High Expression Of Galectin-1 Research Articles

Прогностическое значение экспрессии галектина-1 опухолевыми плазматическими клетками и концентрации некоторых сывороточных цитокинов (IL-2, IL-6, TNF) у пациентов с моноклональной гаммапатией неопределенного значения и множественной миеломой

AIM. To study the prognostic value of the galectin-1 expression by bone marrow (BM) tumor plasma cells (PCs) and the concentration of serum cytokines (interleukins [IL-2, IL-6] and tumor necrosis factor [TNF]) in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (ММ). MATERIALS & METHODS. The trial enrolled 129 patients: 77 patients with newly diagnosed MM (median age 64 years) and 52 patients with MGUS (median age 62.5 years) followed-up at the Republican Scientific and Practical Center for Radiation Medicine and Human Ecology from 2018 to 2023. All patients underwent general clinical examination as well as BM aspirate cytology with myelogram and iliac BM core biopsy with immunohistochemical (IHC) analysis of BM biopsy. RESULTS. In the BM biopsy, the IHC analysis revealed a significant increase of galectin-1 expression (measured by expressing tumor PC count) in MM vs. MGUS patients (p < 0.001). Galectin-1 expression defined as expressing tumor PC count was significantly higher in patients with progressing MGUS compared to progression-free MM patients (p < 0.001). The median galectin-1 expression level was 8.5 % (Q25 0.2 %; Q75 15.7 %) in progression-free MGUS patients and 37.4 % (Q25 24.7 %; Q75 64.0 %) in progressing MGUS patients. Among MM patients, no significant differences were identified either in those with and without tumor progression. The IHC analysis of BM core biopsies in MM patients showed that high galectin-1 expression level is associated with pronounced vasculature but not with fibrotic changes, it also identified an increase in serum concentrations of IL-2 and TNF as well as a direct correlation with β2-microglobulin level. With MGUS progression into ММ, there was a direct correlation between galectin-1 expression level and serum M-protein. An increase of IL-2 concentration was registered only when MGUS progressed into ММ. CONCLUSION. The results of this study indicate the evidence of a high level of galectin-1 expression by tumor PCs in MM. In MGUS, an increase of galectin-1 expression by clonal BM PCs was associated with the disease progression. Galectin-1 expression by clonal BM PCs can well be clinically used as a marker for MGUS progression into MM.

Galectin-1 confers resistance to doxorubicin in hepatocellular carcinoma cells through modulation of P-glycoprotein expression

Galectin-1 (GAL1), a β-galactoside-binding protein abundantly expressed in the tumor microenvironment, has emerged as a key mechanism of chemoresistance developed by different tumors. Although increased expression of GAL1 is a hallmark of hepatocellular carcinoma (HCC) progression, aggressiveness and metastasis, limited information is available on the role of this endogenous lectin in HCC resistance to chemotherapy. Moreover, the precise mechanisms underlying this effect are uncertain. HCC has evolved different mechanisms of resistance to chemotherapy including those involving the P-glycoprotein (P-gp), an ATP-dependent drug efflux pump, which controls intracellular drug concentration. Here, we investigated the molecular mechanism underlying GAL1-mediated chemoresistance in HCC cells, particularly the involvement of P-gp in this effect. Our results show that GAL1 protected HepG2 cells from doxorubicin (DOX)- and sorafenib-induced cell death in vitro. Accordingly, GAL1-overexpressing HepG2 cells generated DOX-resistant tumors in vivo. High expression of GAL1 in HepG2 cells reduced intracellular accumulation of DOX likely by increasing P-gp protein expression rather than altering its membrane localization. GAL1-mediated increase of P-gp expression involved activation of the phosphatidylinositol-3 kinase (PI3K) signaling pathway. Moreover, ‘loss-of-function’ experiments revealed that P-gp mediates GAL1-driven resistance to DOX, but not to sorafenib, in HepG2 cells. Conversely, in PLC/PRF/5 cells, P-gp protein expression was undetectable and GAL1 did not control resistance to DOX or sorafenib, supporting the critical role of P-gp in mediating GAL1 effects. Collectively, our findings suggest that GAL1 confers chemoresistance in HCC through mechanisms involving modulation of P-gp, thus emphasizing the role of this lectin as a potential therapeutic target in HCC.

