Inflammatory mechanisms contributing to pancreatic cancer development

Buckminster Farrow, Yuko Sugiyama, Andy Chen, Ekong Uffort, William Nealon, B. Mark Evers, Henry A. Pitt, David J. Cole, David W Mercer, J. Patrick O'Leary

Research output: Contribution to journalArticle

118 Citations (Scopus)

Abstract

Objective: Pancreatic cancer is the most deadly of all gastrointestinal (GI) malignancies, yet relatively little is known regarding mechanisms of tumor development including the role of inflammation. Summary Background Data: Chronic pancreatitis (CP) increases the risk of developing cancer by 10- to 20-fold; mediators of the chronic inflammatory process and the surrounding fibrotic stroma likely support a transformation to malignancy, yet the exact mechanisms remain undefined. The purpose of our present study was to determine potential inflammatory components in epithelial and stromal cells that may contribute to both CP and pancreatic cancers. Methods: Specimens of normal pancreas, CP, and pancreatic cancer were examined using laser-capture microdissection (LCM), gene array, and immunohistochemistry. Results: Gene array analysis from LCM-dissected tissues demonstrated: (i) increased expression of interleukin-8 (IL-8), an activator of the inflammatory factor nuclear factor-κB (NF-κB), and (ii) decreased expression of IκB (an inhibitor of NF-κB) in CP ductal cells compared with normal ducts. Compared with CP, cancers demonstrated: (i) increased expression of tumor related genes including S100A4, cyclin E1, and epidermal growth factor (EGF) receptor, and (ii) expression of matrix metalloproteinase 2, a proinvasive factor for tumor cells, which was not present in the CP stroma. Increased staining of both the p50 NF-κB subunit and IKKα kinase (a protein that allows activation of NF-κB) was noted in CP and cancers. Conclusions: Our results demonstrate that similar inflammatory components and downstream effectors are present in CP and pancreatic cancers. Importantly, these findings suggest that a common pathway for pancreatic cancer development may be through a chronic inflammatory process including stroma formation. These findings may lead to novel strategies for pancreatic cancer prophylaxis based on inhibition of inflammatory mediators.

Original languageEnglish (US)
Pages (from-to)763-771
Number of pages9
JournalAnnals of surgery
Volume239
Issue number6
DOIs
StatePublished - Jun 1 2004

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Chronic Pancreatitis
Pancreatic Neoplasms
Neoplasms
Laser Capture Microdissection
Genes
Cyclins
Matrix Metalloproteinase 2
Stromal Cells
Interleukin-8
Epidermal Growth Factor Receptor
Protein Kinases
Pancreas
Epithelial Cells
Immunohistochemistry
Staining and Labeling
Inflammation

ASJC Scopus subject areas

  • Surgery

Cite this

Farrow, B., Sugiyama, Y., Chen, A., Uffort, E., Nealon, W., Evers, B. M., ... O'Leary, J. P. (2004). Inflammatory mechanisms contributing to pancreatic cancer development. Annals of surgery, 239(6), 763-771. https://doi.org/10.1097/01.sla.0000128681.76786.07

Inflammatory mechanisms contributing to pancreatic cancer development. / Farrow, Buckminster; Sugiyama, Yuko; Chen, Andy; Uffort, Ekong; Nealon, William; Evers, B. Mark; Pitt, Henry A.; Cole, David J.; Mercer, David W; O'Leary, J. Patrick.

In: Annals of surgery, Vol. 239, No. 6, 01.06.2004, p. 763-771.

Research output: Contribution to journalArticle

Farrow, B, Sugiyama, Y, Chen, A, Uffort, E, Nealon, W, Evers, BM, Pitt, HA, Cole, DJ, Mercer, DW & O'Leary, JP 2004, 'Inflammatory mechanisms contributing to pancreatic cancer development', Annals of surgery, vol. 239, no. 6, pp. 763-771. https://doi.org/10.1097/01.sla.0000128681.76786.07
Farrow B, Sugiyama Y, Chen A, Uffort E, Nealon W, Evers BM et al. Inflammatory mechanisms contributing to pancreatic cancer development. Annals of surgery. 2004 Jun 1;239(6):763-771. https://doi.org/10.1097/01.sla.0000128681.76786.07
Farrow, Buckminster ; Sugiyama, Yuko ; Chen, Andy ; Uffort, Ekong ; Nealon, William ; Evers, B. Mark ; Pitt, Henry A. ; Cole, David J. ; Mercer, David W ; O'Leary, J. Patrick. / Inflammatory mechanisms contributing to pancreatic cancer development. In: Annals of surgery. 2004 ; Vol. 239, No. 6. pp. 763-771.
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abstract = "Objective: Pancreatic cancer is the most deadly of all gastrointestinal (GI) malignancies, yet relatively little is known regarding mechanisms of tumor development including the role of inflammation. Summary Background Data: Chronic pancreatitis (CP) increases the risk of developing cancer by 10- to 20-fold; mediators of the chronic inflammatory process and the surrounding fibrotic stroma likely support a transformation to malignancy, yet the exact mechanisms remain undefined. The purpose of our present study was to determine potential inflammatory components in epithelial and stromal cells that may contribute to both CP and pancreatic cancers. Methods: Specimens of normal pancreas, CP, and pancreatic cancer were examined using laser-capture microdissection (LCM), gene array, and immunohistochemistry. Results: Gene array analysis from LCM-dissected tissues demonstrated: (i) increased expression of interleukin-8 (IL-8), an activator of the inflammatory factor nuclear factor-κB (NF-κB), and (ii) decreased expression of IκB (an inhibitor of NF-κB) in CP ductal cells compared with normal ducts. Compared with CP, cancers demonstrated: (i) increased expression of tumor related genes including S100A4, cyclin E1, and epidermal growth factor (EGF) receptor, and (ii) expression of matrix metalloproteinase 2, a proinvasive factor for tumor cells, which was not present in the CP stroma. Increased staining of both the p50 NF-κB subunit and IKKα kinase (a protein that allows activation of NF-κB) was noted in CP and cancers. Conclusions: Our results demonstrate that similar inflammatory components and downstream effectors are present in CP and pancreatic cancers. Importantly, these findings suggest that a common pathway for pancreatic cancer development may be through a chronic inflammatory process including stroma formation. These findings may lead to novel strategies for pancreatic cancer prophylaxis based on inhibition of inflammatory mediators.",
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AU - Farrow, Buckminster

