An Exploratory Study of Inflammatory Cytokines as Prognostic Biomarkers in Patients With Ductal Pancreatic Adenocarcinoma

Dima, Simona; Tănase, Cristiana; Albulescu, Radu; Herlea, Vlad; Chivu‐Economescu, Mihaela; Purnichescu-Purtan, Raluca; Dumitraşcu, Traian; Duda, Dan G.; Popescu, Irinel

doi:10.1097/mpa.0b013e3182546e13

Cited by 74 publications

(63 citation statements)

References 18 publications

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“…Proinflammatory and anti-inflammatory cytokine production is increased in PDAC and acts on cancer cells and other cells in the tumor microenvironment (Ling et al 2012). Specifically, proinflammatory cytokines such as IL6, TNFα, MIF, IL-1β, and IL8 play critical roles in proliferation, angiogenesis, invasion, migration, and EMT (Miron et al 2010;Lesina et al 2011;Dima et al 2012;Funamizu et al 2013), whereas anti-inflammatory cytokines such as TGFβ and IL10 are involved in immune evasion and immune tolerance.…”

Section: Inflammatory Cytokines and Chemokinesmentioning

confidence: 99%

Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

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With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival. Pancreatic ductal adenocarcinoma (PDAC) pathogenesisOn gross inspection, PDAC presents as a poorly demarcated, firm white-yellow mass, with the surrounding nonmalignant pancreas typically showing atrophy, fibrosis, and dilated ducts due to the obstructive effects of expanding carcinoma. Microscopically, these neoplasms vary from well-differentiated gland-forming carcinomas to poorly differentiated "sarcomatoid" carcinomas diagnosed only upon immunolabeling due to predominant mesenchymal features (Hruban et al. 2007). PDAC evolves from well-defined precursor lesions that, in the context of their genetic features, define the genetic progression model of pancreatic carcinogenesis (Yachida et al. 2010). Early disease histology manifests as several distinct types of precursor lesions-the most common are microscopic pancreatic intraepithelial neoplasia (PanIN), followed by the macroscopic cysts; namely, the intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN) (Matthaei et al. 2011). Since most PDAC cases become clinically apparent at advanced stages, major opportunities to reduce mortality rest with diagnostics and treatments that would enable the reliable identification and elimination of high-risk precursor lesions. Thus, the identification of these precursor lesions has provided an essential framework to define the genomic features that drive progression to advanced disease and develop effective screening and targeted therapeutics for earlier stage disease (Eser et al. 2011).The noninvasive PanIN lesions were formerly classified into three grades according to the extent of cytological and architectural atypia: PanIN1A (flat lesion) and PanIN1B (micropapillary...

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Section: Inflammatory Cytokines and Chemokinesmentioning

confidence: 99%

Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

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“…IL-6, IL-1β, and TNF-α levels were also significantly correlated with circulating levels of CA 19-9 while IL-8, IL-10, TNF-α levels were significantly correlated with CEA levels in the patients with PDAC. Tumor volume was significantly correlated with IL-1β, IL-10 and VEGF levels; all the inflammatory markers analyzed, as well as VEGF and bFGF levels, were correlated with tumor stage (1). Another biomarker with potential prognostic value in PDAC patients seems to be circulating IL-8.…”

Section: Angiogenesis and Inflammatory Angiogenesis And Inflammatory mentioning

confidence: 92%

“…The main risk factors for pancreatic cancer are smoking, type 2 diabetes mellitus, obesity and pancreatitis, and family history (9). Chronic inflammatory conditions mediated by pro-inflammatory cytokines and their receptors, reactive oxygen species, up-regulated proinflammatory pathways, and immune cell infiltrates are associated with pancreatic carcinogenesis (1).…”

Section: Introduction Introductionmentioning

confidence: 99%

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The Association Between Inflammation and Angiogenesis in Human Pancreatic Adenocarcinoma

Tănase¹,

Necula²,

Neagu³

et al. 2016

JTMR

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Pancreatic cancer represents one of the deadliest cancers with a high mortality rate, characterized by an aggressive local invasion and early metastases. This malignancy is poorly responsive to chemotherapy or chemo-radiotherapy. Several proangiogenic factors were associated with pancreatic carcinogenesis, highlighting the importance of using antiangiogenic agents as therapeutic strategy. Further studies suggest the involvement of chronic inflammation in angiogenesis processes in pancreatic carcinogenesis and inflammatory cytokines should be considered as potential biomarkers, as well as therapeutic targets in pancreatic cancer patients.

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“…The main activators of MAP4K4 are stressrelated factors and proinflammatory cytokines such as TNF- (19). Indeed, we have recently reported that increase in blood circulating proinflammatory cytokines is a poor prognostic factor PDA patients (20). In other malignancies, it has been shown that MAP4K4 can directly activated JNK through TAK1, MKK4, and MKK7 (21).…”

Section: Discussion Discussionmentioning

confidence: 99%

MAP4K4 Expression is selectively upregulated and increases cell invasion in pancreatic ductal adenocarcinoma

Dima¹,

Chivu‐Economescu²,

Purnichescu-Purtan³

et al. 2016

JTMR

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The objective of this study was to determine whether the mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) expression can differentiate pancreatic ductal adenocarcinoma (PDA) from chronic pancreatitis (CP) and to analyze its biological and clinical significance in PDA. We have previously found by gene array analysis that MAP4K4 is overexpressed in PDA tissues. Here, we measured MAP4K4 gene and protein expression in 58 PDA and 9 CP surgical specimens using RT-PCR and immunohistochemistry, and analyzed their association with clinical outcomes. MAP4K4 mRNA expression was significantly higher in PDA versus CP tissues (Mann Whitney test, p<0.003), and correlated with TNM stage (Kruskal-Wallis test, p£0.026). MAP4K4 protein expression was significantly correlated with tumor grade (Spearman's Rho = 0.449, p£0.01), and tended to associate with shorter overall survival (p£0.076, log-rank test). In conclusion, our data indicate that the level of MAP4K4 expression directly correlates with PDA progression. Thus these data suggest that MAP4K4 may be a biomarker and potentially a target for therapy in PDA.

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An Exploratory Study of Inflammatory Cytokines as Prognostic Biomarkers in Patients With Ductal Pancreatic Adenocarcinoma

Cited by 74 publications

References 18 publications

Genetics and biology of pancreatic ductal adenocarcinoma

Genetics and biology of pancreatic ductal adenocarcinoma

The Association Between Inflammation and Angiogenesis in Human Pancreatic Adenocarcinoma

MAP4K4 Expression is selectively upregulated and increases cell invasion in pancreatic ductal adenocarcinoma

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