An achaete-scute homologue essential for neuroendocrine differentiation in the lung

Borges, Michael; Linnoila, R. Ilona; Velde, H. J. K. Van De; Chen, Herbert; Nelkin, Barry D.; Mabry, Mack; Baylin, Stephen B.; Ball, Douglas W.

doi:10.1038/386852a0

Cited by 411 publications

(397 citation statements)

References 18 publications

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“…However, both of these two hASH1 þ adenocarcinomas also expressed neuroendocrine markers. Thus, our data confirmed and extended the findings of previous in vitro studies that hASH1 was specifically expressed in lung cancers with neuroendocrine differentiation, 12,14,18,19 indicating that besides being instrumental in development of a subset of neurons and neuroendocrine cells, 8,[13][14][15][16][17] hASH1 also plays a key role in regulating neuroendocrine differentiation of tumor cells. The term 'neuroendocrine differentiation' in a broad sense is used to define cells expressing a neural and/or an endocrine phenotype.…”

Section: Discussionsupporting

confidence: 89%

“…This work was supported by Grants from the Ministry of Education, Culture, Sports, Science and Technology (15590314 and High-tech research center) and from the Ministry of Health, Labor and Welfare (11)(12)(13)(14)(15)(16)(17)(18)(19) 2002), Japan…”

Section: Acknowledgementsmentioning

confidence: 99%

“…8,13 MASH1 is also indispensable for the development of pulmonary neuroendocrine cells, thyroid C cells and adrenal chromaffin cells in fetal mice, and homozygous MASH1 null mice lack pulmonary neuroendocrine cells, while mice deficient in HES1, a specific repressor gene of hASH1, show a marked increase in pulmonary neuroendocrine cells. [14][15][16][17] In vitro studies also documented restrictive hASH1 expression in tumor cell lines with neuroendocrine or neuronal differentiation such as pulmonary small-cell carcinoma, medullary thyroid carcinoma and neuroblastoma, 12,14,[18][19][20][21][22][23] suggesting a key role for hASH1 in dictating cellular neuroendocrine differentiation in lung cancer. However, few data about in vivo hASH1 expression in lung cancer, as well as in other neuroendocrine tumors, are currently available.…”

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confidence: 99%

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hASH1 expression is closely correlated with endocrine phenotype and differentiation extent in pulmonary neuroendocrine tumors

et al. 2004

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The human homolog 1 of the Drosophila neurogenic achaete-scute genes, hASH1, is specifically expressed in fetal pulmonary neuroendocrine cells and in some neuroendocrine tumor cell lines. However, no data have been gathered regarding its in vivo expression in tumors. hASH1 mRNA expression was investigated by in situ hybridization in 238 surgically resected lung carcinomas, and the correlations between hASH1 expression status and immunostaining results of neuroendocrine markers chromogranin A, neural cell adhesion molecule, gastrin-releasing peptide and calcitonin, and clinical outcome were analyzed. hASH1 expression was detected in 2/20 (10%) adenocarcinomas, 4/30 (13.3%) typical carcinoids, 11/13 (84.6%) atypical carcinoids, 38/67 (56.7%) large-cell neuroendocrine carcinomas and 56/78 (71.8%) small-cell carcinomas, respectively, but not in any squamous cell carcinoma (0/21) or large-cell carcinoma (0/9). The 2 hASH1 þ adenocarcinomas also expressed multiple neuroendocrine markers. Thus, hASH1 expression was restricted to lung cancers with neuroendocrine phenotypes. However, not all neuroendocrine tumors expressed hASH1. Within the entities of large-cell neuroendocrine carcinoma and small-cell carcinoma, hASH1 expression correlated very closely with chromogranin A, gastrin-releasing peptide and calcitonin expression (Po0.0001, r ¼ 0.852), but was not related to neural cell adhesion molecule expression (P ¼ 0.8892), suggesting that hASH1 expression, at least in lung cancer, is associated with endocrine phenotype expression other than 'neuroendocrine differentiation' in a broad sense. The fact that hASH1 was virtually absent in almost fully differentiated typical carcinoids, but was expressed in most, if not all, less differentiated atypical carcinoids as well as large-cell neuroendocrine carcinomas and small-cell carcinomas, suggests that hASH1 expression in lung cancer imitates its early and transient expression in fetal development, and that hASH1 is instrumental in the establishment, but not in the maintenance, of a cellular endocrine phenotype. Finally, hASH1 expression correlated with a significantly shortened survival in small-cell carcinoma patients (P ¼ 0.041).

