Prognostic role and correlation of CA9, CD31, CD68 and CD20 with the desmoplastic stroma in pancreatic ductal adenocarcinoma

This study aims at clarifying the prognostic role of high-grade tumor budding (TB) in pancreatic ductal adenocarcinoma (PDAC) with the first systematic review and meta-analysis on this topic. Furthermore, we analyzed with a systematic review the relationship between TB and a recently suggested TB-associated mechanism: the epithelial to mesenchymal transition (EMT). Analyzing a total of 613 patients, 251 of them (40.9%) with high grade-TB, we found an increased risk of all-cause mortality (RR, 1.46; 95% CI, 1.13–1.88, p = 0.004; HR, 2.65; 95% CI, 1.79–3.91; p < 0.0001) and of recurrence (RR, 1.61; 95% CI, 1.05–2.47, p = 0.03) for PDAC patients with high-grade TB. Moreover, we found that EMT is a central process in determining the presence of TB in PDAC. Thanks to this meta-analysis, we demonstrate the potential clinical significance of high-grade TB for prognostic stratification of PDAC. TB also shows a clear association with the process of EMT. Based on the results of the present study, TB should be conveyed in pathology reports and taken into account by future oncologic staging systems.

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Prognostic role of HER2 amplification based on fluorescence in situ hybridization (FISH) in pancreatic ductal adenocarcinoma (PDAC): a meta-analysis

World Journal of Surgical Oncology ◽

10.1186/s12957-016-0792-x ◽

2016 ◽

Vol 14 (1) ◽

Cited By ~ 7

Author(s):

Xiaoping Li ◽

Hua Zhao ◽

Jianchun Gu ◽

Leizhen Zheng

Keyword(s):

In Situ Hybridization ◽

Fluorescence In Situ Hybridization ◽

Pancreatic Ductal Adenocarcinoma ◽

Meta Analysis ◽

Ductal Adenocarcinoma ◽

Her2 Amplification ◽

Prognostic Role

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Emerging Kinase Therapeutic Targets in Pancreatic Ductal Adenocarcinoma and Pancreatic Cancer Desmoplasia

International Journal of Molecular Sciences ◽

10.3390/ijms21228823 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8823

Author(s):

Justin F. Creeden ◽

Khaled Alganem ◽

Ali S. Imami ◽

Nicholas D. Henkel ◽

F. Charles Brunicardi ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Tyrosine Kinases ◽

Tumor Development ◽

Review Literature ◽

Ductal Adenocarcinoma ◽

Pancreatic Tumors ◽

Desmoplastic Stroma ◽

B Lymphoid ◽

Therapeutic Research ◽

Lymphocyte Cell

Kinase drug discovery represents an active area of therapeutic research, with previous pharmaceutical success improving patient outcomes across a wide variety of human diseases. In pancreatic ductal adenocarcinoma (PDAC), innovative pharmaceutical strategies such as kinase targeting have been unable to appreciably increase patient survival. This may be due, in part, to unchecked desmoplastic reactions to pancreatic tumors. Desmoplastic stroma enhances tumor development and progression while simultaneously restricting drug delivery to the tumor cells it protects. Emerging evidence indicates that many of the pathologic fibrotic processes directly or indirectly supporting desmoplasia may be driven by targetable protein tyrosine kinases such as Fyn-related kinase (FRK); B lymphoid kinase (BLK); hemopoietic cell kinase (HCK); ABL proto-oncogene 2 kinase (ABL2); discoidin domain receptor 1 kinase (DDR1); Lck/Yes-related novel kinase (LYN); ephrin receptor A8 kinase (EPHA8); FYN proto-oncogene kinase (FYN); lymphocyte cell-specific kinase (LCK); tec protein kinase (TEC). Herein, we review literature related to these kinases and posit signaling networks, mechanisms, and biochemical relationships by which this group may contribute to PDAC tumor growth and desmoplasia.

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Pentraxin 3 is a stromally-derived biomarker for detection of pancreatic ductal adenocarcinoma

npj Precision Oncology ◽

10.1038/s41698-021-00192-1 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Michelle R. Goulart ◽

Jennifer Watt ◽

Imran Siddiqui ◽

Rita T. Lawlor ◽

Ahmet Imrali ◽

...

