Key Points
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The process of malignant transformation occurs in discrete histopathological steps, many of which correlate with specific genetic alterations. Several lines of evidence implicate a limited number of molecular pathways, the disruption of which contributes to most, if not all, cancers.
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Rodent and human experimental models of cancer have contributed to our understanding of specific cancer-associated mutations. Although these cancer models share many essential components, several important signalling pathways seem to function differently in human and rodent models of transformation.
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Immortalization is an essential prerequisite for the formation of a tumour cell. Human cells must circumvent two barriers — replicative senescence and cellular crisis — that limit cell lifespan to achieve immortalization. These barriers are regulated by telomere shortening and by the RB and p53 tumour-suppressor pathways.
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Ablation of the ARF–p53 pathway suffices to immortalize many mouse cells. Telomere shortening does not seem to limit the lifespan of cells that are derived from inbred mice.
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In parallel with these differences in immortalization, pairs of introduced oncogenes will transform mouse cells, whereas the transformation of human cells requires additional introduced genes.
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Identifying and characterizing these species-specific differences will allow the construction of human and rodent models of cancer that increasingly phenocopy human cancer. Such models will revolutionize the screening and testing of candidate chemical and biological anticancer therapies.
Abstract
Cancer arises from a stepwise accumulation of genetic changes that liberates neoplastic cells from the homeostatic mechanisms that govern normal cell proliferation. In humans, at least four to six mutations are required to reach this state, but fewer seem to be required in mice. By rationalizing the shared and unique elements of human and mouse models of cancer, we should be able to identify the molecular circuits that function differently in humans and mice, and use this knowledge to improve existing models of cancer.
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Glossary
- HYPERPLASIA
-
An increase in the number of cells in a tissue or organ without gross morphological changes.
- DYSPLASIA
-
The disordered growth that is characterized by changes in size, shape or differentiation programmes of cells in a tissue, often leading to architectural changes to the tissue or organ and generally representing a premalignant state.
- ADENOMA
-
An ordinarily benign neoplasm of epithelial tissue in which the tumour cells form glands or gland-like structures.
- CARCINOMA
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A malignant neoplasm of epithelial cells that is characterized by dysplasia, hyperplasia and invasion of surrounding tissues.
- REPLICATIVE SENESCENCE
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Normal human cells that are propagated serially in culture eventually reach a growth arrest that is characterized by a flattened cell morphology and continued metabolic activity without widespread cell death.
- SV40 LARGE T ANTIGEN
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(LT). A multifunctional protein product of the simian virus 40 early region that is necessary to establish a permissive host-cell environment for viral replication by interactions with host proteins. Large T antigen binds and functionally inactivates both the RB and p53 tumour-suppressor proteins.
- HUMAN PAPILLOMAVIRUS E6 AND E7
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Viral oncoproteins that are derived from certain human papillomavirus types that are associated with increased risk of cervical cancer. E6 binds to and targets p53 for ubiquitin-mediated degradation. E7 binds and inactivates RB.
- ANEUPLOIDY
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The state of having an abnormal number of chromosomes. Most human epithelial cancers harbour genomes that are characterized by gross aneuploidy.
- PHENOCOPY
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A model that recapitulates the clinical and biological characteristics of a specific disease state.
- NON-RECIPROCAL TRANSLOCATION
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Transposition of two segments between non-homologous chromosomes with loss or gain of genetic material as the result of abnormal breakage and fusion.
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Hahn, W., Weinberg, R. Modelling the molecular circuitry of cancer. Nat Rev Cancer 2, 331–341 (2002). https://doi.org/10.1038/nrc795
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DOI: https://doi.org/10.1038/nrc795
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