A new mouse model to explore the initiation, progression, and therapy of <i>BRAF<sup>V600E</sup></i>-induced lung tumors

Dankort, David; Filenova, Elena; Collado, Manuel; Serrano, Manuel; Jones, Kirk D.; McMahon, Martin

doi:10.1101/gad.1516407

Cited by 446 publications

(591 citation statements)

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“…However, in settings unrelated to either HPV infection or deregulation of Rb, P16 ink4A has a function as a negative regulator of cell proliferation, and its expression can be linked to oncogene-induced senescence, causing irreversible growth arrest. [16][17][18][19] The induction of P16 INK4A in premalignant lesions and its loss during malignant transformation have been demonstrated in carcinogenesis of the liver, lung, and pancreas. [16][17][18][19] In the previous study, 1 P16 INK4A expression was completely lost in 50% of low-grade mucinous adenocarcinomas, and the remaining cases showed very patchy expression.…”

Section: Discussionmentioning

confidence: 99%

“…[16][17][18][19] The induction of P16 INK4A in premalignant lesions and its loss during malignant transformation have been demonstrated in carcinogenesis of the liver, lung, and pancreas. [16][17][18][19] In the previous study, 1 P16 INK4A expression was completely lost in 50% of low-grade mucinous adenocarcinomas, and the remaining cases showed very patchy expression. 1 In our study, P16 INK4A was specifically expressed in papillary tufts, and not in the surrounding flat mucinous epithelium.…”

Section: Discussionmentioning

confidence: 99%

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Papillary mucinous metaplasia of the endometrium as a possible precursor of endometrial mucinous adenocarcinoma

et al. 2012

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Mucinous adenocarcinoma is an uncommon type of endometrial adenocarcinoma for which precursor lesions have yet to be clarified. During a review of noncancerous endometrial lesions in postmenopausal women, we found that mucinous endometrial glands showed variable degrees of epithelial changes that ranged from the formation of simple tubular glands to the formation of complex glands with papillary tufts, and some of the glands with papillary tufts were architecturally similar to low-grade mucinous adenocarcinomas. Based on histological similarities, we have postulated that mucinous metaplasia could be a precursor lesion of mucinous adenocarcinoma. To explain the pathogenetic significance of endometrial mucinous metaplasia, we analyzed the immunohistochemical expression of ER, PR, MKI67, PTEN, b-catenin, P16 INK4A , TP53, and PAX2 in 21 endometrial mucinous metaplasias, screened for KRAS (n ¼ 16) and PTEN (n ¼ 14) mutations, and compared expression patterns between samples with simple mucinous glands, those with complex glands having intraglandular papillary tufts, and endometrioid adenocarcinomas. Compared with the surrounding flat mucinous epithelium and simple mucinous metaplasia, the intraglandular papillary tufts associated with papillary mucinous metaplasia were characterized by selectively decreased expression of PAX2 (P ¼ 0.029) and PR (Po0.001), and overexpression of P16 INK4A (P ¼ 0.014). There were no significant differences in the levels of expression of ER, PTEN, b-catenin, TP53, and MKI67 between the two groups. In contrast with endometrioid adenocarcinomas, rates of MKI67 proliferation were very low in both groups. Mutations in KRAS were identified in 89% of cases with papillary mucinous metaplasia, in contrast to 14% in simple mucinous metaplasia (P ¼ 0.001). No PTEN mutations were observed in either of the two groups. In conclusions, immunohistochemical and molecular genetic profiling suggest that papillary mucinous metaplasia is a possible precancerous lesion in a subset of endometrial carcinomas. Modern Pathology (2012Pathology ( ) 25, 1496Pathology ( -1507 doi:10.1038/modpathol.2012; published online 6 July 2012Keywords: endometrium; mucinous; mucinous metaplasia; papillary metaplasia; PAX2; P16 INK4A ; senescence Endometrial carcinoma is classified into two major groups, types I and II, according to clinicopathological features and molecular pathogenetic mechanisms. Most type I tumors are characterized by an endometrioid histology and are frequently associated with PTEN mutations, whereas type II tumors show a serous histology and are frequently associated with the altered expression of TP53 tumor-suppressor genes. Endometrial hyperplasia and endometrial intraepithelial carcinoma are thought to be precursor lesions of type I and II endometrial carcinomas, respectively. However, this simplified classification and their precursor lesions cannot explain the pathogenesis of all endometrial carcinomas.Mucinous adenocarcinoma, an uncommon type of endometrial adenocarcinoma comprising o10% of endometr...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Papillary mucinous metaplasia of the endometrium as a possible precursor of endometrial mucinous adenocarcinoma

