2021 cancer misc

Question 1

Hanahan and Weinberg 2000

Answer 1

6 original hallmarks

1. Failure of apoptosis
2. Sustained proliferative signalling
3. Evading growth suppressors
4. Sustained angiogenesis
5. Enabling replicative immortality
6. Tissue invasion and metastasis

Question 2

Hanahan and Weinberg 2011

Answer 2

2 new hallmarks:
Deregulating cellular energetics and avoiding immune destruction
2 enabling characteristics:
Genome instability and mutation, tumour promoting inflammation

Question 3

Muthukkaruppan and colleagues 1982

Answer 3

Compared the behaviour of cancer cells infused into different regions of the same organ. One region was the iris with blood circulation and another was the anterior chamber with no circulation. The cancer cells without blood circulation grew 1-2mm3 in diameter and then stopped by grew beyond 2mm3 when placed in an area where angiogenesis was possible

Question 4

PCAWG

Answer 4

International collaboration to identify common patterns of mutation - Results published by Campbell et al 2020
Consortium conducted an analysis of the genome of 38 different tumour types, including 2658 distinct genomes
4-5 drivers - several barriers to increased proliferation must be overcome
were grouped into classes including germline mutations, somatic copy number alterations (SCNAs), structural variants (SVs), non-coding point mutations and coding point mutations. Mutations were classed as being coding, promoter, splicing, 3’UTR (untranslated region) and 5’ UTR mutations. SCAs and SVs were classed as amplified oncogenes, deleted tumour supressor genes (TSGs), truncated TSGs, fusion genes, and cis-activating growth receptors
Find mutations to target treatment, find what mutations cancers have in common, it also found that cancer is not dependent on the organ of origin but rather defined by the genetic changes - this is an argument that genetics are super important

Question 5

Korsisaari et al (2007)

Answer 5

investigated the role of VEGF in the growth of intestinal benign tumors in Apc+/min mice. In situ hybridization analysis has demonstrated the up-regulation of VEGF in epithelial and stromal cells of adenomas compared with the adjacent normal mucosa. These authors have initiated VEGF blocking treatment with Mab G6–31 (5 mg/kg, once weekly), which blocks both murine and human VEGF, in Apc+/min mice when the animals are 13 weeks old and have found that the inhibition of VEGF reduces vascular density and prevents further growth of intestinal adenomas. The mean lifespan of animals that receive Mab G6–31 treatment is extended by nearly 10 weeks when compared with control treated animals. Interestingly, despite the tumor growth arrest, no reduction has been observed in tumor numbers. These data demonstrate that VEGF signaling is involved in tumor progression, but not in tumor initiation.

Question 6

Gerber et al 2007 - same group that made the mouse model

Answer 6

The hum-X VEGF mouse model was then used to compare the activity and safety of a panel of VEGF Mabs with different affinities for VEGF-A. Although in vitro studies clearly showed a correlation between binding affinity and potency at blocking endothelial cell proliferation stimulated by VEGF, in vivo experiments failed to document any consistent correlation between antibody affinity and the ability to inhibit tumor growth and angiogenesis in most animal models. However, higher-affinity antibodies were more likely to result in glomerulosclerosis during long-term treatment. Just shows how much more powerful humanised models can be