Description:
<jats:p>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 TNFα for the malignancy of PDAC cells <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo. In vitro</jats:italic>, TNFα strongly increased invasiveness of Colo357‐, BxPc3‐ and PancTuI‐cells and showed only moderate anti‐proliferative effect. TNFα treatment of mice bearing orthotopically growing PDAC tumors led to dramatically enhanced tumor growth and metastasis. Notably, we found that PDAC cells themselves secrete TNFα. While inhibition of TNFα with infliximab or etanercept only marginally affected proliferation and invasiveness of PDAC cells <jats:italic>in vitro</jats:italic>, both reagents exerted strong anti‐tumoral effects <jats:italic>in vivo</jats:italic>. In SCID mice with orthotopically growing Colo357‐, BxPc3‐ or PancTuI‐tumors, infliximab reduced tumor growth and metastasis by 30% and 50%, respectively. Importantly, in a PDAC resection model performed with PancTuI cells, we found a significant therapeutic effect for both anti‐ TNF compounds. Infliximab‐treatment reduced the volume of recurrent tumor by 70% and etanercept by almost 60%. Furthermore, both drugs strongly reduced the number of liver metastases. Thus, tumor cell‐derived TNFα plays a profound role in malignancy of PDAC and inhibition of TNFα represents a promising therapeutic option particularly in adjuvant therapy after subtotal pancreatectomy.</jats:p>