AU - Sugiyama, Yuko

AU - Chen, Andy

AU - Uffort, Ekong

AU - Nealon, William

AU - Evers, B. Mark

AU - Pitt, Henry A.

AU - Cole, David J.

AU - Mercer, David W

AU - O'Leary, J. Patrick

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N2 - Objective: Pancreatic cancer is the most deadly of all gastrointestinal (GI) malignancies, yet relatively little is known regarding mechanisms of tumor development including the role of inflammation. Summary Background Data: Chronic pancreatitis (CP) increases the risk of developing cancer by 10- to 20-fold; mediators of the chronic inflammatory process and the surrounding fibrotic stroma likely support a transformation to malignancy, yet the exact mechanisms remain undefined. The purpose of our present study was to determine potential inflammatory components in epithelial and stromal cells that may contribute to both CP and pancreatic cancers. Methods: Specimens of normal pancreas, CP, and pancreatic cancer were examined using laser-capture microdissection (LCM), gene array, and immunohistochemistry. Results: Gene array analysis from LCM-dissected tissues demonstrated: (i) increased expression of interleukin-8 (IL-8), an activator of the inflammatory factor nuclear factor-κB (NF-κB), and (ii) decreased expression of IκB (an inhibitor of NF-κB) in CP ductal cells compared with normal ducts. Compared with CP, cancers demonstrated: (i) increased expression of tumor related genes including S100A4, cyclin E1, and epidermal growth factor (EGF) receptor, and (ii) expression of matrix metalloproteinase 2, a proinvasive factor for tumor cells, which was not present in the CP stroma. Increased staining of both the p50 NF-κB subunit and IKKα kinase (a protein that allows activation of NF-κB) was noted in CP and cancers. Conclusions: Our results demonstrate that similar inflammatory components and downstream effectors are present in CP and pancreatic cancers. Importantly, these findings suggest that a common pathway for pancreatic cancer development may be through a chronic inflammatory process including stroma formation. These findings may lead to novel strategies for pancreatic cancer prophylaxis based on inhibition of inflammatory mediators.

AB - Objective: Pancreatic cancer is the most deadly of all gastrointestinal (GI) malignancies, yet relatively little is known regarding mechanisms of tumor development including the role of inflammation. Summary Background Data: Chronic pancreatitis (CP) increases the risk of developing cancer by 10- to 20-fold; mediators of the chronic inflammatory process and the surrounding fibrotic stroma likely support a transformation to malignancy, yet the exact mechanisms remain undefined. The purpose of our present study was to determine potential inflammatory components in epithelial and stromal cells that may contribute to both CP and pancreatic cancers. Methods: Specimens of normal pancreas, CP, and pancreatic cancer were examined using laser-capture microdissection (LCM), gene array, and immunohistochemistry. Results: Gene array analysis from LCM-dissected tissues demonstrated: (i) increased expression of interleukin-8 (IL-8), an activator of the inflammatory factor nuclear factor-κB (NF-κB), and (ii) decreased expression of IκB (an inhibitor of NF-κB) in CP ductal cells compared with normal ducts. Compared with CP, cancers demonstrated: (i) increased expression of tumor related genes including S100A4, cyclin E1, and epidermal growth factor (EGF) receptor, and (ii) expression of matrix metalloproteinase 2, a proinvasive factor for tumor cells, which was not present in the CP stroma. Increased staining of both the p50 NF-κB subunit and IKKα kinase (a protein that allows activation of NF-κB) was noted in CP and cancers. Conclusions: Our results demonstrate that similar inflammatory components and downstream effectors are present in CP and pancreatic cancers. Importantly, these findings suggest that a common pathway for pancreatic cancer development may be through a chronic inflammatory process including stroma formation. These findings may lead to novel strategies for pancreatic cancer prophylaxis based on inhibition of inflammatory mediators.

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