Galectin-1 Expression Is Associated with the Response and Survival Following Preoperative Chemoradiotherapy in Locally Advanced Esophageal Squamous Cell Carcinoma.

Simple SummaryGalectin-1 has been found to be involved in therapeutic resistance in a variety of cancers. However, the prognostic significance of galectin-1 expression in patients with locally advanced esophageal squamous cell carcinoma (ESCC) treated with chemoradiotherapy remains unknown. Immunohistochemically, we observed that galectin-1 overexpression in pretreatment biopsied specimens was significantly associated with a lower pathological complete response rate, worse overall survival and disease-free survival in 93 patients with locally advanced ESCC receiving preoperative chemoradiotherapy. Our findings suggest that galectin-1 may be a potential therapeutic target for patients with ESCC treated with preoperative chemoradiotherapy.The galectin-1 has been found to be involved in poor outcomes after treatment of a variety of cancers. To the best of our knowledge, however, the significance of galectin-1 expression in the sensitivity to chemoradiotherapy (CCRT) of patients with locally advanced esophageal squamous cell carcinoma (ESCC) remains unclear. Expression levels of galectin-1 were evaluated by immunohistochemistry and correlated with the treatment outcome in 93 patients with locally advanced ESCC who received preoperative CCRT between 1999 and 2012. Galectin-1 expression was significantly associated with the pathological complete response (pCR). The pCR rates were 36.1% and 13.0% (p = 0.01) in patients with low and high galectin-1 expression, respectively. Univariate analyses revealed that galectin-1 overexpression, clinical 7th American Joint Committee on Cancer (AJCC) stage III and a positive surgical margin were significant factors of worse overall survival and disease-free survival. In multivariate analyses, galectin-1 overexpression and a positive surgical margin represented the independent adverse prognosticators. Therefore, galectin-1 expression both affects the pCR and survival in patients with locally advanced ESCC receiving preoperative CCRT. Our results suggest that galectin-1 may be a potentially therapeutic target for patients with ESCC treated with preoperative CCRT.

Myeloma-Secreted Galectin-1 Potently Interacts with CD304 on Monocytic Myeloid-Derived Suppressor Cells.

Progression of multiple myeloma is regulated by factors intrinsic to the clonal plasma cells (PC) and by the immune effector cells in the tumor microenvironment. In this study, we investigated the interaction between CD304 expression on myeloid-derived suppressor cells (MDSC) and galectin-1 from malignant PCs in the context of autologous stem cell transplantation (ASCT) for multiple myeloma. Using high-throughput screening, CD304 expression on circulating monocytic MDSCs (M-MDSC; CD14+HLA-DRlow/-) was compared before and after ASCT. There was a significantly higher M-MDSC expression of CD304 before ASCT and a clear correlation between circulating pre-ASCT M-MDSC frequency and serum galectin-1 concentration. Treatment of pre-ASCT M-MDSCs, but not post-ASCT M-MDSCs, with galectin-1 in vitro expanded the M-MDSC population and increased expression of CD304. High galectin-1 expression by malignant PCs was associated with poor clinical outcomes. M-MDSC development and expression of CD304 were differentially induced when healthy donor peripheral blood mononuclear cells were cultured with the human multiple myeloma cell lines RPMI-8226 and JJN3, which express high and low galectin-1, respectively. Inhibition of galectin-1 reduced M-MDSC proliferation induced by RPMI-8226 cells but not by JJN3 cells, and blockade of CD304 reduced M-MDSC migration induced by RPMI-8226 cells but not by JJN3 cells. In addition, blockade of CD304 reversed suppression of the in vitro cytotoxic effect of melphalan by pre-ASCT M-MDSCs. Our data demonstrate that multiple myeloma-derived galectin-1 could mediate the tumor-promoting effect of M-MDSCs through its interaction with CD304 on M-MDSCs and contribute to multiple myeloma progression after ASCT.See related Spotlight on p. 488.