Keyword(s):

Clinical Trial ◽

Pancreatic Ductal Adenocarcinoma ◽

Ex Vivo ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Diagnostic Biomarkers ◽

All Trans Retinoic Acid ◽

Desmoplastic Stroma ◽

Predictive Role

AbstractPancreatic ductal adenocarcinoma (PDAC), characterized by dense desmoplastic stroma laid down by pancreatic stellate cells (PSC), has no reliable diagnostic biomarkers for timely detection. A multi-center cohort of PDAC patients and controls (chronic pancreatitis, intra-ductal papillary neoplasms, gallstones and otherwise healthy) donated serum in an ethically approved manner. Serum PTX3 above 4.34 ng/mL has a higher sensitivity (86%, 95% confidence interval (CI): 65–97%) and specificity (86%, 95% CI: 79–91%), positive predictive value (97%) and likelihood ratio (6.05), and is superior when compared to serum CA19-9 and CEA for detection of PDAC. In vitro and ex vivo analyses of PTX3, in human PDAC samples, PSCs, cell lines and transgenic mouse model for PDAC, suggest that PTX3 originates from stromal cells, mainly PSC. In activated PSC, PTX3 secretion could be downregulated by rendering PSC quiescent using all-trans-retinoic acid (ATRA). PTX3 organizes hyaluronan in conjunction with tumor necrosis factor-stimulated gene 6 (TSG-6) and facilitates stellate and cancer cell invasion. In SCALOP clinical trial (ISRCTN96169987) testing chemo-radiotherapy without stromal targeting, PTX3 had no prognostic or predictive role. However, in STARPAC clinical trial (NCT03307148), stromal modulation by ATRA even at first dose is accompanied with serum PTX3 response in patients who later go on to demonstrate disease control but not those in whom the disease progresses. PTX3 is a putative stromally-derived biomarker for PDAC which warrants further testing in prospective, larger, multi-center cohorts and within clinical trials targeting stroma.

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Clinicopathological significance and prognostic role of chemokine receptor CXCR4 expression in pancreatic ductal adenocarcinoma, a meta-analysis and literature review

International Journal of Surgery ◽

10.1016/j.ijsu.2019.03.009 ◽

2019 ◽

Vol 65 ◽

pp. 32-38 ◽

Cited By ~ 7

Author(s):

Yong Ding ◽

Yaowu Du

Keyword(s):

Literature Review ◽

Pancreatic Ductal Adenocarcinoma ◽

Chemokine Receptor ◽

Meta Analysis ◽

Cxcr4 Expression ◽

Ductal Adenocarcinoma ◽

Prognostic Role ◽

Chemokine Receptor Cxcr4 ◽

Clinicopathological Significance

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KRASG12D and TP53R167H Cooperate to Induce Pancreatic Ductal Adenocarcinoma in Sus Scrofa Pigs

10.1101/358416 ◽

2018 ◽

Author(s):

Daniel R. Principe ◽

Nana Haahr Overgaard ◽

Alex J. Park ◽

Andrew M. Diaz ◽

Carolina Torres ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Sus Scrofa ◽

Cancer Biology ◽

Ductal Adenocarcinoma ◽

Large Animal Model ◽

Large Animal ◽

Desmoplastic Stroma ◽

Immunocompromised Mice

AbstractAlthough survival has improved in recent years, the prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remains poor. Despite substantial differences in anatomy, physiology, genetics, and metabolism, the overwhelming majority of preclinical testing relies on transgenic mice. Hence, while mice have allowed for tremendous advances in cancer biology, they have been a poor predictor of drug performance/toxicity in the clinic. Given the greater similarity of sus scrofa pigs to humans, we engineered transgenic sus scrofa expressing a LSL-KRASG12D-TP53R167H cassette. By applying Adeno-Cre to pancreatic duct cells in vitro, cells self-immortalized and established tumors in immunocompromised mice. When Adeno-Cre was administered to the main pancreaticduct in vivo, pigs developed extensive PDAC at the injection site hallmarked by excessive proliferation and desmoplastic stroma. This serves as the first large animal model of pancreatic carcinogenesis, and may allow for insight into new avenues of translational research not before possible in rodents.

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