Morphogenesis of pancreatic cancer: role of pancreatic intraepithelial neoplasia (PanINs)

Koorstra, Jan Bart M.; Feldmann, Georg; Habbe, Nils; Maitra, Anirban

doi:10.1007/s00423-008-0282-x

Cited by 44 publications

(39 citation statements)

References 88 publications

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“…The mortality rate for patients diagnosed with pancreatic cancer has remained stagnant for the last 5 decades, despite advanced surgical procedures and improvements in chemotherapeutics (23). Because most patients present with advanced metastatic disease, it is critical to understand the properties of invasive pancreatic tumors.…”

Section: Discussionmentioning

confidence: 99%

Quiescin Sulfhydryl Oxidase 1 Promotes Invasion of Pancreatic Tumor Cells Mediated by Matrix Metalloproteinases

Katchman

Antwi

Hostetter

et al. 2011

Molecular Cancer Research

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Quiescin sulfhydryl oxidase 1 (QSOX1) oxidizes sulfhydryl groups to form disulfide bonds in proteins. We previously mapped a peptide in plasma from pancreatic ductal adenocarcinoma (PDA) patients back to an overexpressed QSOX1 parent protein. In addition to overexpression in pancreatic cancer cell lines, 29 of 37 patients diagnosed with PDA expressed QSOX1 protein in tumor cells, but QSOX1 was not detected in normal adjacent tissues or in a transformed, but nontumorigenic cell line. To begin to evaluate the advantage QSOX1 might provide to tumors, we suppressed QSOX1 protein expression using short hairpin (sh) RNA in two pancreatic cancer cell lines. Growth, cell cycle, apoptosis, invasion, and matrix metalloproteinase (MMP) activity were evaluated. QSOX1 shRNA suppressed both short and long isoforms of the protein, showing a significant effect on cell growth, cell cycle, and apoptosis. However, QSOX1 shRNA dramatically inhibited the abilities of BxPC-3 and Panc-1 pancreatic tumor cells to invade through Matrigel in a modified Boyden chamber assay. Mechanistically, gelatin zymography indicated that QSOX1 plays an important role in activation of MMP-2 and MMP-9. Taken together, our results suggest that the mechanism of QSOX1-mediated tumor cell invasion is by activation of MMP-2 and MMP-9. Mol Cancer Res; 9(12); 1621-31. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Quiescin Sulfhydryl Oxidase 1 Promotes Invasion of Pancreatic Tumor Cells Mediated by Matrix Metalloproteinases

Katchman

Antwi

Hostetter

et al. 2011

Molecular Cancer Research

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“…30 Morphologically benign flat and papillary pancreatic precursors (PanIN-1A and 1B) contrast with severe atypias (PanIN-3), similar to SCOUTs and p53 signatures and tubal intraepithelial carcinomas of the fallopian tube. 31 Like SCOUTs and p53 signatures, low-grade PanINs are common in the general population but are more common in cancers vs controls (43% vs 28%). 32 Like tubal intraepithelial carcinoma, high-grade PanIN is much rarer and even more likely to be associated with malignancy.…”

Section: Discussionmentioning

confidence: 99%

“…33 Overall, PanINs increase in frequency as a function of age, similar to SCOUTs and (in more recent reports) p53 signatures. 4,12,13,26,31,34,35 Currently used methods of assessing PanIN frequency are by either measuring the number of PanINs per cm 2 of pancreatic tissue 19,20,36 or by measuring PanIN frequency per slide. 32 The first method measures both epithelium and parenchyme within the studied fields and as such measuring errors may occur when comparing the frequency of PanINs in fields with a variable epithelial/parenchymal ratio.…”

