Abstract
Colorectal cancer arises through a gradual series of histological changes, each of which is accompanied by a specific genetic alteration. In general, an intestinal cell needs to comply with two essential requirements to develop into a cancer: it must acquire selective advantage to allow for the initial clonal expansion, and genetic instability to allow for multiple hits in other genes that are responsible for tumour progression and malignant transformation. Inactivation of APC — the gene responsible for most cases of colorectal cancer — might fulfil both requirements.
Key Points
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Colorectal cancers arise through a gradual series of histological changes — the adenoma–carcinoma sequence — resulting from specific genetic 'hits' at a handful of oncogenes and tumour suppressor genes.
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A crucial determinant of the biological properties of the resulting tumour is the temporal sequence rather than the accumulation of these genetic hits: APC (adenomatous polyposis coli)and KRAS mutations are associated with initiation and progression of the benign tumour, whereas loss of TP53, SMAD4 and SMAD2 function is correlated with malignant transformation.
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The APC gene is regarded as the gene for colorectal cancer as it is found mutated in most sporadic cases regardless of the histological stage. APC encodes a multifunctional protein that is involved in several processess, including signal transduction, cell adhesion and migration, proliferation, apoptosis and differentiation.
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Tumorigenesis is an evolutionary process: a cell must acquire a selective growth advantage to allow clonal expansion. The selective advantage provided by loss of APC function resides in the uncontrolled activation of the WNT/β-catenin signal transduction pathway.
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Genetic instability is an important feature of the nascent (colorectal) cancer cell, as it continuously ensures sufficient genetic variability to overcome additional selection barriers. Two types of genetic instability are known in colorectal cancer: microsatellite instability (MIN) and chromosomal instability (CIN).
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The carboxyl terminus of APC encompasses functional domains (microtubulin- and EB1-binding) that ensure proper attachment of the mitotic spindle to the kinetochore. Loss of this function elicits CIN.
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The APC mutation that triggers tumorigenesis by activating β-catenin signalling also causes CIN, although with low penetrance owing to surveillance by the cell cycle and mitotic checkpoint machinery. Additional synergisms between APC and other tumour-suppressor genes in eliciting CIN will progressively lead to malignant transformation and metastasis.
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urokinase-type plasminogen activator receptor
FURTHER INFORMATION
The Hopkins hereditary colon cancer web site
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Glossary
- DYSPLASIA
-
Disordered growth: that is, an abnormally organized cell. The alterations include size, shape (pleomorphism), hypochromatic nuclei, and also architectural orientation of adult cells, generally representing a premalignant stage.
- LOSS OF HETEROZYGOSITY
-
(LOH). In cells that carry a mutated allele of a tumour-suppressor gene, the gene becomes fully inactivated when the cell loses a large part of the chromosome carrying the wild-type allele. Regions with high frequency of LOH are believed to harbour tumour-suppressor genes.
- KNUDSON'S TWO-HIT-MODEL
-
Proto-oncogenes become active oncogenes by a single 'gain-of-function' (activating) mutation, whereas two inactivating 'hits' (mutations) are required to achieve loss of function in a tumour-suppressor gene.
- MISMATCH REPAIR
-
A system to repair base-pair mismatches that can occur, for instance, during DNA replication. Mutations in genes that encode components of the mismatch-repair machinery result in microsatellite instability (MIN).
- BUB1
-
This gene encodes one of the components of a complex that localizes to chromosomal kinetochores and mediates the mitotic-spindle checkpoint. This checkpoint inhibits the metaphase to anaphase transition until all the chromosomes are properly attached to the mitotic spindle.
- SCF (FOR SKP/CULLIN/F-BOX) COMPLEXES
-
In these so-called E3-ubiquitin ligase complexes, F-box proteins recognize substrates, after which ubiquitin is enzymatically transferred by the complex to a lysine residue on the substrate. The ubiquitin tail marks the substrate protein for degradation by the proteasome.
- TCF
-
Transcription factors of the T-cell factor/lymphoid-enhancer factor (LEF) family that bind to DNA HMG boxes and constitute the most downstream components of the WNT pathway. Mammals possess four TCF/LEF genes, whereas worms and flies each carry one Tcf gene in heir genome.
- ADHERENS JUNCTIONS
-
Intercellular adhesion structures that tightly seal the lateral spaces between cells in simple epithelia. They contain the intercellular adhesion molecule E-cadherin, and α- and β-catenin.
- ALLELIC IMBALANCE
-
The hallmark of chromosomal instability at the molecular level, representing losses or gains of specific chromosomal regions.
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Fodde, R., Smits, R. & Clevers, H. APC, Signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer 1, 55–67 (2001). https://doi.org/10.1038/35094067
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DOI: https://doi.org/10.1038/35094067