Prognostic role of galectins expression in patients with hepatic cancer: A meta-analysis.

Objective:The objective of this study was to illustrate the prognostic value of diversified galectins in patients with hepatic cancer via meta-analysis.Methods:We conducted a systematic search on PubMed, Embase, The Cochrane Library, Web of Science, the Chinese National Knowledge Infrastructure (CNKI) database, and Wanfang Data for studies that reported associations between galectin expression and the prognosis for hepatic cancer patients, from the inception of each database to March 20, 2019. The combined hazard ratio (HR) and 95% confidence interval (CI) were estimated to investigate the prognosis.Results:We collected 11 studies of 1957 patients in our meta-analysis. The pooled results indicated that overall galectin expression was not correlated with OS (HR = 1.23, 95% CI = 0.84–1.79, P = .29) or DFS/RFS (HR = 0.808, 95% CI = 0.376–1.735, P = .42) in liver cancer patients. In stratified analyses, we observed that high galectin-1 and galectin-3 expression was significantly associated with poor OS. The pooled HR of galectin-4 and galectin-9 was correlated with improved OS.Conclusion:Our results indicate that the high expression of galectin-1 and -3 and the low expression of galectin-4 and -9 may be predictive prognostic factors for poor OS in liver cancer patients.

Galectin-1 Overexpression Activates the FAK/PI3K/AKT/mTOR Pathway and Is Correlated with Upper Urinary Urothelial Carcinoma Progression and Survival.

Galectin-1 (GAL1) is a β-galactoside-binding protein involved in multiple aspects of tumorigenesis. However, the biological role of GAL1 in upper tract urothelial carcinoma (UTUC) has not been entirely understood. Herein, we investigated the oncological effects of GAL1 expression in tumor specimens and identified related gene alterations through molecular analysis of GAL1. Clinical parameter data and tumor specimens were collected from 86 patients with pT3N0M0 UTUC who had undergone radical nephroureterectomy. We analyzed the difference in survival by using Kaplan–Meier analyses and Cox proportional regression models and in GAL1 expression by using immunohistochemical (IHC) methods. Public genomic data from the Cancer Genome Atlas (TCGA) and GSE32894 data sets were analyzed for comparison. Using four urothelial carcinoma (UC) cell lines (BFTC-909, T24, RT4, and J82) as in vitro models, we evaluated the functions of GAL1 in UC cell growth, invasiveness, and migration and its role in downstream signaling pathways. The study population was classified into two groups, GAL1-high (n = 35) and GAL1-low (GAL1 n = 51), according to IHC interpretation. Univariate analysis revealed that high GAL1 expression was significantly associated with poor recurrence-free survival (RFS; p = 0.028) and low cancer-specific survival (CSS; p = 0.025). Multivariate analysis revealed that GAL1-high was an independent predictive factor for RFS (hazard ratio (HR) 2.43; 95% confidence interval (CI) 1.17–5.05, p = 0.018) and CSS (HR 4.04; 95% CI 1.25–13.03, p = 0.019). In vitro studies revealed that GAL1 knockdown significantly reduced migration and invasiveness in UTUC (BFTC-909) and bladder cancer cells (T24). GAL1 knockdown significantly reduced protein levels of matrix metalloproteinase-2 (MMP-2) and MMP-9, which increased tissue inhibitor of metalloproteinase-1 (TIMP-1) and promoted epithelial–mesenchymal transition (EMT). Through gene expression microarray analysis of GAL1 vector and GAL1-KD cells, we identified multiple significant signaling pathways including p53, Forkhead box O (FOXO), and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT). We validated microarray results through immunoblotting, thus proving that downregulation of GAL1 reduced focal adhesion kinase (FAK), p-PI3K, p-AKT, and p-mTOR expression. We concluded that GAL1 expression was highly related to oncological survival in patients with locally advanced UTUC. GAL1 promoted UC invasion and metastasis by activating the FAK/PI3K/AKT/mTOR pathway.

