ABSTRACT
Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal tumor types, with extremely low survival rates due to late diagnosis and resistance to standard therapies. A more comprehensive understanding of the complexity of PDA pathobiology, and especially of the role of the tumor microenvironment in disease progression, should pave the way for therapies to improve patient response rates. In this study, we identify galectin-1 (Gal1), a glycan-binding protein that is highly overexpressed in PDA stroma, as a major driver of pancreatic cancer progression. Genetic deletion of Gal1 in a Kras-driven mouse model of PDA (Ela-KrasG12Vp53-/- ) results in a significant increase in survival through mechanisms involving decreased stroma activation, attenuated vascularization, and enhanced T cell infiltration leading to diminished metastasis rates. In a human setting, human pancreatic stellate cells (HPSCs) promote cancer proliferation, migration, and invasion via Gal1-driven pathways. Moreover, in vivo orthotopic coinjection of pancreatic tumor cells with Gal1-depleted HPSCs leads to impaired tumor formation and metastasis in mice. Gene-expression analyses of pancreatic tumor cells exposed to Gal1 reveal modulation of multiple regulatory pathways involved in tumor progression. Thus, Gal1 hierarchically regulates different events implicated in PDA biology including tumor cell proliferation, invasion, angiogenesis, inflammation, and metastasis, highlighting the broad therapeutic potential of Gal1-specific inhibitors, either alone or in combination with other therapeutic modalities.
Subject(s)
Carcinoma, Pancreatic Ductal/therapy , Galectin 1/physiology , Galectins/physiology , Molecular Targeted Therapy , Pancreatic Neoplasms/therapy , Animals , Carcinoma, Pancreatic Ductal/blood supply , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/immunology , Cell Division/genetics , Cell Movement/genetics , Culture Media, Conditioned , Galectins/genetics , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Gene Ontology , Heterografts , Humans , Lymphocytes, Tumor-Infiltrating/immunology , Mice , Mice, Knockout , Mice, Transgenic , Neoplasm Metastasis , Neovascularization, Pathologic , Pancreatic Neoplasms/blood supply , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/immunology , Pancreatic Stellate Cells/metabolism , Pancreatic Stellate Cells/transplantation , Paracrine Communication , RNA, Small Interfering/genetics , Stromal Cells/metabolism , Tumor MicroenvironmentABSTRACT
Pancreatic stellate cells (PSCs) are the precursors of cancer-associated fibroblasts (CAFs), which potentiate pancreatic tumor growth and progression. In this study, we investigated whether Lipoxin A4 (LXA4), an endogenous bioactive lipid, can inhibit the differentiation of human PSCs (hPSCs) into CAF-like myofibroblasts and thereby hPSC-induced pro-tumorigenic effects. LXA4 significantly inhibited TGF-ß-mediated differentiation of hPSCs by inhibiting pSmad2/3 signalling. Furthermore, treatment with LXA4 abolished the paracrine effects (proliferation and migration of Panc-1 tumor cells) of hPSCs in vitro. These data demonstrated that LXA4 can interrupt pro-tumoral paracrine signalling of hPSCs. Furthermore, LXA4 treatment significant decreased the size and growth rate of 3D-heterospheroids comprised of hPSC and Panc-1 and these effects were exhibited due to inhibition of hPSC-induced collagen1 expression. In vivo, we examined the therapeutic efficacy of LXA4 in a co-injection (Panc-1 and hPSCs) subcutaneous tumor model. Intriguingly, LXA4 significantly abolished the tumor growth (either injected intratumor or intraperitoneally), attributed to a significant reduction in fibrosis, shown with collagen1 expression. Altogether, this study proposes LXA4 as a potent inhibitor for hPSCs which can be applied to reprogram tumor stroma in order to treat pancreatic cancer.
Subject(s)
Cellular Reprogramming/drug effects , Lipoxins/administration & dosage , Pancreatic Neoplasms/therapy , Pancreatic Stellate Cells/cytology , Pancreatic Stellate Cells/transplantation , Animals , Cell Differentiation/drug effects , Cell Line, Tumor , Collagen Type I/metabolism , Combined Modality Therapy , Gene Expression Regulation, Neoplastic/drug effects , Humans , Lipoxins/pharmacology , Mice , Pancreatic Neoplasms/metabolism , Pancreatic Stellate Cells/drug effects , Paracrine Communication/drug effects , Signal Transduction/drug effects , Smad Proteins/metabolism , Transforming Growth Factor beta/pharmacologyABSTRACT
Desmoplasia is a fibro-inflammatory process and a well-established feature of pancreatic cancer. A key contributor to pancreatic cancer desmoplasia is the pancreatic stellate cell. Various in vitro and in vivo methods have emerged for the isolation, characterization, and use of pancreatic stellate cells in models of cancer-associated fibrosis. In addition to cell culture models, genetically engineered animal models have been established that spontaneously develop pancreatic cancer with desmoplasia. These animal models are currently being used for the study of pancreatic cancer pathogenesis and for evaluating therapeutics against pancreatic cancer. Here, we review various in vitro and in vivo models that are being used or have the potential to be used to study desmoplasia in pancreatic cancer.
Subject(s)
Biomedical Research/methods , Disease Models, Animal , Fibroma/etiology , Pancreatic Neoplasms/physiopathology , Animals , Animals, Genetically Modified , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Biomedical Research/trends , Cell Line, Tumor , Drugs, Investigational/pharmacology , Drugs, Investigational/therapeutic use , Female , Fibroma/drug therapy , Fibroma/immunology , Fibroma/pathology , Fibrosis , Humans , Male , Mice , Neoplasm Transplantation/methods , Neoplasm Transplantation/trends , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/pathology , Pancreatic Stellate Cells/drug effects , Pancreatic Stellate Cells/immunology , Pancreatic Stellate Cells/pathology , Pancreatic Stellate Cells/transplantation , Rats , Tumor Cells, Cultured , Xenograft Model Antitumor Assays/methodsABSTRACT
The identity of pancreatic stem/progenitor cells is still under discussion. They were suggested to derive from the pancreatic ductal epithelium and/or islets. Here we report that rat pancreatic stellate cells (PSC), which are thought to contribute to pancreatic fibrosis, have stem cell characteristics. PSC reside in islets and between acini and display a gene expression pattern similar to umbilical cord blood stem cells and mesenchymal stem cells. Cytokine treatment of isolated PSC induced the expression of typical hepatocyte markers. The PSC-derived hepatocyte-like cells expressed endodermal proteins such as bile salt export pump along with the mesodermal protein vimentin. The transplantation of culture-activated PSC from enhanced green fluorescent protein-expressing rats into wild type rats after partial hepatectomy in the presence of 2-acetylaminofluorene revealed that PSC were able to reconstitute large areas of the host liver through differentiation into hepatocytes and cholangiocytes. This developmental fate of transplanted PSC was confirmed by fluorescence in situ hybridization of chromosome Y after gender-mismatched transplantation of male PSC into female rats. Transplanted PSC displayed long-lasting survival, whereas muscle fibroblasts were unable to integrate into the host liver. The differentiation potential of PSC was further verified by the transplantation of clonally expanded PSC. PSC clones maintained the expression of stellate cell and stem cell markers and preserved their differentiation potential, which indicated self-renewal potential of PSC. These findings demonstrate that PSC have stem cell characteristics and can contribute to the regeneration of injured organs through differentiation across tissue boundaries.