Resection of pancreatic cancer normalizes the preoperative increase of tumor necrosis factor alpha gene expression

Ariapart, Parisa; Bergstedt‐Lindqvist, Susanne; Harmelen, Vanessa van; Permert, Johan; Wu, Feng; Lundkvist, Inger

doi:10.1159/000064719

Cited by 18 publications

(8 citation statements)

References 8 publications

(7 reference statements)

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“…NF-nB activation has been reported in PDAC cell lines and primary tumor samples, and furthermore, increased TNFa levels were found in patients suffering from pancreatic cancer (18,19,39). Moreover, a recent study showed that the TNFa-processing enzyme ADAM17 is aberrantly expressed in PDAC and contributes to the invasiveness of pancreatic tumor cell lines in vitro (40).…”

Section: Discussionmentioning

confidence: 99%

Anti–Tumor Necrosis Factor Therapy Inhibits Pancreatic Tumor Growth and Metastasis

et al. 2008

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Chronic inflammation has been implicated in the pathogenesis of many severe autoimmune disorders, as well as in diabetes, pulmonary diseases, and cancer. Inflammation accompanies most solid cancers including pancreatic ductal adenocarcinoma (PDAC), one of the most fatal cancers with surgery being the only curative therapeutic approach currently available. In the present work, we investigated the role of the major proinflammatory cytokine tumor necrosis factor A (TNFA) in the malignancy of PDAC cells in vitro and in vivo. In vitro, TNFA strongly increased invasiveness of Colo357, BxPc3, and PancTuI cells and showed only moderate antiproliferative effect. TNFA treatment of mice bearing orthotopically growing PDAC tumors led to dramatically enhanced tumor growth and metastasis. Notably, we found that PDAC cells themselves secrete TNFA. Although inhibition of TNFA with infliximab or etanercept only marginally affected proliferation and invasiveness of PDAC cells in vitro, both reagents exerted strong antitumoral effects in vivo. In severe combined immunodeficient mice with orthotopically growing Colo357, BxPc3, or PancTuI tumors, human-specific anti-TNF antibody infliximab reduced tumor growth and metastasis by about 30% and 50%, respectively. Importantly, in a PDAC resection model performed with PancTuI cells, we found an even stronger therapeutic effect for both anti-TNF compounds. Infliximab and etanercept reduced the number of liver metastases by 69% and 42%, respectively, as well as volumes of recurrent tumors by 73% and 51%. Thus, tumor cell-derived TNFA plays a profound role in malignancy of PDAC, and inhibition of TNFA represents a promising therapeutic option particularly in adjuvant therapy after subtotal pancreatectomy.

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Section: Discussionmentioning

confidence: 99%

Anti–Tumor Necrosis Factor Therapy Inhibits Pancreatic Tumor Growth and Metastasis

et al. 2008

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“…34 Interestingly, increased levels of TNFα, IL1, IL6 and IL8 were found in patients suffering from pancreatic cancer. 18,19,36 Furthermore, a high constitutive activity of NFκB has been reported in various pancreatic cell lines and primary tumor samples. 37 Thus, the inhibition of NFκB and pro-inflammatory pathways could be a promising treatment strategy for PDAC and various other solid tumors.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone reduces tumor recurrence and metastasis after pancreatic tumor resection in SCID mice

Egberts

Schniewind²,

Pätzold³

et al. 2008

Cancer Biology & Therapy

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Conclusions: DEX has a profound influence on the malignant phenotype of PDAC tumor cells in vitro in terms of inhibition of invasiveness and pro-inflammatory signaling. This was approved in vivo by reduced metastasizing capacity and reduced size of local tumor recurrence. Therefore, DEX-treatment appears to be an interesting therapeutical option in an adjuvant setting after pancreatic cancer resection.

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“…8 The expression of the TNFa is upregulated in patients with pancreatic cancer and normalized after the pancreatic tumor is removed. 39 All pancreatic cancer cell lines expressed low levels of MMP-21 basally independent on their differentiation status. EGF was the only cytokine that was consistently able to induce MMP-21 in the cell line with high metastatic ability, PANC-1, that has also been reported to produce MMP-2 and MMP-9.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of matrix metalloproteinases-21 and -26 and TIMP-4 in pancreatic adenocarcinoma

et al. 2007

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Pancreatic adenocarcinoma is known for early aggressive local invasion, high metastatic potential, and a low 5-year survival rate. Matrix metalloproteinases (MMPs) play important roles in tumor growth and invasion. Earlier studies on pancreatic cancer have found increased expression of certain MMPs to correlate with poorer prognosis, short survival time or presence of metastases. We studied the expression of MMP-21, -26, and tissue inhibitor of matrix metalloproteinases ( Keywords: matrix metalloproteinase; adenocarcinoma; tissue inhibitor of metalloproteinase Pancreatic cancer is one of the most lethal types of cancer: the 5-year survival rate of pancreatic adenocarcinoma is under 5%.1,2 Other types of pancreatic tumors (15% of all tumors) include insulinoma, gastrinoma, and carcinoid tumor. Pancreatic cancer is notorious for its late clinical presentation, early and aggressive local invasion, and metastatic potential.3 The diagnosis is confirmed using ultrasound combined with biopsy as well as computed tomography, and tumor markers such as CA 19-9. If metastases are not found, the Whipple operation (pancreaticoduodenectomy) is performed to remove the tumor. If metastases are detected, palliative treatments are chosen, such as biliary bypass procedure or chemo/radiotherapy. A known risk factor for pancreatic cancer is smoking, which increases the risk two-to three-fold. 4 Also, patients with chronic pancreatitis have increased risk for developing pancreatic carcinoma. 5,6

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Resection of pancreatic cancer normalizes the preoperative increase of tumor necrosis factor alpha gene expression

Cited by 18 publications

References 8 publications

Anti–Tumor Necrosis Factor Therapy Inhibits Pancreatic Tumor Growth and Metastasis

Anti–Tumor Necrosis Factor Therapy Inhibits Pancreatic Tumor Growth and Metastasis

Dexamethasone reduces tumor recurrence and metastasis after pancreatic tumor resection in SCID mice

Increased expression of matrix metalloproteinases-21 and -26 and TIMP-4 in pancreatic adenocarcinoma

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