et al. 2012

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“…However, several reports have now demonstrated that oncogene-induced senescence does indeed occur in vivo in human tumors and in mouse tumor models (Braig et al, 2005;Chen et al, 2005;Collado et al, 2005;Michaloglou et al, 2005;Courtois-Cox et al, 2006;Dankort et al, 2007;Sarkisian et al, 2007). Collectively, investigators have observed that mutations in K-ras, B-raf, PTEN and NF1 can trigger cellular senescence in vivo.…”

Section: History Of Oncogene-induced Senescencementioning

confidence: 99%

Many roads lead to oncogene-induced senescence

2008

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“…In addition to the first reported cellular senescence imposed by extensive proliferation and telomere shortening in human fibroblasts, it has become increasingly clear that genetic alterations and cellular stresses or damages linked to cancer development also trigger senescence. Animal models have suggested that preventing senescence can promote more malignant tumour progression and cells carrying characteristics of senescent cells can be found in pre-malignant samples that are lost as the state of transformation of the tumour cells increases (Braig et al, 2005;Collado et al, 2005;Dankort et al, 2007).…”

Section: P53 Isoforms Unravel P53 Functional Domainsmentioning

confidence: 99%

p53 isoforms gain functions

Olivares‐Illana

Fåhræus

2010

Oncogene

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Many different cell stress pathways converge on p53 to induce a number of distinct cell biological responses such as G1 or G2 arrest, senescence or apoptosis. One of the outstanding questions with regard to p53 is how the cells can differentiate between different stresses so that p53 activation leads to the correct response. It has been known for some time that the p53 gene expresses isoforms that carry unique domains and properties, and more recent works have started to reveal some of their functions. The alternative mRNA translation product p53/47, which lacks the first 40 codons, including the first of p53's two trans-activation domains, is being linked to endoplasmic reticulum stress and the unfolded protein response to which it causes a specific G2 arrest. On the other hand, p53 itself induces G1 arrest and has no effect on the G2. The two isoforms D133p53, which lacks the first 133 amino acids, and p53b, which carries an alternative C-terminus, are derived from alternative promoter usage or splicing, respectively, and are together implied in controlling cellular senescence. Hence, through different mechanisms of gene expression control, alternative levels of p53 isoforms help the cell to differentiate between p53 activation and the response to diverse stresses. This holds promise to a better understanding of how upstream and downstream p53 pathways have evolved relative to specific p53 domains.

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A new mouse model to explore the initiation, progression, and therapy of BRAF^V600E-induced lung tumors

Cited by 446 publications

References 21 publications

Papillary mucinous metaplasia of the endometrium as a possible precursor of endometrial mucinous adenocarcinoma

Papillary mucinous metaplasia of the endometrium as a possible precursor of endometrial mucinous adenocarcinoma

Many roads lead to oncogene-induced senescence

p53 isoforms gain functions

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A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors

Cited by 446 publications

References 21 publications

Papillary mucinous metaplasia of the endometrium as a possible precursor of endometrial mucinous adenocarcinoma

Papillary mucinous metaplasia of the endometrium as a possible precursor of endometrial mucinous adenocarcinoma

Many roads lead to oncogene-induced senescence

p53 isoforms gain functions

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Product

Resources

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A new mouse model to explore the initiation, progression, and therapy of BRAF^V600E-induced lung tumors