Clonal Analysis of Adenosquamous Carcinoma of the Lung

Niho, Seiji; Yokose, Tomoyuki; Kodama, Tetsuro; Nishiwaki, Yutaka; Mukai, Kiyoshi

doi:10.1111/j.1349-7006.1999.tb00703.x

Cited by 36 publications

(35 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nkx2-1 deletion promotes lung ADC to transdifferentiate towards gastric lineage 34 . Consistently, clinical studies have found convergent mutations in both ADC and SCC components from a single lesion of human Ad-SCC [35][36][37][38][39] , leading to the hypothesis that there exists dynamic cell lineage conversion between these two pathologically and morphologically distinct tumour subtypes. Our work in Lkb1-deficient mouse models has recently provided the first de novo evidences supporting this hypothesis 18 .…”

Section: Discussionmentioning

confidence: 73%

YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression

et al. 2014

View full text Add to dashboard Cite

Whether the Hippo pathway contributes to cell lineage transition under pathological conditions, especially tumorigenesis, remains largely unknown. Here we show that YAP, the major effector of the Hippo pathway, displays a distinct activation pattern in lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC); YAP is initially activated by LKB1 loss in lung ADC, which upregulates ZEB2 expression and represses DNp63 transcription in a default manner. During transdifferentiation, YAP is inactivated, which in turn relieves ZEB2-mediated default repression of DNp63 and triggers squamous differentiation reprogramming. Disruption of the YAP barrier for phenotypic transition significantly accelerates squamous transdifferentiation, whereas constitutive YAP activation conversely inhibits this transition. More importantly, ectopic DNp63 expression rescues the inhibitory effect of YAP on squamous transdifferentiation. These findings have established YAP as an essential barrier for lung cancer cell fate conversion and provided a mechanism for regulating cancer plasticity, which might hold important implication for YAP-targeted therapies.

show abstract

Section: Discussionmentioning

confidence: 73%

YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Thus, dierent animals or dierent breasts in the same animal developed independently invasive tumors with a predominating solid, nodular form that possibly evolved into a few variants, including a pattern of adenoacanthomatous metaplasia. Although adenosquamous carcinomas developing in the breast or in other organs are rarely observed in humans (see, for example, Denley et al, 2000), it is interesting to note that independent molecular analyses of lung tumors have suggested that the squamous and adenocarcinomatous components had originated from the same cell (Niho et al, 1999;Kanazawa et al, 2000).…”

Section: Tumor Pathogenesis In the Absence Of Brca2mentioning

confidence: 99%

Development of mammary adenocarcinomas by tissue-specific knockout of Brca2 in mice

et al. 2001

View full text Add to dashboard Cite

Cre-mediated deletion of exons 3 and 4 of the mouse Brca2 gene occurring speci®cally in mammary epithelial cells of conditional female mutants carrying a combination of loxP-modi®ed and null Brca2 alleles resulted in a high incidence (77%) of breast tumors that were often palpable and developed in one or more glands after long latency (time for median tumor-free survival of *1.4 years; total of 40 tumors in 20 animals). These invasive adenocarcinomas were histologically quite uniform, exhibiting predominantly a solid, nodular tumor pattern with very few variants, in striking contrast to the morphological heterogeneity of analogous Brca1-associated tumors. The karyotypes of tumor cells lacking Brca2 had various chromosomal aberrations and ranged from diploid to hypertetraploid, but this wide variability was incongruous with the histological appearance of carcinomas that was comparable between specimens. The implications of these observations in the context of models positing that Brca2 is involved in the maintenance of genomic stability are discussed. Oncogene (2001) 20, 3937 ± 3948.

show abstract

“…To our knowledge, 2 reports have also described the monoclonality of 2 components in adenosquamous carcinoma by genetic analysis. 10,11 Immunohistochemical analyses have indicated that the protein expression characteristics of the adenocarcinomatous and squamous cell carcinomatous components differ. 3,9,11 Taking together these findings, the tumorigenesis in some population of adenosquamous carcinoma is hypothesized; the critical event causing oncogenesis, such as a mutation in K-ras or EGFR, occurs in the progenitor cells of the adenosquamous carcinoma, then, in the process of multistep tumorigenesis, subsequent differences in the protein expression profiles may cause the cells to differentiate into 2 different phenotypes.…”

