In our recent Oncogene article: ‘Onco-ontogeny recapitulates phylogeny – a consideration’, we have taken Ernst Haeckel’s dismissed theorem and, as a thought experiment, applied it to that compressed evolution that is cancer.
Whilst oncogenes and suppressor genes drive cancers individually or together, nevertheless, the cancer requires the help of fundamental (non-mutated) embryonic developmental and patterning genes to progress – the two way epithelial-mesenchymal transition (EMT) being a good example. EMT is essential in normal embryology, at the time of gastrulation (at 3 weeks post fertilisation) with cell migration down the primitive streak to form the 2nd and 3rd germ layers viz. endoderm and mesoderm. In cancer, EMT is essential for cancer progression and metastatic spread – the acquisition of mesenchyme being critical.
Other fundamental embryonic genes (FEG), notably Notch, TGFb, WnT/beta catenin, Sonic Hedgehog, FGF and transcription factors: Snail, Slug, SOX, twist – all are harnessed or ‘pressganged’ into the service of developing cancer – indeed the cancer’s progression depends on their qualities.
Just as different embryonic anatomic structures are shaped by patterning genes in the developing embryo, so too do those genes influence a cancer arising from such structures. We selected two continuum, anatomic structures viz. the colon (with a midgut/hindgut boundary) and the brainstem (with rhombencephalon, metencephalon/mesencephalon/diencephalon boundaries) to exemplify how the differential (qualitative/quantitative) effect these FEG have on the derivative cancers. We further exemplify how immigrant neural crest cells may shape, or be shaped by, these different embryonic anatomical boundaries. Immigrant bone marrow stem cells may similarly influence.
Beyond the genotype, and its influence by FEG, comes variation of the phenotype. The acquired methylome seems to increase the ‘aggression’ of the cancer. Upregulation of physiological transducer cascades and even the acquisition of a different transcriptome in response to external stimuli seem to occur and we have proposed the term ‘knock on metabolome’. This last appears to somewhat redeem Jean Baptiste Lamarck, who, incidentally, Haeckel admired in this context.
Of course, Darwinism is critical to the evolution of cancer – all the moreso in this age of targeted therapy, when selective pressures in the cancer necessitate genetic variation to survive, often in less random ways than one might expect (e.g. MEK-escape in BRAF mutant melanoma treated with targeted BRAF inhibition). However, the heavy reliance of cancer on FEG and physiological signalling systems – subverted to assist a cancer’s development – is worthy of further research.
Read the full article: < https://www.nature.com/articles/s41388-020-01624-1 >
C. E. Plowman1, P. N. Plowman2
1 University College London, London, UK.
2 Department of Clinical Oncology, St. Bartholomew’s Hospital, West Smithfield, London, UK.