PSC-derived Galectin-1 inducing epithelial-mesenchymal transition of pancreatic ductal adenocarcinoma cells by activating the NF-κB pathway

Abstract

Galectin-1 has previously been shown to be strongly expressed in activated pancreatic stellate cells (PSCs) and promote the development and metastasis of pancreatic ductal adenocarcinoma (PDAC). However, the molecular mechanisms by which Galectin-1 promotes the malignant behavior of pancreatic cancer cells remain unclear. In this study, we examined the effects of Galectin-1 knockdown or overexpression in PSCs co-cultured with pancreatic cancer (PANC-1) cells. Immunohistochemical analysis showed expression of epithelial-mesenchymal transition (EMT) markers and MMP9 were positively associated with the expression of Galectin-1 in 66 human PDAC tissues. In addition, our in vitro studies showed PSC-derived Galectin-1 promoted the proliferation, invasion, and survival (anti-apoptotic effects) of PANC-1 cells. We also showed PSC-derived Galectin-1 induced EMT of PANC-1 cells and activated the NF-кB pathway in vitro. Our mixed (PSCs and PANC-1 cells) mouse orthotopic xenograft model indicated that overexpression of Galectin-1 in PSCs significantly promoted the proliferation, growth, invasion, and liver metastasis of the transplanted tumor. Moreover, Galectin-1 overexpression in PSCs was strongly associated with increased expression of EMT markers in both the orthotopic xenograft tumor in the pancreas and in metastatic lesions of naked mice. We conclude that PSC-derived Galectin-1 promotes the malignant behavior of PDAC by inducing EMT via activation of the NF-κB pathway. Our results suggest that targeting Galectin-1 in PSCs could represent a promising therapeutic strategy for PDAC progression and metastasis.

Failed immune responses across multiple pathologies share pan-tumor and circulating lymphocytic targets

“…In cancer, MMP-9 is associated with genetic instability, tissue remodeling, tumor cell proliferation, invasion and motility, progression, extravasation, metastasis, epithelial-mesenchymal transition, angiogenesis, apoptosis, inflammation, and immunosurveillance (36). MMP-9 in PBLs, serum, and tumors predicts prognosis, invasiveness, grade and differentiation, recurrence, metastasis, and treatment resistance, for bladder, lung, blood, colorectal, prostate, and liver cancers (42)(43)(44)(45)(46)(47)(48)(49). In patients with RCC, MMP-9 is increased in tumors and plasma (50) and correlates with histological grade (51), poor prognosis, and lowered survival (52), metastasis, decreased time to progression, and poor response to sunitinib (53).…”

Galectins as Molecular Targets for Therapeutic Intervention

“…Based on clinical data the presence of e.g., Gal-1 has been correlated with increased rates of metastasis and poor patient survival outcome [ 91 ]. Gal-1 induces epithelial-mesenchymal transition (EMT) in multiple cancer types by various signaling pathways [ 91 , 92 , 93 , 94 , 95 , 96 , 97 ]. Tumor cells undergoing EMT differentiate into a mesenchymal state, often indicated by molecular markers such as vimentin, desmin and α-smooth muscle actin (α-SMA).…”

The Galectin Family as Molecular Targets: Hopes for Defeating Pancreatic Cancer

“…Paracrine effects of Gal1 secreted by PSC are also observed in pancreatic tumor cell growth. Pancreatic tumor cells co-cultured with Gal1-overexpressing PSCs show significantly higher proliferation rates than those co-cultured in the presence of PSC with decreased Gal1 expression [61,67,68]. Likewise, conditioned media from human PSC increases RWP1 cell proliferation while Gal1 depleted PSC does not [65].…”

“…Similarly, migration and invasion of the RWP1 pancreatic cancer cell line was induced by conditioned media from human PSCs but not if they had been depleted for Gal1 [65]. Invasion and migration can be stimulated by increased levels of vimentin, MMP-9, and MMP-2 as well as by decreased levels of E-cadherin, induced by extracellular Gal1 in epithelial tumor cells [67,68]. Paracrine effects of Gal1 secreted by PSC are also observed in pancreatic tumor cell growth.…”

“…The relevance of Gal1 in tumor-stroma crosstalk during PDA progression has also been demonstrated in xenograft experiments using human pancreatic tumor cells and activated PSC. Specifically, co-injection of tumor cells together with activated PSCs (which express high levels of Gal1) leads to increased tumor size and metastasis as compared to injecting tumor cells alone; correspondingly, depletion of Gal1 in the co-injected PSCs significantly reduces tumor growth and size [58,65,68]. Mechanistically, microarray studies have suggested candidate genes and pathways that are potentially involved in these effects on growth and metastasis, such as STAT and Hh signaling, IL1A, MMP-1, and ANK3 [62,65].…”