Section: Discussionmentioning

confidence: 99%

Digital quantification of precursor frequency in the fallopian tube and its significance

et al. 2012

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A high frequency of precursor lesions is a risk factor for cancer in many organ systems but must be precisely quantified. Pelvic serous neoplasia is associated with an estimated increase in frequency of secretory cell outgrowths (SCOUTs) with loss of PAX2 protein (PAX2p) expression (PAX2p-null SCOUTs) in the fallopian tube. However, to confirm this, PAX2p-null SCOUTs must be precisely quantified relative to the epithelial surface. We developed a method by which fallopian tube sections were digitized using an iScan brightfield scanner (BioImagene) and uploaded in Adobe Photoshop CS3 Extended. Pixel length was translated into microns and epithelial length measured with the Magic Wand tool. SCOUTs were expressed as a function of total epithelial perimeter. Frequency, required perimeter length, topographic clustering tendency and effects of age were ascertained. SCOUT frequency per 10 cm was 0-4.60 for cases and 0-1.66 for controls, averaging 0.84 and 0.27, respectively, (P ¼ 0.007). Required perimeter length for SCOUT detection was less in serous cancer cases and topographic distribution followed a random pattern without aberrant clustering. Age was also associated with SCOUT frequency (P ¼ 0.025) and differences between cancers and controls were still significant after adjusting for age (P ¼ 0.001). We describe an efficient method for quantifying epithelial perimeter in the fallopian tube and verify its relevance to precursor frequency. This has important implications for assessing precursor frequency both in the fallopian tube and in other organs-such as prostate, pancreas and colon-where epithelial precursors are integral to carcinogenesis. Modern Pathology (2012) 25, 1654-1661; doi:10.1038/modpathol.2012.100; published online 6 July 2012 Keywords: fallopian tube; precancer; secretory cell; serous cancer Although traditionally presumed to originate primarily in the ovarian cortex, high-grade ovarian cancers, specifically serous cancers, have been reassessed based on recent observations in the fallopian tube. 1 These include the frequent discovery of early serous cancers-termed tubal intraepithelial carcinomas-in the tubal fimbriae of women undergoing risk reducing salpingo-oophorectomy for germ-line BRCA1 or BRCA2 mutations, the observation of similar early cancers in 35-60% of un-selected women with fully developed pelvic serous cancer, and the description of a precursor condition in benign tubal mucosa with altered TP53 expression, termed the 'p53 signature'. 2-10 The latter has focused attention on the early molecular changes that may occur before the onset of either tubal intraepithelial or invasive serous carcinoma in the fallopian tube. Although the p53 signature, by virtue of its location (fimbria), p53 staining, evidence of DNA damage and proximity to intraepithelial carcinomas, is a presumptive direct precursor to intraepithelial carcinoma, a range of other discrete epithelial cell expansions have been described, termed secretory cell outgrowths or SCOUTs. [11][12][13] SCOUTs share with p53 signatures a...

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“…These steps were defined by histology of precancerous lesions at various stages that are collectively described as pancreatic intraepithelial neoplasias (PanINs) (Koorstra, et al, 2008b). They are further subdivided into PanIN-1A, PanIN-1B, and PanIN-2/3 based on distinct histology and genetic background (Koorstra, et al, 2008b, Koorstra, et al, 2008a. PanINs present as microscopic lesions situated in the smaller pancreatic ducts (Maitra, Anirban, et al, 2005).…”

Section: Progression Model Of Pancreatic Cancer Developmentmentioning

confidence: 99%

“…There is also CpG island methylation of promoters, telomere disruptions, and microsatellite instability, along with specific mutations in important oncogenes and tumor suppressors (Lin, et al, 2011, López-Casas & López-Fernández, 2010, Welsch, et al, 2007. Precursor lesions display an increasing proliferation rate as they progress towards an adenocarcinoma (Koorstra, et al, 2008b).…”

Section: Progression Model Of Pancreatic Cancer Developmentmentioning

confidence: 99%

Disruption of Cell Cycle Machinery in Pancreatic Cancer

Kennedy¹,

Berrett²,

Sheaff³

2012

Pancreatic Cancer - Molecular Mechanism and Targets

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Morphogenesis of pancreatic cancer: role of pancreatic intraepithelial neoplasia (PanINs)

Cited by 44 publications

References 88 publications

Quiescin Sulfhydryl Oxidase 1 Promotes Invasion of Pancreatic Tumor Cells Mediated by Matrix Metalloproteinases

Quiescin Sulfhydryl Oxidase 1 Promotes Invasion of Pancreatic Tumor Cells Mediated by Matrix Metalloproteinases

Digital quantification of precursor frequency in the fallopian tube and its significance

Disruption of Cell Cycle Machinery in Pancreatic Cancer

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