Hallmarks of Cancer

What are the 7 principles of the evolution of cancer?

1. Cancer is mediated by somatic evolution 2. Cancer is many tissue-specific and age-associated diseases, with one commonality in uncontrolled cell replication 3. The somatic evolution of cancer is mediated by the population-genetic forces of mutation, selection & genetic drift, in a phylogenetic, phylogeographic context 4. Cancer is a polygenic, heritable, and environmental disease, mediated in part by mismatches between current and ancestral conditions 5. The ultimate causes of cancer involve evolutionary tradeoffs & co-option of normal evolved functions involving growth, maintenance, and reproduction 6. Anticancer adaptations have evolved 7. Cancer cell populations evolve in response to therapies

Mutation in what gene could give rise to self-sufficiency in growth signalling?

Activation of H-Ras oncogene--> greater Ras signalling

What's the largest a tumour can grow to without establishing its own blood supply?

No greater than 5mm

What is meant by self-sufficiency in growth signalling?

Through the use of oncogenes, cancer cells can mimic normal growth signalling (similar to the mitogenic growth signals of normal cells) to reduce their dependence on stimulation from their normal tissue microenvironment which allows them to go from a quiescent state into an active proliferative state without regulation. Activation of H-Ras oncogene would give rise to this

What are the 6 pre-established hallmarks of cancer?

1. Inducing angiogenesis 2. Enabling replicative immortality 3. Activating invasion and metastasis 4. Evading growth suppressors 5. Sustaining proliferative signalling (can stimulate own growth signals) 6. Resisting cell death (evading apoptosis)

Name the hallmarks of cancer (10) including the emerging hallmarks

1. Inducing angiogenesis 2. Enabling replicative immortality 3. Activating invasion and metastasis 4. Evading growth suppressors 5. Sustaining proliferative signalling (can stimulate own growth signals) 6. Resisting cell death (evading apoptosis) Emerging hallmarks: 7. Deregulating cellular energetics 8. Genome instability and mutation 9. Tumour-promoting inflammation 10. Avoiding immune destruction

What's an oncogene?

A cancer inducing gene that can transform cells

What's a tumour suppressor gene?

A gene whose partial or complete inactivation, occurring in either the germ line or the genome of a somatic cells, leads to the increased likelihood of cancer developing. These genes are responsible for constraining cell proliferation.

What are the 4 new emerging hallmarks of cancer?

Emerging hallmarks: 7. Deregulating cellular energetics 8. Genome instability and mutation 9. Tumour-promoting inflammation 10. Avoiding immune destruction

Outline the characteristics of cancer cells

Frequent mitoses Loss of contact inhibition Increase in growth factor secretion Increase in oncogene expression Loss of tumour suppressor gene Neovascularisation

Describe the different components that make up the tumour microenvironment

Involves: Cancer cells Cancer stem cells Immune inflammatory cells Pericytes (of capillaries) Endothelial cells (of capillaries) Cancer-Associated fibroblasts Invasive cancer cells

Outline the molecular changes involved in the development of colorectal adenocarcinoma

Loss of APC (tumour suppressor) --> hyper plastic epithelium --> loss of DNA methylation --> early adenoma --> activation of K-Ras gene --> intermediate adenoma --> loss of 18q tumour suppressor gene --> late adenoma --> loss of p53 --> carcinoma

What are some of the potential consequences of TP53 mutation?

Loss of function of the p53 tumor suppressor can facilitate both angiogenesis and resistance to apoptosis, as well as enabling the characteristic of genomic instability.

The mutation of what gene may give rise to the evasion of apoptosis?

Loss of p53 would prevent the cell from entering apoptosis

The mutation of what gene may give rise to insensitivity to anti-growth signals?

Loss of retinoblastoma (RB) tumour suppressor gene

What is meant by 'evasion of apoptosis'?

The ability of tumor cell populations to expand in number is determined not only by the rate of cell proliferation but also by the rate of cell attrition. Programmed cell death — apoptosis — represents a major source of this attrition. Therefore, cancer cells also develop mechanisms to evade this cell death (apoptosis).

What is meant by insensitivity to anti-growth signals?

Within a normal tissue, multiple antiproliferative signals operate to maintain cellular quiescence and tissue homeostasis; including soluble growth inhibitors and immobilized inhibitors in the extracellular matrix and on the surfaces of nearby cells. These growth-inhibitory signals, like their positively acting counterparts, are received by transmembrane cell surface receptors coupled to intracellular signaling circuits. Antigrowth signals can block proliferation by two distinct mechanisms. Cells may be forced out of the active proliferative cycle into the quiescent (G0). Alternatively, cells may be induced to permanently relinquish their proliferative potential by being induced to enter into post-mitotic state associated with differentiation.