Diabetes mellitus als Risikofaktor des Pankreasadeno- karzinoms: Einfluss von Hyperglykämie auf den Phänotyp von Makrophagen und ihre Wirkung auf Pankreasgangepithelzellen

With less than 4 %, pancreatic ductal adenocarcinoma (PDAC) represents a small share in newly detected cancers but is among the few tumour entities with increasing incidence and mortality. By the year of 2030, PDAC is predicted to be the second most lethal neoplasia in western countries. Due to the lack of specific early symptoms, 80% of the patients are diagnosed in late tumour stages, leaving palliative treatment as the only therapeutic option. Besides chronic inflammation, obesity and type 2 diabetes mellitus (T2DM) - both associated with hyperglycaemia - are risk factors contributing to the initiation and progression of PDAC. However, underlying mechanisms are not yet fully understood. It is known that already precursor lesions are characterised by an inflammatory stroma. Macrophages, representing one of the largest immune cell populations within this stroma, impact on pancreatic ductal epithelial cells (PDEC) by promoting their malignant progression. Previous studies showed that high glucose levels influence the phenotype of macrophages, leading to the question whether these changes in macrophages’ phenotype in a T2DM-related inflammatory and hyperglycaemic microenvironment further facilitate malignancy-associated alterations in PDEC. In order to address this question, both, macrophages differentiated from human monocytes and H6c7-pBp and H6c7-kras cells mimicking benign and premalignant PDEC, were analysed after direct coculture under hyperglycaemia and compared to normoglycemic conditions. In macrophages, IL-6 levels were most strongly elevated, along with other pro-inflammatory cytokines such as IL-8 and of TNF-. In PDEC, the pro-inflammatory hyperglycaemic microenvironment enhanced the acquisition of tumourigenesis-associated alterations: Epithelial-Mesenchymal-Transition (EMT) and the acquisition of cancer stemness properties were promoted; and common soluble mediators of these two phenomena were increased in their expression levels as well. Many of these alterations were slightly more pronounced in H6c7-kras cells, however, also benign PDEC cells were shown to be driven into malignant progression through the complex interplay of an inflammatory hyperglycaemic surrounding. This underlines the importance of early intervention options in high-risk patients. Blockade of TGF- signalling partially reversed the above-mentioned changes in PDEC, as did the blockade of IL-6 trans-signalling via sgp130Fc, suggesting a partial involvement of these factors in inflammation and hyperglycaemia driven acquisition of malignancy-associated alterations and pointing to possible therapeutic points of attack. Overall, the current study corroborates the importance of the interplay of macrophages and hyperglycaemia as a leading contributor to the acquisition of malignancy-associated alterations in PDEC. It gives a new understanding of how metabolic disorders such as T2DM and obesity might initiate and promote PDAC. A better understanding of this is essential to foster ideas for potential early therapeutic intervention in high-risk patients - the current study pointing out an early anti-inflammatory therapy as one promising option in PDAC prevention