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Cancers make their own luck: theories of cancer origins

Abstract

Cancer has been a leading cause of death for decades. This dismal statistic has increased efforts to prevent the disease or to detect it early, when treatment is less invasive, relatively inexpensive and more likely to cure. But precisely how tissues are transformed continues to provoke controversy and debate, hindering cancer prevention and early intervention strategies. Various theories of cancer origins have emerged, including the suggestion that it is ‘bad luck’: the inevitable consequence of random mutations in proliferating stem cells. In this Review, we discuss the principal theories of cancer origins and the relative importance of the factors that underpin them. The body of available evidence suggests that developing and ageing tissues ‘walk a tightrope’, retaining adequate levels of cell plasticity to generate and maintain tissues while avoiding overstepping into transformation. Rather than viewing cancer as ‘bad luck’, understanding the complex choreography of cell intrinsic and extrinsic factors that characterize transformation holds promise to discover effective new ways to prevent, detect and stop cancer before it becomes incurable.

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Fig. 1: Major causes of disease-related death.
Fig. 2: Organ sites of common human cancers.
Fig. 3: Principal theories of cancer origins.
Fig. 4: Origins of childhood cancer.
Fig. 5: Origins of adult cancer.

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Acknowledgements

The authors are grateful to B. Simons for helpful discussions during writing of the manuscript. R.J.G is supported by Major Centre Core and Children’s Brain Tumour Centre of Excellence grants from Cancer Research UK, The Brain Tumour Charity, and P01CA96832 and U54CA243125 from the US National Cancer Institute.

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Glossary

Apolipoprotein B mRNA-editing enzyme catalytic polypeptide

(APOBEC). An enzyme that edits mRNA species by deaminating cytosine to uracil.

Barrett oesophagus

A precursor condition for oesophageal cancer in which there is an abnormal (metaplastic) change in the mucosal cells lining the lower portion of the oesophagus, from stratified squamous epithelium to simple columnar epithelium.

Blastocysts

Clusters of dividing cells made by a fertilized egg, comprising the early stage of an embryo.

Developmental regulators

Genes that play an important role in the control of normal tissue development.

Dysplasia

The presence of abnormal cells within a tissue that may represent the precursor of malignant change.

Ependymoma

The third most common brain tumour of children arising from radial glia throughout the neural axis.

Internal tandem duplication

Duplication of sections of DNA adjacent to the original sequence.

Medulloblastoma

The most common malignant brain tumour to affect children, arising in the hindbrain from progenitor cells of the upper or lower rhombic lips.

Melanoblast

A neural crest-derived precursor cell of melanocytes, the cells that make pigment in the skin.

Metaplasia

The emergence of new cell types or disproportionate numbers of normal cell types.

Reprogramming factors

Transcription factors including OCT3 and OCT4, SOX2, MYC and KLF4 that can convert a differentiated somatic cell state into a pluripotent embryonic-like state.

Rhombomere

A transiently divided segment of the developing neural tube within the hindbrain.

Telomerase reverse transcriptase

(TERT). Part of a distinct subgroup of RNA-dependent polymerases that lengthen telomeres (the ends of DNA strands).

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Jassim, A., Rahrmann, E.P., Simons, B.D. et al. Cancers make their own luck: theories of cancer origins. Nat Rev Cancer 23, 710–724 (2023). https://doi.org/10.1038/s41568-023-00602-5

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