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Tumorigenesis

Intricate insights

Nature Reviews Cancer volume 6, page 901 (2006)Cite this article

The effect of transforming growth factor-β (TGFβ) on tumour development and progression is complex. TGFβ can suppress the growth of early, precancerous lesions, but can also promote the growth of established carcinomas. The disruption of this pathway is evident in human pancreatic cancer, so two groups have generated mouse models of pancreatic carcinogenesis that involve the disruption of the TGFβ signalling pathway.

In mice, the expression of a knock-in allele of activated Kras (KrasG12D) induces the development of pancreatic intraepithelial neoplasias (PanINs; precursors of PDAC). The authors found that the loss of SMAD4 accelerated PDAC development in these mice. However, the loss of SMAD4 was more frequently associated with the development of intraductal papillary mucinous neoplasms (IPMNs), another potential precursor of PDAC. The combination of activated KrasG12D with the loss of one allele of Cdkn2a and the loss of both alleles of Smad4 induced the rapid development of IPMNs that progressed to advanced PDACs. Therefore, the loss of Smad4 changes the histology of the precursor lesions, and the loss of Cdkn2a is required for full malignant progression to PDAC. The loss of Smad4 also altered the degree of differentiation seen in the tumours. Those without SMAD4 expression retained a differentiated phenotype, whereas tumours with intact SMAD4 expression were frequently associated with an epithelial–mesenchymal transition (EMT) phenotype. These mouse models indicate that SMAD4 functions to suppress initial tumour formation in response to activated KRAS, and in tumours in which SMAD4 remains expressed TGFβ can induce EMT and TGFβ-dependent growth.

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ORIGINAL RESEARCH PAPERS

  1. Bardeesy, N. et al. Smad4 is dispensible for normal pancreas development yet critical in progression and tumour biology of pancreas cancer. Genes Dev. 15 November 2006 (doi: 10.1101/gad.1478706)

  2. Ijichi, H. et al. Aggressive pancreatic adenocarcinoma in mice caused by pancreas-specific blockade of transorming growth factor β-signalling in coope-ration with active Kras expression. Genes Dev. 15 November 2006 (doi: 10.1101/gad.1475506)

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Authors
  1. Nicola McCarthy
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McCarthy, N. Intricate insights. Nat Rev Cancer 6, 901 (2006). https://doi.org/10.1038/nrc2039

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  • DOI: https://doi.org/10.1038/nrc2039

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