Abstract
We review the significance of a network of proneural basic helix-loop-helix (bHLH) factors. Immunohistochemically, pulmonary neuroendocrine cells (PNECs) are positive for Mash1, one of the activator bHLHs, and non-PNECs such as Clara cells are positive for Hes1, one of the repressor bHLHs. Since mice deficient for the Mash1 gene do not possess PNEC and mice deficient for the Hes1 gene have many PNECs, it is suggested that a network of bHLHs work in cell fate determination of lung epithelium. Moreover, the Notch pathway could play a role in cell differentiation mechanisms in the lung because this signaling pathway has been reported to work in various tissues. PNECs have been reported to modulate various nonneoplastic human lung diseases. We demonstrate that PNECs in usual interstitial pneumonia and hASH1 (human homolog of Mash1) are upregulated in diseased lung tissues. Moreover, studies of small cell carcinoma and non-small cell carcinoma suggest that neuroendocrine differentiation could be regulated by hASH1. In non-small cell carcinoma, Hes1 and Notch signaling may have roles in maintaining cell differentiation. Thus, a network of bHLHs and Notch signaling are important in cell differentiation of normal and pathologic lung epithelial cells.
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References
Cutz E. Structure, molecular markers, ontogeny and distribution of pulmonary neuroepithelial bodies. In: Cutz E, ed. Cellular and molecular biology of airway chemoreceptors. Austin, TX: Landes, 1997; 1–33.
Gosney JR. Pulmonary endocrine pathology. Oxford; Butterworth Heinemann, 1992.
Ito T. Differentiation and proliferation of pulmonary neuroendocrine cells. Prog Histochem Cytochem 34:245–324, 1999.
Emura M, Ochiai A, Gobert-Bohlen A, Panning B, Dungworth DL. Neuroendocrine phenotype differentiation in a hamster lung epithelial cell line under low oxygen pressure or after transformation by diethylnitrosamine. Toxicol Lett 72:59–64, 1994.
Ito T, Nogawa H, Udaka N, Kitamura H, Kanisawa M. Development of pulmonary neuroendocrine cells in explant culture. Lab Invest 77:449–457, 1997.
Sidhu GS. The endodermal origin of digestive and respiratory tract APUD cells. Am J Pathol 96:5–20, 1979.
Pearse AGE, Takor T. Embryology of the diffuse neuroendocrine system and its relationship to the common peptides. Fed Proc 38:2288–2294, 1979.
Ito T, Udaka N, Ikeda M, Yazawa T, Kageyama R, Kitamura H. Significance of proneural basic helix-loop-helix transcription factors in neuroendocrine differentiation of fetal lung epithelial cells and lung carcinoma cells. Histol Histopathol 16:335–343, 2001.
Jan YN, Jan LY. Genetic control of cell fate specification in Drosophia peripheral nervous system. Annu Rev Genet 28:373–393, 1994.
Kageyama R, Nakanishi S. Helix-loop-helix factors in growth and differentiation of the vertebrate nervous system. Curr Opin Genet Dev 7:659–665, 1997.
Sasai Y, Kageyama R, Tagawa Y, Shigemoto R, Nakanishi S. Two mammalian helix-loop-helix factors structurally related to Drosophila hairy and Enhancer of split. Genes Dev 6:2620–2634, 1992.
Chen H, Thiagalingam A, Chopra H, Borges MW, Feder JN, Nelkin BD, Baylin SB, Ball DW. Conservation of the Drosophila lateral pathway in human lung cancer: a hairy-related protein (Hes-1) directly represses achaetescute homolog-1 expression. Proc Natl Acad Sci USA 94:5355–5360, 1997.
Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signalling: cell fate control and signal integration in development. Science 284:770–776, 1999.
Borges M, Linnoila RI, Van De Velde HJK, Chen H, Nelkin BD, Marby M, Baylin SB, Ball DW. An achaete-scute homologue essential for neuroendocrine differentiation in the lung. Nature 386:852–855, 1997.
Ito T, Udaka N, Yazawa T, Okudela K, Hayashi H, Sudoh T, Guillemot F, Kageyama R, Kitamura H. Basic helix-loop-helix transcription factors regulate the neuroendocrine cell differentiation of fetal mouse pulmonary epithelium. Development 127:3913–3921, 2000.
