Galectin-1-driven upregulation of SDF-1 in pancreatic stellate cells promotes pancreatic cancer metastasis.

Galectin-1, mainly expressed in activated pancreatic stellate cells (PSCs), is involved in many important cancer-related processes. However, very little is known how Galectin-1 modulates PSCs and subsequently impacts pancreatic cancer cells (PCCs). Our chemokine antibody array and in vitro studies demonstrates that Galectin-1 induces secretion of stromal cell-derived factor-1(SDF-1) in PSCs by activating NF-κB signaling. The secreted SDF-1 increases migration and invasion of PCCs. Knockdown of Galectin-1 and inhibitor-mediated blockade of SDF-1 as well as its ligand CXCR4 and NF-κB verifies the findings. In vivo experiment by knockdown of Galectin-1 in PSCs further demonstrates the conclusion. Collectively, the present studies demonstrate that Galectin-1-driven production of SDF-1 in PSCs through activation of NF-κB promotes metastasis in PDAC, offering a potential target in the treatment of pancreatic cancer.

Qian D ，Lu Z ，Xu Q ，Wu P ，Tian L ，Zhao L ，Cai B ，Yin J ，Wu Y ，Staveley-O'Carroll KF ，Jiang K ，Miao Y ，Li G ... -  《-》

Galectin-3 Mediates Tumor Cell-Stroma Interactions by Activating Pancreatic Stellate Cells to Produce Cytokines via Integrin Signaling.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by activated pancreatic stellate cells (PSCs), abundance of extracellular matrix (ECM), and production of cytokines and chemokines. Galectin 3 (GAL3), a β-galactoside-specific lectin, contributes to PDAC development but its effects on the stroma and cytokine production are unclear. The effect of recombinant human GAL3 (rGAL3) on activation of PSCs, production of cytokines, and ECM proteins was determined by proliferation, invasion, cytokine array, and quantitative polymerase chain reaction. We assessed co-cultures of PDAC cells with GAL3 genetic alterations with PSCs. Production of interleukin 8 (IL8) and activities of nuclear factor (NF)-κB were determined by enzyme-linked immunosorbent assay and luciferase reporter analyses. We studied the effects of inhibitors of NF-κB and integrin-linked kinase (ILK) on pathways activated by rGAL3. In analyses of the Gene Expression Omnibus database and our dataset, we observed higher levels of GAL3, IL8, and other cytokines in PDAC than in nontumor tissues. Production of IL8, granulocyte-macrophage colony-stimulating factor, chemokine ligand 1, and C-C motif chemokine ligand 2 increased in PSCs exposed to rGAL3 compared with controls. Culture of PSCs with PDAC cells that express different levels of GAL3 resulted in proliferation and invasion of PSCs that increased with level of GAL3. GAL3 stimulated transcription of IL8 through integrin subunit beta 1 (ITGB1) on PSCs, which activates NF-κB through ILK. Inhibitors of ILK or NF-κB or a neutralizing antibody against ITGB1 blocked transcription and production of IL8 from PSCs induced by rGAL3. The GAL3 inhibitor significantly reduced growth and metastases of orthotopic tumors that formed from PDAC and PSC cells co-implanted in mice. GAL3 activates PSC cells to produce inflammatory cytokines via ITGB1signaling to ILK and activation of NF-κB. Inhibition of this pathway reduced growth and metastases of pancreatic orthotopic tumors in mice.

Zhao W ，Ajani JA ，Sushovan G ，Ochi N ，Hwang R ，Hafley M ，Johnson RL ，Bresalier RS ，Logsdon CD ，Zhang Z ，Song S ... -  《-》

Artemin regulates CXCR4 expression to induce migration and invasion in pancreatic cancer cells through activation of NF-κB signaling.

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal human malignant tumor because of the early onset of local invasion and distant metastasis. Perineural invasion is a prominent characteristic of pancreatic adenocarcinoma, which is a multifactorial process that involves various signaling molecules from different signaling pathways. The glial cell line-derived neurotrophic factor family of ligands was reported to be involved in perineural invasion in pancreatic cancer. Artemin is one member of the glial cell line-derived neurotrophic factor family of ligands. Although Artemin has previously been demonstrated to promote invasiveness of pancreatic cancer, the mechanisms remain poorly understood. In this study, we performed an analysis to determine the effects of Artemin on modulating tumor cell metastatic potential and invasion activity and explored its mechanisms in pancreatic cancer. We indicated that Artemin and CXCR4 were overexpressed in cancer tissues and widely expressed in pancreatic cancer cell lines. We observed that activation of ERK1/2 and Akt in Artemin-treated cells led to enhanced nuclear accumulation of NF-κB, which then induced CXCR4 expression. Through regulation of the expression of CXCR4, Artemin functionally promoted the migration and invasion in pancreatic cancer cells. The present study indicated that Artemin induced CXCR4 expression by activating Akt and ERK 1/2/NF-κB signaling, thereby modulating tumor cell metastatic potential and invasion activity in pancreatic cancer by regulating SDF-1α/CXCR4 axis. Artemin might be an effective and potent therapeutic target for pancreatic cancer metastasis, especially in perineural invasion.

Wang J ，Wang H ，Cai J ，Du S ，Xin B ，Wei W ，Zhang T ，Shen X ... -  《-》

Paracrine SDF-1α signaling mediates the effects of PSCs on GEM chemoresistance through an IL-6 autocrine loop in pancreatic cancer cells.

Zhang H ，Wu H ，Guan J ，Wang L ，Ren X ，Shi X ，Liang Z ，Liu T ... -  《Oncotarget》

Asporin promotes pancreatic cancer cell invasion and migration by regulating the epithelial-to-mesenchymal transition (EMT) through both autocrine and paracrine mechanisms.

Pancreatic cancer is histopathologically characterized by excessive desmoplasia induced by pancreatic stellate cells (PSCs). Asporin, an extracellular matrix (ECM) protein, is highly expressed in cancer-associated fibroblasts (CAFs). Asporin expression in PSCs and its roles in PSC-pancreatic cancer cell (PCC) interaction remain unclear. The present study firstly showed that Asporin is highly expressed in activated PSCs and is involved in PSC-mediated invasion and migration of PCCs. Exogenous Asporin interacted with the transmembrane receptor CD44 on PCCs to activate NF-κB/p65 and promoted the epithelial-mesenchymal transition (EMT) in PCCs. Furthermore, AKT and ERK pathways participated in Asporin/CD44-induced NF-κB/p65 activation in pancreatic cancer. Asporin had similar effects on PCCs via an autocrine mechanism. Consistent with our in vitro experiments, we showed that Asporin in peritumoral stroma of pancreatic cancer tissues was associated with poor clinical outcome. In conclusion, this is the first study to show that Asporin promotes EMT, invasion, and migration of PCCs by activating CD44-AKT/ERK-NF-κB pathway in paracrine and autocrine manners. Moreover, our results indicate that Asporin may be a prognostic marker and suggest that targeting the tumor microenvironment represents a promising therapeutic strategy in pancreatic cancer.

Wang L ，Wu H ，Wang L ，Zhang H ，Lu J ，Liang Z ，Liu T ... -  《-》