TRAIL promotes metastasis of human pancreatic ductal adenocarcinoma

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted considerable attention for its potential use in tumor therapy, as some recombinant variants of this ligand induce apoptosis in tumor cells without harming most normal cells. Here, we show that TRAIL strongly induces the expression of the proinflammatory cytokines interleukin-8 and monocyte chemoattractant protein 1 and enhances the invasion of apoptosis-resistant pancreatic ductal adenocarcinoma cells in vitro by upregulation of the urokinase-type plasminogen activator expression. Most importantly, we also demonstrate for the first time that TRAIL treatment results in strongly increased distant metastasis of pancreatic tumors in vivo. We orthotopically transplanted human pancreatic ductal adenocarcinoma cells to the pancreata of severe combined immunodeficiency mice and observed a dramatic increase in metastatic spread including a sixfold increase in the volume and fourfold increase in the number of liver metastases upon TRAIL treatment. Our results point to the necessity to carefully evaluate in vivo side effects of TRAIL and to select therapy conditions that not only enhance apoptosis induction but in addition prevent proinvasive and proinflammatory non-apoptotic TRAIL signaling.

Multiple effects of TRAIL in human carcinoma cells: Induction of apoptosis, senescence, proliferation, and cytokine production

“…Several lines of evidence indicate that TRAIL treatment of normal human endothelial cells and apoptosis resistant tumor cell lines can stimulates production of proinflammatory cytokines and chemokines, e.g. IL-1, IL-8, and MCP-1 [14][15][16][17]. We found that TRAIL stimulates production of IL-8 in all three tested human tumor cell lines, RANTES in MCF-7 cells, and bFGF in H460 cells.…”

“…Similarly, TRAIL treatment stimulated proliferation of apoptosis-resistant malignant cells, such as leukemia, neuroblastoma, renal cell carcinoma, and colon carcinoma cell lines [8,12,13]. Moreover, TRAIL promoted metastasis of pancreatic tumors in vivo [14]. In addition, TRAIL can stimulate proinflammatory signaling, leading to increased production of IL-8, IL-1α, IL-1β, and MCP-1 cytokines in normal human endothelial cells and in several apoptosis resistant tumor cell lines [14][15][16][17].…”

“…Moreover, TRAIL promoted metastasis of pancreatic tumors in vivo [14]. In addition, TRAIL can stimulate proinflammatory signaling, leading to increased production of IL-8, IL-1α, IL-1β, and MCP-1 cytokines in normal human endothelial cells and in several apoptosis resistant tumor cell lines [14][15][16][17]. However, the significance of TRAIL-induced cytokine production is still not fully understood.…”

“…However, the significance of TRAIL-induced cytokine production is still not fully understood. It is conceivable that these cytokines may elicit both autocrine and paracrine effects on tumor cells and stromal cells [14,18,19]. Several studies indicate that TRAIL-induced cytokine production could counterbalance TRAIL apoptotic effects [16,20,21].…”

Towards novel paradigms for cancer therapy

“…Moreover, proliferative effects in response to TRAIL have been reported in vitro using glioma and small cell lung cancer cell lines (Belyanskaya et al, 2008;Vilimanovich and Bumbasirevic, 2008) (Figure 2c). In other case, mice in which Bcl-xl-overexpressing Colo357 pancreatic ductal carcinomas were orthotopic transplanted formed more metastases upon TRAIL treatment (Trauzold et al, 2006), and finally two studies with blasts from leukemia patients treated ex vivo report effects of TRAIL exposure ranging from triggering of cell death to induction of cell proliferation (Ehrhardt et al, 2003;Hasegawa et al, 2005). TRAIL-induced proliferative effect has also been reported in synoviocytes from human rheumatoid patients who exhibit a poorly understood biphasic response to the cytokine, as it triggers death in an initial phase but support proliferation for the persisting/resistant cell fraction (Morel et al, 2005).…”