Molecular Basis of Cancer Development and Hallmarks of Cancer

cancer

malignant neoplasms capable of invasion and metastasis

sporadic

most cancers resulting from replication errors

inherited predisposition

increased risk (2 - 3 fold) of cancer in first-degree relatives

- multifactorial & sporadic

inherited cancer syndromes

Mendelian inheritance of initial cancer-causing mutation in every cell of the body

- 5% cancer cases

somatic event

genetic alteration occurring in any cell

second hit

additional somatic event in the same cell

acquired preneoplastic conditions

- chronic inflammation

- precursor lesions

- immunodeficiency states

chronic inflammation

cellular injury leading to compensatory proliferation for repair

- also create reactive O2 species leading to genotoxicity

precursor lesions

abnormal tissue changes preceding cancer development

- inflammatory = can be evidenced by metaplasia (compensatory)

- non-inflammatory (e.g. hyperplasia)

- benign neoplasms that can transform

molecular basis of cancer

- non-lethal genetic damage

- clonal expansion

- initiating & driver mutations

- accumulation of mutations

malignant phenotype

- excessive growth

- invasiveness

- ability to form metastases

driver mutation

mutation causing malignant phenotype

initiating mutation

initial driver mutation that started the path to malignancy

- present in all the cells thereafter

stepwise acquisition of complimentary mutations

- cells evolve genetically under Darwinian selection of survival of the fittest (have necessary mutations for survive)

- originally completely clonal > mass = so many mutations and "selections" = genetically diverse > "tumor progression"

- can also occur after therapy creating resistance

- must maintain original clonal mutation that promote cancer growth/development

tumor progression

more malignant and aggressive cells over time

- "survival of the fittest"

hallmarks of cancer

- replicative immortality

- tumor promoting inflammation

- invading and metastases

- genomic instability

- inducing angiogenesis

- resisting cell death (apoptosis)

- deregulating cellular energetics

- sustaining proliferative signals

- avoiding immune destruction

- evading growth suppressors

inherited cases

1. all cells carry one mutation

2. 1 somatic event in any cell

3. tumor founder cell with 2 mutations

sporadic cases

1. somatic mutation in one cell

2. 2nd somatic event in the same cell

3. 3. tumor founder cell with 2 mutations

immunodeficiency states

immune systems helps protect against cancer

- oncogenic viruses = CD8 T-cells

non-lethal genetic damage

lies at the heart of carcinogenesis

- problem = cell doesn't die when damaged which goes on to acquire more mutations leading to cancer

clonal expansion (clonality)

expansion of a single precursor cell with incurred genetic damage

- can test for clonality

accumulation of mutations

stepwise acquisition of complimentary mutations

- NOT JUST A SINGLE MUTATION

- cancer hallmarks - "malignant phenotype"

replicative immortality

unrestricted proliferation, could take over entire body

tumor promoting inflammation

help promote cellular transformation

invading and metastases

metastases cause most deaths

genomic instability

mutator phenotype

inducing angiogenesis

needs to create blood supply to metastasize

resisting cell death

evasion of apoptosis

deregulating cellular energetics

altered metabolism towards aerobic glycolysis

sustaining proliferative signaling

self-sufficiency to proliferate (no external stimulus)

avoiding immune destruction

evades immune system

- not recognize oncoprotein antigens or inactivate cytotoxic T cells

evading growth suppressors

insensitive to growth inhibitory signals

enhanced mutation rate

increases genetic instability

- defective DNA damage

- accumulate more point mutations & DNA sequence rearrangements

- chromosomes display gross abnormalities (aneuploidy, translocation, breaks)