2 receptor lysosomal degradation
- Blocking Her2 PI3K/AKT intracellular signalling
- Encouraging immune attack
More effective in those with amplified Her2
What is the Her2 receptor?
- Her2 receptor is on the surface of epithelial cells that turns on intracellular signalling pathways (including the PI3K and MAPK pathways)
What happens to Her2 in cancer?
20-30% of breast cancers the Her2 gene is amplified, this turns on cell division and tumour growth