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Section: Discussionsupporting

confidence: 89%

Section: Acknowledgementsmentioning

confidence: 99%

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confidence: 99%

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hASH1 expression is closely correlated with endocrine phenotype and differentiation extent in pulmonary neuroendocrine tumors

et al. 2004

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“…In addition, in some cases, the development of distant metastases occurred many years after surgery and subsequent chemotherapy, suggesting that the different tumor cell populations, exocrine (mucinous), and neuroendocrine may play complex reciprocal interactions. In this respect, the expression of transcription factors known to drive neuroendocrine differentiation in the embryonic life, such as human achaete-scute-homologue type 1 (hASH1) may be involved in the occurrence of neuroendocrine differentiation [16]. Unfortunately, in the present series, no hASH1 expression was observed (data not shown) suggesting that at least in the intestinal area, the development of neuroendocrine differentiated cells may follow alternative pathways, compared to other models such as the prostate [17].…”

Section: Discussionmentioning

confidence: 99%

Increased neuroendocrine cells in resected metastases compared to primary colorectal adenocarcinomas

et al. 2010

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Neuroendocrine differentiation has been described in rectal adenocarcinomas receiving neoadjuvant therapy prior to radical surgery, but its clinical relevance is controversial and no data are currently available in colorectal carcinoma metastases as compared to primary tumors. The presence of chromogranin A positive tumor cells was investigated by means of immunohistochemistry on surgical specimens from 54 primary colorectal carcinomas and their corresponding metastases, resected at diagnosis or during tumor progression. In 47 patients, tumor metastases were resected 1 month to 12 years after chemotherapy and/or radiotherapy, while in the remaining seven patients no additional therapy after primary surgery was performed. In primary tumors, neuroendocrine differentiation was found in 12/54 cases (22.2%) as compared to 25/54 metastatic lesions (46.3%; p=0.01). The presence of neuroendocrine phenotype was not correlated with any clinical pathological parameter nor with a different proliferation index. However, patients having neuroendocrine cells in the primary tumor had a significantly shorter survival from the time of metastatic spread than those having not (33.3 vs. 55.5 months; p=0.04). In summary, our data show that colorectal carcinoma metastases contain a higher percentage of neuroendocrine differentiated cells as compared to their corresponding primaries, a finding possibly related to the influence of chemotherapy in neuroendocrine differentiation during colorectal carcinoma progression.

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“…18 mASH1 is required at an early stage in neuronal differentiation and initiates a differentiation program involving NeuroD. 19 It is reported that hASH1 is expressed selectively in normal fetal pulmonary neuroendocrine cells 20 as well as in pulmonary large cell neuroendocrine carcinoma (56.7%) and small cell carcinoma (71.8%). 21 The frequency of expression of mASH1 in our study was 59% in large cell neuroendocrine carcinoma and 87% in small cell carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Distinction of pulmonary large cell neuroendocrine carcinoma from small cell lung carcinoma: a morphological, immunohistochemical, and molecular analysis

et al. 2006

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The distinction between pulmonary large cell neuroendocrine carcinoma and small cell carcinoma is difficult in some cases. Some propose that these carcinomas should be classified as one high-grade neuroendocrine carcinoma. We examined biological features of small cell carcinoma (n ¼ 23), large cell neuroendocrine carcinoma (n ¼ 17), and classic large cell carcinoma (n ¼ 12). The average ratio of nuclear diameter of the tumor cells to that of lymphocytes for small cell carcinoma was smaller than that for large cell neuroendocrine carcinoma (Po0.0001). The frequencies of the expressions of CD56, mASH1, TTF-1, and p16 were higher and that of NeuroD was lower in small cell carcinoma than in large cell neuroendocrine carcinoma. The frequency of loss of heterozygosity at 3p was higher in high-grade neuroendocrine carcinomas than in classic large cell carcinoma (P ¼ 0.0002). Allelic losses at D5S422 (5q33) were more frequent in small cell carcinoma than in large cell neuroendocrine carcinoma (P ¼ 0.0091). Mean fractional regional loss indices of the tumors were 0.38, 0.65, and 0.72 for patients with classic large cell carcinoma, large cell neuroendocrine carcinoma, and small cell carcinoma, respectively (P ¼ 0.0003). Five-year overall survivals of patients with classic large cell carcinoma, large cell neuroendocrine carcinoma and small cell carcinoma in stage I were 67, 73, 60%, respectively. Patients with NeuroD expression had better survivals, and those with p63 expression had poorer survivals in large cell neuroendocrine carcinoma. Patients with TTF-1 expression had poorer survivals in small cell carcinoma. Our data suggest that large cell neuroendocrine carcinoma and small cell carcinoma are different morphologically, phenotypically, and genetically, although there are some overlapping features. Although further studies are needed to analyze the biological behavior of high-grade neuroendocrine carcinomas including sensitivity to chemotherapy, the pathological distinction of large cell neuroendocrine carcinoma from small cell carcinoma may be necessary to treat the patients with neuroendocrine tumors.

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An achaete-scute homologue essential for neuroendocrine differentiation in the lung

Cited by 411 publications

References 18 publications

hASH1 expression is closely correlated with endocrine phenotype and differentiation extent in pulmonary neuroendocrine tumors

hASH1 expression is closely correlated with endocrine phenotype and differentiation extent in pulmonary neuroendocrine tumors

Increased neuroendocrine cells in resected metastases compared to primary colorectal adenocarcinomas

Distinction of pulmonary large cell neuroendocrine carcinoma from small cell lung carcinoma: a morphological, immunohistochemical, and molecular analysis

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