Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice

/pdf/pathology-and-genetics-of-tumours-of-the-digestive-system-3xy9cwrc3c.pdf

Pathology and genetics of tumours of the digestive system

Trp53R172H and kmsg12d cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice

Invasive pancreatic ductal adenocarcinoma is an almost uniformly fatal disease. Several distinct noninvasive precursor lesions can give rise to invasive adenocarcinoma of the pancreas, and the prevention, detection, and treatment of these noninvasive lesions offers the potential to cure early pancreatic cancers. Noninvasive precursors of invasive ductal adenocarcinoma of the pancreas include pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms. Diagnostic criteria, including a distinct ovarian-type stroma, and a consistent nomenclature are well established for mucinous cystic neoplasms. By contrast, consistent nomenclatures and diagnostic criteria have been more difficult to establish for PanINs and IPMNs. Because both PanINs and IPMNs consist of intraductal neoplastic proliferations of columnar, mucin-containing cells with a variable degree of papilla formation, the distinction between these two classes of precursor lesions remains problematic. Thus, considerable ambiguities still exist in the classification of noninvasive neoplasms in the pancreatic ducts. A meeting of international experts on precursor lesions of pancreatic cancer was held at The Johns Hopkins Hospital from August 18 to 19, 2003. The purpose of this meeting was to define an international acceptable set of diagnostic criteria for PanINs and IPMNs and to address a number of ambiguities that exist in the previously reported classification systems for these neoplasms. We present a consensus classification of the precursor lesions in the pancreatic ducts, PanINs and IPMNs.

An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms

The dismal prognosis of pancreatic adenocarcinoma (PA) is due in part due to a lack of molecular information regarding disease development. Established cell lines remain a useful tool for investigating these molecular events. Here we present a review of available information on commonly used PA cell lines as a resource to help investigators select the cell lines most appropriate for their particular research needs. Information on clinical history, in vitro and in vivo growth characteristics, phenotypic characteristics, such as adhesion, invasion, migration and tumorigenesis, and genotypic status of commonly altered genes (KRAS, p53, p16, and SMAD4) was evaluated. Identification of both consensus and discrepant information in the literature suggests careful evaluation before selection of cell lines and attention be given to cell line authentication.

/pdf/phenotype-and-genotype-of-pancreatic-cancer-cell-lines-frvfdpjbrx.pdf

Phenotype and genotype of pancreatic cancer cell lines.

The Rb/p16 tumor-suppressive pathway is abrogated frequently in human tumors, either through inactivation of the Rb or p16INK4a/CDKN2/MTS1 tumor-suppressor proteins, or through alteration or overexpression of the cyclin D1 or cyclin-dependent kinase 4 oncoproteins. We reported previously that the p16 gene was genetically inactivated in 82% of pancreatic carcinomas. Nearly half of these inactivations were by intragenic mutation of p16, and the remainder were by homozygous deletion of the gene. Here, we analyzed pancreatic carcinomas for additional mechanisms by which the Rb/p16 pathway might be inactivated. Transcriptional silencing of the p16 gene in association with methylation of its 5′-CpG island was examined by methylation-specific PCR in 18 pancreatic carcinomas. Nine of these were known to harbor an intragenic mutation in p16, and nine had a wild-type p16 coding sequence. Seven of the 18 tumors were hypermethylated, and all 7 were p16 wild-type (P = 0.001). Complete silencing of transcription from methylated wild-type gene sequences was demonstrated. Immunohistochemical analysis revealed normal expression levels of the Rb protein in all carcinomas studied. None of the carcinomas had genomic amplification of the cyclin D1 or CDK4 genes, and none had mutation of the p16-binding domain of CDK4. An additional p16 mutation was identified. In total, the Rb/p16 pathway was abrogated in 49 of the 50 carcinomas (98%) studied, all through inactivation of the p16 gene. Similar results were obtained in an independently analyzed series of 19 pancreatic carcinomas. These data demonstrate the central role of the Rb/p16 pathway in the development of pancreatic carcinoma.

https://cancerres.aacrjournals.org/content/canres/57/15/3126.full.pdf

Abrogation of the Rb/p16 Tumor-suppressive Pathway in Virtually All Pancreatic Carcinomas

Background Natural killer (NK) cells play a crucial role in both physiologic and pathologic conditions, including cancer. A number of strategies have been employed to utilize the cytolytic properties of NK cells in the treatment of cancer. 1,2 One hurdle to the efficacy of NK-cell based therapy is NK cell infiltration into tumors. 3 The mechanisms NK cells employ for physical migration are not well described. 4,5 We recently found that fibroblast activation protein (FAP) is expressed by human NK cells. FAP is a type-II transmembrane serine protease previously thought to primarily be expressed in reactive stromal fibroblasts. FAP plays a role in tissue remodeling and extracellular matrix digestion to facilitate cell migration. 6 Methods FAP expression was examined on NK cells by both western blot and immunofluorescence. a specific pharmacological inhibitor of FAP in these assays. Results We have confirmed that fibroblast activation protein (FAP) is expressed by human NK cells, using both western blot and immunofluorescence. To examine the role of FAP in NK cells we find that following inhibition of FAP activity, NK cells demonstrate decreased migration in 3D culture systems, as well as decreased extravasation from the blood vessels of zebrafish.

/pdf/1012-fibroblast-activation-protein-regulates-human-natural-q2vbesfm.pdf

1012 Fibroblast activation protein regulates human natural killer cell migration

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Abrogation of the Rb/p16 Tumor-suppressive Pathway in Virtually All Pancreatic Carcinomas

1012 Fibroblast activation protein regulates human natural killer cell migration