Exploiting inflammation for therapeutic gain in pancreatic cancer

Steele, Colin W.; Jamieson, Nigel B.; Evans, T.R.J.; McKay, Colin; Sansom, Owen J.; Morton, Jennifer P.; Carter, C R

doi:10.1038/bjc.2013.24

Cited by 79 publications

(81 citation statements)

References 51 publications

(58 reference statements)

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“…Recently, it was reported that tumorigenesis in the pancreas is associated with significant intra-and peri-tumoral inflammation and failure of protective immunosurveillance (75). Neutrophil activation and proliferation are indicative of TH-1 pathway of cell-mediated immunity involvement (76).…”

Section: Peripheral Blood Cellmentioning

confidence: 99%

Updates and Critical Evaluation on Novel Biomarkers for the Malignant Progression of Intraductal Papillary Mucinous Neoplasms of the Pancreas

Moris

Damaskos

Spartalis

et al. 2017

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Section: Peripheral Blood Cellmentioning

confidence: 99%

Updates and Critical Evaluation on Novel Biomarkers for the Malignant Progression of Intraductal Papillary Mucinous Neoplasms of the Pancreas

Moris

Damaskos

Spartalis

et al. 2017

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“…A genetic basis for some insulinomas has been linked to the gene for Multiple Endocrine Neoplasia I (MEN1) and k-ras mutations, however chronic inflammation is also known to be oncogenic and may contribute to the malignant transformation in many different types of tumors [12][13][14] . Toll-like receptors (TLR) are a family of cell surface pattern recognition receptors in immune cells which recognize signature molecules of different environmental pathogens and are important components of the innate and acquired immune system [15] .…”

Section: Introductionmentioning

confidence: 99%

Proinsulinoma causing severe hypoglycemia in a patient with type 1 diabetes mellitus

Bertheau¹,

Herceg

Malgor

et al. 2014

CRCP

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Case presentation: A 49 year male a 35 year history of Type 1 Diabetes Mellitus (T1DM) was evaluated for recurrent episodes of hypoglycemia. After being weaned off of all exogenous insulin, the patient continued to have frequent and severe episodes of hypoglycemia often associated with seizures. Results:During an observed hypoglycemic reaction in our office he was found to have a serum glucose level of 64 mg/dl, a serum insulin level of 64 μIU/ml (reference range is <17 μIU/ml) and a C-peptide level of 0.6 ng/ml (reference range is 0.8 ng/ml -3.1 ng/ml). Serum and urine sulfonylurea levels were negative. During a formal diagnostic 72 hour fast, he developed severe hypoglycemia within four hours of beginning the fast and seized. No diagnostic laboratory studies were obtained during the hypoglycemic event! He underwent surgical exploration, where a 0.8 cm well-differentiated, islet cell tumor was resected. Following resection of the tumor, the spontaneous hypoglycemia resolved, and maintenance exogenous insulin was reinstituted. Histoimmunochemical staining was positive for chromogranin, synaptophysin, amylin, and proinsulin but negative for insulin. Immunostaining of the tumor was also positive for Toll-like receptors-3 (TLR3) and Wnt5a.Conclusion: This is the first case report of a patient with a long history of T1DM who developed a recurrent hypoglycemia due to a proinsulin-secreting islet cell tumor which resolved following its resection.

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“…Although the mechanism is not entirely understood, sustained inflammation contributes to a compromised anti-tumor immune response via the infiltration of immunosuppressive regulatory T cells and MDSC (29,30). In addition, these inflammatory stimuli activate stellate cells and fibroblasts, leading to fibrotic remodeling of the pancreatic tissue, which in turn enhances oncogenic KRAS signaling (29).…”

Section: Microenvironmentmentioning

confidence: 99%

Critical role of oncogenic KRAS in pancreatic cancer (Review)

Liu

Liang

et al. 2016

Molecular Medicine Reports

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Abstract. Pancreatic cancer is a human malignancy with one of the highest mortality rates and little progress has been achieved in its treatment in recent decades. Further improvement to the understanding of the biological and molecular mechanisms underlying the initiation and development of pancreatic ductal adenocarcinoma (PDAC) is required. Previous studies using genetically engineered mouse models have demonstrated that oncogenic GTPase KRas (KRAS) mutation is involved in the formation of pancreatic intraepithelial neoplasia and promotes the progression of PDAC. However, attempts to target KRAS directly by pharmacological inhibition have been unsuccessful. This has resulted in increased efforts to identify pharmacological targets and nodes associated with the mutated KRAS. The present review discusses the recent progress and prospects of KRAS signaling in pancreatic cancer. IntroductionPancreatic ductal adenocarcinoma (PDAC) is an incurable disease that results in mortality. The number of newly diagnosed cases almost equals the annual number of deaths despite advances in surgery and chemoradiotherapy in the past decades. Although the 5-year survival of pancreatic cancer patients has almost doubled over the past decade, it remains low at ~7-8% according to the US National Cancer Institute (1). A lack of early diagnostic strategies, high resistance to chemoradiotherapy and early local or distant metastatic recurrence following surgery are the three predominant factors that contribute to poor outcomes. Further understanding of the biological and molecular mechanisms underlying the initiation and development of PDAC are required. Genetically, cancer progresses as a result of the combined activation of oncogenes and inactivation of tumor suppressors. Similarly, numerous molecular alterations are also required for pancreatic intraepithelial neoplasias (PanIN) lesions to develop into PDAC. Previous studies have established that PDAC is characterized by four signature mutations including mutations in GTPase KRas (KRAS) oncogene and in cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein p53 (TP53), and SMAD family member 4 (SMAD4) tumor suppressor genes (2,3). Approximately 90% of pancreatic neoplasms express mutant KRAS, which has been hypothesized to be the initiator of PDAC. However, the development of therapeutic agents targeting KRAS in PDAC remains unsuccessful. The present review discusses recent research regarding KRAS and explores potential therapeutic targets. InitiationPDAC develops with progressive cellular, morphological and architectural changes from normal ductal epithelium to preneoplastic lesions, and then PanINs and PDAC. The majority of PDAC and early PanIN lesions involve mutations in the KRAS oncogene. Almoguera et al (4) and Smit et al (5) first established the association between the mutant KRAS gene and PDAC in 1988. To investigate the role of the KRAS oncogene in the onset of PDAC, multiple genetically engineered mouse (GEM) models were established. The first model was the endogen...

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Exploiting inflammation for therapeutic gain in pancreatic cancer

Cited by 79 publications

References 51 publications

Updates and Critical Evaluation on Novel Biomarkers for the Malignant Progression of Intraductal Papillary Mucinous Neoplasms of the Pancreas

Updates and Critical Evaluation on Novel Biomarkers for the Malignant Progression of Intraductal Papillary Mucinous Neoplasms of the Pancreas

Proinsulinoma causing severe hypoglycemia in a patient with type 1 diabetes mellitus

Critical role of oncogenic KRAS in pancreatic cancer (Review)

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