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Macrophages are attracted to developing tumors and can participate in immune surveillance to eliminate neoplastic cells. In response, neoplastic cells utilize NF-κB to suppress this killing activity, but the mechanisms underlying their self-protection remain unclear. Here, we report that this dynamic interaction between tumor cells and macrophages is integrally linked by a soluble factor identified as growth and differentiation factor 15 (GDF-15). In vitro, tumor-derived GDF-15 signals in macrophages to suppress their proapoptotic activity by inhibiting TNF and nitric oxide (NO) production. In vivo, depletion of GDF-15 in Ras-driven tumor xenografts and in an orthotopic model of pancreatic cancer delayed tumor development. This delay correlated with increased infiltrating antitumor macrophages. Further, production of GDF-15 is directly regulated by NF-κB, and the colocalization of activated NF-κB and GDF-15 in epithelial ducts of human pancreatic adenocarcinoma supports the importance of this observation. Mechanistically, we found that GDF-15 suppresses macrophage activity by inhibiting TGF-β-activated kinase (TAK1) signaling to NF-κB, thereby blocking synthesis of TNF and NO. Based on these results, we propose that the NF-κB/GDF-15 regulatory axis is important for tumor cells in evading macrophage immune surveillance during the early stages of tumorigenesis.

Background Cancer‐associated wasting, termed cancer cachexia, has a profound effect on the morbidity and mortality of cancer patients but remains difficult to recognize and diagnose. While increases in circulating levels of a number of inflammatory cytokines have been associated with cancer cachexia, these associations were generally made in patients with advanced disease and thus may be associated with disease progression rather than directly with the cachexia syndrome. Thus, we sought to assess potential biomarkers of cancer‐induced cachexia in patients with earlier stages of disease. Methods A custom multiplex array was used to measure circulating levels of 25 soluble factors from 70 pancreatic cancer patients undergoing attempted tumour resections. A high‐sensitivity multiplex was used for increased sensitivity for nine cytokines. Results Resectable pancreatic cancer patients with cachexia had low levels of canonical pro‐inflammatory cytokines including interleukin‐6 (IL‐6), interleukin‐1β (IL‐1β), interferon‐γ (IFN‐γ), and tumour necrosis factor (TNF). Even in our more sensitive analysis, these cytokines were not associated with cancer cachexia. Of the 25 circulating factors tested, only monocyte chemoattractant protein‐1 (MCP‐1) was increased in treatment‐naïve cachectic patients compared with weight stable patients and identified as a potential biomarker for cancer cachexia. Although circulating levels of leptin and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) were found to be decreased in the same cohort of treatment‐naïve cachectic patients, these factors were closely associated with body mass index, limiting their utility as cancer cachexia biomarkers. Conclusions Unlike in advanced disease, it is possible that cachexia in patients with resectable pancreatic cancer is not associated with high levels of classical markers of systemic inflammation. However, cachectic, treatment‐naïve patients have higher levels of MCP‐1, suggesting that MCP‐1 may be useful as a biomarker of cancer cachexia.

BackgroundCancer patients who exhibit cachexia lose weight and have low treatment tolerance and poor outcomes compared with cancer patients without weight loss. Despite the clear increased risk for patients, diagnosing cachexia still often relies on self‐reported weight loss. A reliable biomarker to identify patients with cancer cachexia would be a valuable tool to improve clinical decision making and identification of patients at risk of adverse outcomes.MethodsTargeted metabolomics, which included panels of amino acids, tricarboxylic acids, fatty acids, acylcarnitines, and sphingolipids, were conducted on plasma samples from patients with confirmed pancreatic ductal adenocarcinoma (PDAC) with and without cachexia and control patients without cancer (n = 10/group, equally divided by sex). Additional patient samples were analysed (total n = 95), and receiver operating characteristic (ROC) analyses were performed to establish if any metabolite could effectively serve as a biomarker of cachexia.ResultsTargeted profiling revealed that cachectic patients had decreased circulating levels of three sphingolipids compared with either non‐cachectic PDAC patients or patients without cancer. The ratio of C18‐ceramide to C24‐ceramide (C18:C24) outperformed a number of other previously proposed biomarkers of cachexia (area under ROC = 0.810). It was notable that some biomarkers, including C18:C24, were only altered in cachectic males.ConclusionsOur findings identify C18:C24 as a potentially new biomarker of PDAC‐induced cachexia that also highlight a previously unappreciated sexual dimorphism in cancer cachexia.

Macrophages are attracted to developing tumors and can participate in immune surveillance to eliminate neoplastic cells. In response, neoplastic cells utilize NF-[kappa]B to suppress this killing activity, but the mechanisms underlying their self-protection remain unclear. Here, we report that this dynamic interaction between tumor cells and macrophages is integrally linked by a soluble factor identified as growth and differentiation factor 15 (GDF-15). In vitro, tumor-derived GDF-15 signals in macrophages to suppress their proapoptotic activity by inhibiting TNF and nitric oxide (NO) production. In vivo, depletion of GDF-15 in Ros-driven tumor xenografts and in an orthotopic model of pancreatic cancer delayed tumor development. This delay correlated with increased infiltrating antitumor macrophages. Further, production of GDF-15 is directly regulated by NF-[kappa]B, and the colocalization of activated NF-[kappa]B and GDF-15 in epithelial ducts of human pancreatic adenocarcinoma supports the importance of this observation. Mechanistically, we found that GDF-15 suppresses macrophage activity by inhibiting TGF-[beta]-activated kinase (TAK1) signaling to NF-[kappa]B, thereby blocking synthesis of TNF and NO. Based on these results, we propose that the NF-[kappa]B/GDF-15 regulatory axis is important for tumor cells in evading macrophage immune surveillance during the early stages of tumorigenesis.