Section: Dear Sirmentioning

confidence: 99%

“…[10][11][12] In our study, we investigated the molecular features of adenosquamous carcinoma, a typical heterogeneous tumor of the lung.…”

Section: Dear Sirmentioning

confidence: 99%

See 1 more Smart Citation

Mutations of epidermal growth factor receptor andK-rasgenes in adenosquamous carcinoma of the lung

et al. 2005

View full text Add to dashboard Cite

Dear Sir,Lung cancer is one of the most common malignant diseases in developed countries and is classified into nonsmall cell lung cancer (NSCLC) and small cell lung cancer.1 Adenocarcinoma and squamous cell carcinoma are the 2 major subtypes of NSCLC. However, significant differences in etiology and genetic and epigenetic alterations exist between these 2 subtypes.2-4 For example, squamous cell carcinoma generally arises in smokers and rarely occurs in never-smokers; mutations in the K-ras and EGFR genes are also infrequent. In contrast, adenocarcinoma is the dominant histological subtype in female never-smokers, and K-ras or EGFR mutations are frequently present in this subtype. 5,6 Adenosquamous carcinoma of the lung is a rather rare subtype of NSCLC, comprising 0.4-4% of pulmonary carcinomas.3 According to the World Health Organization's classification, adenosquamous carcinoma is defined as a carcinoma showing components of both adenocarcinoma and squamous cell carcinoma, with each component comprising at least 10% of the tumor. 3 The etiology of adenosquamous carcinoma, including age, smoking status and race, is similar to that of other types of lung cancers.7 A clinicopathological analysis has demonstrated that adenosquamous carcinoma is more aggressive and results in a poorer prognosis than does adenocarcinoma or squamous cell carcinoma, 7 indicating that its biological features are different from these major types of NSCLCs. Regarding the histogenesis of adenosquamous carcinoma, monoclonal or polyclonal pathways have been proposed. Monoclonality is considered to be a fundamental feature of neoplasms and consists of the transformation of 1 component to the other, whereas the polyclonal pathway may result from a collision of 2 types of independent tumors. 8,9 However, little is known about the progenitor cells and the process of tumorigenesis in adenosquamous carcinoma of the lung.3 Information on genetic alterations is also limited; only TP53, K-ras mutation and loss of heterozygosity at several loci have been reported in a limited number of adenosquamous carcinomas. [10][11][12] In our study, we investigated the molecular features of adenosquamous carcinoma, a typical heterogeneous tumor of the lung.In our previous analysis for EGFR mutation in 397 cases of NSCLCs, we found somatic mutations in 2 cases for EGFR and 1 for K-ras out of 6 adenosquamous carcinomas by direct sequence of exon 18-21 for EGFR and codon 12 and 13 for K-ras genes.13,14 The rates of EGFR mutation in each histology of lung cancer are shown in Table I. In our study, we added 5 new cases of adenosquamous carcinomas of the lung for EGFR and K-ras analysis, and EGFR mutation was present in 1 case and K-ras mutation was absent in 5 cases. Thus, 4 of 11 cases showed either EGFR or K-ras mutations (27% for EGFR and 9% for K-ras). The characteristics of 11 cases are exhibited in Table II. These results provoked considerable interest, because mutations in these genes were assumed to be usually present in adenocarcinoma and rarely present in ...

show abstract

Clonal Analysis of Adenosquamous Carcinoma of the Lung

Cited by 36 publications

References 20 publications

YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression

YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression

Development of mammary adenocarcinomas by tissue-specific knockout of Brca2 in mice

Mutations of epidermal growth factor receptor andK-rasgenes in adenosquamous carcinoma of the lung

Contact Info

Product

Resources

About