Ito T, Ogura T, Ogawa N, Udaka N, Hayashi H, Inayama Y, Yazawa T, Kitamura H. Modulation of pulmonary neuroendocrine cells in idiopathic interstitial pneumonia. Histol Histopathol 17:1121–1127, 2002.
Taylor W. Pulmonary argyrophilic cells at high altitude. J Pathol 122:137–144, 1977.
Haley KJ, Patidar K, Zhang F, Emanuel RL, Sunday ME. Tumor necrosis factor induces neuroendocrine differentiation in small lung cancer cell lines. Am J Physiol 275:L311-L321, 1998.
Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E. World Health Organization international histological classification of tumors: histological typing of lung and pleural tumours. 3rd ed. Berlin, Springer Verlag, 1999.
Ball DW, Azzoli CG, Baylin SB, Chi D, Duo S, Donis-Keller H, Cumaraswamy A, Borges M, Nelkin BD. Identification of a human achaete-scute homolog highly expressed in neuroendocrine tumors. Proc Natl Acad Sci USA 90:5648–5652, 1993.
Chen H, Carson-Walter EB, Baylin SB, Nelkin BD, Ball DW. Differentiation of medullary thyroid cancer by C-Raf-1 silences expression of the neural transcription factor human achaete-scute homolog-1. Surgery 120:168–173, 1996.
Rostomily RC, Bermingham-McDonogh O, Berger MS, Tapscott SJ, Reh TA, Olson JM. Expression of neurogenic basic helix-loop-helix genes in primitive neuroectodermal tumors. Cancer Res 57:3526–2531, 1997.
Gestblom C, Grynfeld A, Ora I, Ortift E, Larsson C, Axelson H, Sandstedt B, Cserjesi P, Olson EN, Pahlman S. The basic helix loop-helix transcription factor dHNAD, a marker gene for the developing human sympathetic nervous system, is expressed in both high- and low-stage neuroblastoma. Lab Invest 79:67–79, 1999.
Soderholm H, Ortoft E, Johansson I, Ljungberg J, Larsson C, Axelson H, Pahlman S. Human achaete-scute homologue 1 (HASH-1) is downregulated in differentiating neuroblastoma cells. Biochem Biophys Res Commun 256:557–563, 1999.
Westerman BA, Neijenhuis S, Poutsma A, Steenbergen RDM, Breuer RHJ, Egging M, van Wijk IJ. Oudejans CBM. Quantitative reverse transcription-polymerase chain reaction measurement of HASH (SASCL1), a marker for small cell lung carcinomas with neuroendocrine features. Clin Cancer Res 8:1082–1086, 2002.
Linnoila RI, Zhao B, DeMayo JL, Nelkin BD, Baylin SB, Mayo FJ, Ball DW. Constitutive achaete-scute homologue-1 promotes airway dysplasia and lung neuroendocrine tumors in transgenic mice. Cancer Res 60:4005–4009, 2000.
Yazawa T, Ito T, Kamma H, Suzuki T, Okudela K, Hayashi H, Horiguchi H, Ogata T, Mitsui H, Ikeda M, Kitamura H. Complicated mechanisms of class II transactivator transcription deficiency in small cell lung cancer and neuroblastoma. Am J Pathol 161:291–300, 2002.
Nakakura EK, Watkins DN, Schuebel KE, Sriuranpong V, Borges MW, Nelkin BD, Ball DW. Mammalian Scratch: a neural-specific Snail family transcriptional repressor. Proc Natl Acad Sci USA 98:4010–4015, 2001.
Sriuranpong V, Borges MW, Ravi RK, Nelkin BD, Balylin SB, Ball DW. Notch signaling induces cell cycle arrest in small cell lung cancer cells. Cancer Res 61:3200–3205, 2001.
Gazdar AF, Carbone DP. The biology and molecular genetics of lung cancer. Austin, TX: Landes, 1994.
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Ito, T., Udaka, N., Okudela, K. et al. Mechanisms of neuroendocrine differentiation in pulmonary neuroendocrine cells and small cell carcinoma. Endocr Pathol 14, 133–139 (2003). https://doi.org/10.1385/EP:14:2:133
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DOI: https://doi.org/10.1385/EP:14:2:133