We read the insightful review by Garraway and Sellers , which highlighted 'lineage dependency' as a new aspect of carcinogenic mechanism1, with great interest. The authors proposed the 'lineage-survival oncogene' concept and described the basic-helix-loop-helix (bHLH) transcription factor MITF as a prototype2,3, and also speculated about other putative candidates. We would like to suggest the addition of another bHLH gene, achaete-scute homologue 1 (ASH1), as a prototypic lineage-survival oncogene on the basis of existing experimental evidence. Although pulmonary neuroendocrine cells (PNECs) that reside in the airway epithelium are suggested to have a role as a stem-cell niche for the lung4, it has also been reported that gene-targeting of ASH1 results in the loss of PNECs in the lung5, and the ASH1 transgene promotes the development of lung tumours with a neuroendocrine feature in coordination with SV40 large-T antigen6. Further, suppression of ASH1 expression by RNAi has been shown to induce cell-cycle arrest and apoptosis in vitro, as well as the inhibition of tumour growth in vivo in an ASH1-expression-dependent manner7. These findings support the 'lineage-survival oncogene' concept proposed by Garraway and Sellers, in that ASH1 has a decisive role in the differentiation and survival of both normal and malignant cells of neuroendocrine lineage in the lung. Together, MITF and ASH1 seem to constitute what is at present a very limited group of prototypic lineage-survival oncogenes with sufficient supportive evidence. However, we anticipate that the list of lineage-survival oncogenes will expand considerably in the near future with solid evidence from experimental results.
References
Garraway, L. A. & Sellers, W. R. Lineage dependency and lineage-survival oncogenes in human cancer. Nature Rev. Cancer 6, 593–602 (2006).
McGill, G. G. et al. Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. Cell 109, 707–718 (2002).
Garraway, L. A. et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436, 117–122 (2005).
Hong, K. U., Reynolds, S. D., Giangreco, A., Hurley, C. M. & Stripp, B. R. Clara cell secretory protein-expressing cells of the airway neuroepithelial body microenvironment include a label-retaining subset and are critical for epithelial renewal after progenitor cell depletion. Am. J. Respir. Cell Mol. Biol. 24, 671–681 (2001).
Borges, M. et al. An achaete-scute homologue essential for neuroendocrine differentiation in the lung. Nature 386, 852–855 (1997).
Linnoila, R. I. et al. Constitutive achaete-scute homologue-1 promotes airway dysplasia and lung neuroendocrine tumors in transgenic mice. Cancer Res. 60, 4005–4009 (2000).
Osada, H., Tatematsu, Y., Yatabe, Y., Horio, Y. & Takahashi, T. ASH1 gene is a specific therapeutic target for lung cancers with neuroendocrine features. Cancer Res. 65, 10680–10685 (2005).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Osada, H., Takahashi, T. Inclusion of the ASH1 gene that governs the neuroendocrine differentiation of lung epithelium as an additional prototypic 'lineage-survival oncogene'. Nat Rev Cancer 7, 68 (2007). https://doi.org/10.1038/nrc1947-c1
Issue Date:
DOI: https://doi.org/10.1038/nrc1947-c1
