Stromal Fibrosis and Expression of Matricellular Proteins Correlate With Histological Grade of Intraductal Papillary Mucinous Neoplasm of the Pancreas

Kakizaki, Yasuharu; Makino, Naohiko; Tozawa, Tomohiro; Honda, Takao; Matsuda, Akiko; Ikeda, Yushi; Ito, Miho; Saito, Yoshihiko; Kimura, Wataru; Ueno, Yoshiyuki

doi:10.1097/mpa.0000000000000617

Cited by 19 publications

(12 citation statements)

References 45 publications

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“…5.3.1A). PanIN-and IPMN-associated stroma has been identified with increasing fibrosis correlated with increasing grade (50,105). This observation suggests that PAK1 is involved in the stroma of pre-and established pancreatic cancers and could be a potential therapeutic target.…”

Section: Discussionmentioning

confidence: 87%

The Role of p21-Activated Kinases in Pancreatic Cancer

Yeo

Baldwin

et al. 2015

Pancreas

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Pancreatic cancer is an aggressive cancer with a poor prognosis and an overall 5-year survival rate of less than 5%. Management has not improved significantly over the last 30 years, and a better understanding of the genetic and molecular changes that occur is urgently required. Many of these changes appear to involve the p21-activated kinases (PAKs). The PAK family consists of 6 isoforms, 2 of which, PAK1 and PAK4, are up-regulated and/or hyperactivated in pancreatic cancer. p21-Activated kinases can mediate many different cellular processes especially those contributing to cancer development and progression. These processes include the regulation of cytoskeletal dynamics and cell adhesion, the evasion of apoptosis, and the promotion of cell survival, proliferation, migration, and invasion. p21-Activated kinases may also be involved in characteristics unique to pancreatic tumors, such as interplay with the pancreatic stroma, the re-emergence of embryonic pathways, and the involvement of a subset of microRNAs and heat shock proteins. This review highlights the potential role of PAKs in pancreatic cancer and provides a foundation for more effective therapeutics to improve our current treatment of pancreatic cancer.

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Section: Discussionmentioning

confidence: 87%

The Role of p21-Activated Kinases in Pancreatic Cancer

Yeo

Baldwin

et al. 2015

Pancreas

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“…Several studies reported that ST and the malignant transformation of IPMN were significantly related . ST represents interstitial fibrosis and is caused by several microenvironmental factors .…”

Section: Discussionmentioning

confidence: 99%

“…Several studies reported that ST and the malignant transformation of IPMN were significantly related. [31][32][33] ST represents interstitial fibrosis and is caused by several microenvironmental factors. [34][35][36] Shindo et al 37 found that podoplanin hyperexpression in the intramural regions of IPMN significantly affected cancer invasion and interstitial fibrosis and that the malignant transformation of IPMN correlated with ST. Based on these molecular pathological findings, we believe that although ST was an indirect finding, it was closely associated with the malignant transformation of IPMN.…”

Section: T He Present Study Investigated Whether St Mnmentioning

confidence: 99%

Usefulness of septal thickness measurement on endoscopic ultrasound as a predictor of malignancy of branched‐duct and mixed‐type intraductal papillary mucinous neoplasm of the pancreas

Iwaya

Hijioka²,

Mizuno³

et al. 2019

Digestive Endoscopy

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Background and Aim Septal thickness (ST) can predict a malignant branch‐duct (BD) and mixed‐type intraductal papillary mucinous neoplasm (IPMN) of the pancreas, but its cut‐off value has not been established. The aim of the present study was to determine the optimal ST cut‐off value to predict malignancy using endoscopic ultrasound (EUS). Methods We retrospectively identified 200 patients with IPMN, including 132 with BD‐ and mixed‐IPMN, who underwent surgical resection between 1989 and 2017. ST was defined as the septum or lesion wall with the maximum diameter in BD‐ and mixed‐IPMN. The possibility of ST as a malignant predictor was examined, as well as the diagnostic ability of ST combined with mural nodule (MN) height for malignant IPMN. Results Among the 132 IPMN patients, pathological diagnosis was benign in 81 (61.4%) and malignant in 51 (38.6%). Area under the curve for the diagnosis of malignancy using ST was 0.74 for pathological specimens, 0.70 for EUS and 0.56 for computed tomography. Multivariate analysis showed that the odds ratios for ST ≥2.5 mm and MN height ≥5 mm were 3.51 [95% confidence interval (CI), 1.55–7.97, P = 0.003] and 3.36 (95% CI, 1.52–7.45, P = 0.003), respectively. Conclusions Septal thickness was an independent predictive factor similar to MN height for malignant IPMN in a multivariate analysis. The ST on EUS appeared to be the thickness of a fibrotic septum associated with the malignant transformation of IPMN. An ST cut‐off value of 2.5 mm might provide an accurate prediction of malignant IPMN.

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“…Pre-invasive lesions (i.e. PanIN 38 , MCN 39 or IPMN 40 ) in humans and mice [19][20][21][22][23][24][25] also induce PSC activation, either as a result of microscopic structural deformations and ductal obstruction (inducing injury and obstructive lobular atrophy) 41 or by direct paracrine signaling from transformed epithelia.…”

Section: Delineation Of Pda-associated Fibroblast Subtypes or Activatmentioning

confidence: 99%

Fibroblasts in Pancreatic Ductal Adenocarcinoma: Biological Mechanisms and Therapeutic Targets

2019

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The desmoplastic reaction of pancreas cancer may begin as a wound healing response to the nascent neoplasm, but it soon creates an insidious shelter that can sustain the growing tumor and rebuff therapy. Among the many cell types subverted by transformed epithelial cells, fibroblasts are recruited and activated to lay a foundation of extracellular matrix proteins and glycosaminoglycans that alter tumor biophysics and signaling. Their near-universal presence in pancreas cancer and ostensible support of disease progression make fibroblasts attractive therapeutic targets. More recently, however, it has also become apparent that diverse subpopulations of fibroblasts with distinct phenotypes and secretomes inhabit the stroma, and that targeted depletion of particular fibroblast subsets could either provide substantial therapeutic benefit or accelerate disease progression. An improved characterization of these fibroblast subtypes, along with their potential relationships to tumor subtypes and mutational repertoires, is needed in order to make anti-fibroblast therapies clinically viable.

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Stromal Fibrosis and Expression of Matricellular Proteins Correlate With Histological Grade of Intraductal Papillary Mucinous Neoplasm of the Pancreas

Cited by 19 publications

References 45 publications

The Role of p21-Activated Kinases in Pancreatic Cancer

The Role of p21-Activated Kinases in Pancreatic Cancer

Usefulness of septal thickness measurement on endoscopic ultrasound as a predictor of malignancy of branched‐duct and mixed‐type intraductal papillary mucinous neoplasm of the pancreas

Fibroblasts in Pancreatic Ductal Adenocarcinoma: Biological Mechanisms and Therapeutic Targets

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