Original ResearchFull Report: Basic and Translational—PancreasGalectin-3 Mediates Tumor Cell–Stroma Interactions by Activating Pancreatic Stellate Cells to Produce Cytokines via Integrin Signaling
Section snippets
Materials and Methods
Please refer to the online Supplementary Materials for detailed additional Methods.
Activation of Human PSCs by GAL3
To assess the expression of GAL3 in PDAC tissues, we observed that GAL3 was expressed in both PDAC cells and tumor-associated stromal cells (Supplementary Figure 1A and C) of human PDAC tissues. There was weak expression of GAL3 in normal tissues and human pancreatic ductal epithelial cells (Supplementary Figure 1A and D). In addition, GAL3 was up-regulated in mouse PDAC tissues isolated from several genetic mouse models (LSL-K-RasG12D and other genetic mouse models LSL-p53 and cyclo-oxygenase
Discussion
PDAC is characterized by extreme desmoplastic infiltration that may impede effectiveness of therapy leading to poor patient survival. PSCs are thought to manipulate the TME, producing dense stroma and an abundance of cytokine/chemokines that are increasingly recognized to impart an aggressive tumor phenotype by promoting proliferation, invasion, and metastases. In this study, using cytokine array and co-culture of PSCs and PDAC cells with genetically altered GAL3 levels, we identified that GAL3
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Interplay in galectin expression predicts patient outcomes in a spatially restricted manner in PDAC
2024, Biomedicine and PharmacotherapyThe microbiota and aging microenvironment in pancreatic cancer: Cell origin and fate
2022, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :M2 macrophages and Th2 cells are recruited to the TME by microbiota, secrete TGF-β [131,133,145], effectively activate PSCs, mediate the pro-fibroblast proliferation response, secrete a large amount of fibronectin and type I and III collagens, and promote pancreatic fibrosis and the metastasis of cancer cells in the stromal region [77,146]. Microbe-mediated ROS production by immune cells induces senescence in PSCs and promotes SASP secretion [147], including IL8, granulocyte-macrophage colony-stimulating factor, chemokine ligand 1, C-C motif chemokine ligand 2, and dickkopf-3 (DKK3), promoting cancer cell proliferation, invasion and migration, enhancing PDAC resistance to gemcitabine and inhibiting CD8+ T-cell activity [92,148,149]. Furthermore, activated PSCs can be significantly stimulated by factors such as PDGF, VEGF, and TGF-β1 secreted by tumor cells and can proliferate and differentiate into cancer-associated fibroblasts (CAFs) under hypoxic conditions.
Chemokine-mucinome interplay in shaping the heterogeneous tumor microenvironment of pancreatic cancer
2022, Seminars in Cancer BiologyThe interactive role of inflammatory mediators and metabolic reprogramming in pancreatic cancer
2022, Trends in CancerCitation Excerpt :Inflammatory mediators play a central role in PDAC progression by modulating the TME and contributing to PDAC desmoplastic stroma [3]. Additionally, through secretion of inflammatory mediators, growth factors, and enzymes, CAFs contribute to desmoplastic stroma, recruitment of inflammatory and immune cells into TME, and metabolic alterations [3,15–19]. Furthermore, adipocytes, muscle cells, and hepatocytes interact with PDAC cells through IL-6 signaling [20,21], and neurons support PDAC under serine-deprived conditions [22].
Strategies targeting tumor immune and stromal microenvironment and their clinical relevance
2022, Advanced Drug Delivery ReviewsCitation Excerpt :A phase I trial of pamrevlumab (anti-CTGF mAb, FG-3019) combined with chemotherapy in patients with advanced PDAC has demonstrated improved OS [228]. Gal3 is a β-galactoside–binding protein often over-expressed in tumor cells and TME that has been implicated in TAF activation and immune regulation [229]. The combination of belapectin (small molecule Gal3 inhibitor) and anti-PD-1 mAb showed ORR of 50% and 33% in patients with melanoma and SCCHN, associated with increased effector memory T-cell activation and reduced M−MDSCs in responders in a phase I trial [230].
Conflicts of interest The authors declare no competing interests in the present study.
Funding Grant support was provided by the following: American Gastroenterological Association Research Scholar Award (Shumei Song) and Public Health Service Grant DF56338, which supports the Texas Medical Center Digestive Diseases Center (Shumei Song). University of Texas M.D. Anderson Cancer Center IRG (3-0026317; Shumei Song); CA160433 from DOD (Shumei Song). National Key Research & Development Program of China (2016 YFA 0500303), National Natural Science Foundation of China (grant numbers 81330051, 81372594), the ‘‘863’’ Project (2014AA021606 and 2015AA020403), Beijing Natural Science Foundation (7182030) and CA138671, CA129906, CA127672, CA172741, CA150334, and CA160445 from the National Cancer Institute and DOD (Jaffer A. Ajani).
Author names in bold designate shared co-first authorship.