Abstract
BackgroundA hallmark of pancreatic ductal adenocarcinoma is the desmoplastic reaction, but its impact on the tumor behavior remains controversial. Our aim was to introduce a computer -aided method to precisely quantify the amount of pancreatic collagenic extra-cellular matrix, its spatial distribution pattern, and the degradation process.MethodsA series of normal, inflammatory and neoplastic pancreatic ductal adenocarcinoma formalin-fixed and paraffin-embedded Sirius red stained sections were automatically digitized and analyzed using a computer-aided method.ResultsWe found a progressive increase of pancreatic collagenic extra-cellular matrix from normal to the inflammatory and pancreatic ductal adenocarcinoma. The two-dimensional fractal dimension showed a significant difference in the collagenic extra-cellular matrix spatial complexity between normal versus inflammatory and pancreatic ductal adenocarcinoma. A significant difference when comparing the number of cycles necessary to degrade the pancreatic collagenic extra-cellular matrix in normal versus inflammatory and pancreatic ductal adenocarcinoma was also found. The difference between inflammatory and pancreatic ductal adenocarcinoma was also significant. Furthermore, the mean velocity of collagenic extra-cellular matrix degradation was found to be faster in inflammatory and pancreatic ductal adenocarcinoma than in normal.ConclusionThese findings demonstrate that inflammatory and pancreatic ductal adenocarcinomas are characterized by an increased amount of pancreatic collagenic extra-cellular matrix and by changes in their spatial complexity and degradation. Our study defines new features about the pancreatic collagenic extra-cellular matrix, and represents a basis for further investigations into the clinical behavior of pancreatic ductal adenocarcinoma and the development of therapeutic strategies.
Highlights
A hallmark of pancreatic ductal adenocarcinoma is the desmoplastic reaction, but its impact on the tumor behavior remains controversial
Morphometric and fractal analysis In keeping with previous studies, we found a statistically significant progressive increase of collagen extra-cellular matrix deposition from normal pancreatic tissue
With regard to the 2-D fractal surface dimension we found a statistically significant difference (p < 0.0001) in the geometrical spatial complexity of extracellular matrix (ECM) between normal pancreatic tissue (nPA) (1.35 ± 0.02) versus pancreatic inflammatory (iPA) (1.70 ± 0.01) and Pancreatic ductal adenocarcinoma (PDAC) (1.73 ± 0.01), but no differences were found between iPA and PDAC (Fig. 1e)
Summary
A hallmark of pancreatic ductal adenocarcinoma is the desmoplastic reaction, but its impact on the tumor behavior remains controversial. Changes in telomere length, complex karyotypes and multiple copy number alterations often spanning very large genomic regions, as well as several DNA changes have been reported [3, 7] The latter consists of activating mutations in oncogenes, such as KRAS, or inactivating alterations in tumor suppressor genes, including P16, TP53, and SMAD4 or in additional genes, such as MLL3, TGFBR2, ARID1A, CDKN2a and ATM [8]. These mutations, observed in non-invasive precursor lesions known as pancreatic intraepithelial neoplasia (PanIN) [9, 10], accumulate and drive neoplastic transformation and tumor progression [9, 11, 12]. A critical role of stroma in pancreatic carcinogenesis had been recognized for many years, only recently the study of this crucial tissue component has gained a considerable interest and has been considered in clinical practice [14, 27]
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