The Significance of Galectin-1 and Galectin-9 Expression in Endometrial Carcinoma

Objectives: To explore the expression of Galectin-1 and -9 and clinicopathological features in endometrial carcinoma (EC). Methods: Normal endometrium (NE), atypical endometrial hyperplasia (AH), and endometrial cancer were collected, and immunohistochemistry was used to detect the expression of Galectin-1 and -9 in all specimens in the same condition. Results: The positive rate of Galectin-1 expression in NE, AH, and endometrial cancer was 30, 70, and 90.2%. The positive rate of Galectin-9 expression in them was 20, 75, and 78.4%, respectively. The expression of Galectin-1 and -9 in the EC and AH was significantly higher than that in the NE (p< 0.05). However, there was no significant difference between the EC and the AH (p > 0.05). The expression of Galectin-1 in endometrial adenocarcinoma was significantly different among tissues of different histological grades, pathological stages, degrees of myometrial infiltration, or lymph node metastasis (p > 0.05). The expression of Galectin-9 in endometrial adenocarcinoma was significantly different among different historical grades, pathological stages, degrees of myometrial infiltration, and lymph node metastasis (p < 0.05). The expression of Galectin-9 in tissues at an early stage, with the degree of myometrial infiltration <1/2, and without lymph node metastasis, was significantly stronger than in those in the late stage, with a degree of myometrial infiltration ≥1/2 and lymph node metastasis. Conclusion: Both Galectin-1 and -9 were associated with the occurrence of EC and its pathological behavior. High expression of Galectin-1 suggests a poor prognosis, whereas high expression of Galectin-9 was associated with early pathological changes. Galectin-1 and -9 can provide references for early screening and indicate the prognosis of endometrial lesions, which are of great significance for patients’ quality of life.

High Expression of Galectin-1, VEGF and Increased Microvessel Density Are Associated with MELF Pattern in Stage I-III Endometrioid Endometrial Adenocarcinoma.

BackgroundIn this study, we investigate the expression of markers of angiogenesis and microvessel density (MVD) in cases of microcystic, elongated and fragmented (MELF) pattern, with its prognostic role in the survival of endometrioid endometrial adenocarcinomas (EA) patients.MethodsIn this study, 100 cases of EA, 49 cases with MELF pattern and 51 without, were immunohistochemically stained for galectin-1, vascular endothelial growth factor (VEGF), and MVD. Morphometry and statistical (univariate and multivariate) analyses were performed to assess overall survival (OS) and disease-free survival.ResultsThe expression of VEGF (p<.001) and galectin-1 (p<.001), as well as MVD area (p<.001) and number of vessels/mm2 (p<.050), were significantly higher in the +MELF pattern group compared to the –MELF group. A low negative correlation between MELF-pattern and the number of days of survival (p<.001, r=–0.47) was also found. A low positive correlation of MELF-pattern with galectin-1 expression (p<.001, r=0.39), area of vessels/mm2 (p<.001, r=0.36), outcome of EA (p<.001, r=0.42) and VEGF expression (p<.001, r=0.39) suggests potential pathological relevance of these factors in the prognosis of EA. A univariate survival analysis indicated a role for all parameters of survival. Multivariate Cox proportional hazard regression analysis revealed that only area of vessels/mm2 (hazard ratio [HR], 1.018; 95% confidence interval [CI], 1.002 to 1.033), galectin-1 (HR, 1.049; 95% CI, 1.025 to 1.074) and VEGF (HR, 1.049; 95% CI, 1.022 to 1.077) play key roles in OS.ConclusionsThis study reports an increase in MVD, VEGF and galectin-1 expression in EA with MELF pattern and suggests that MELF pattern, along with the angiogenic profile, may be a prognostic factor in EA.

Pooling analysis reveals that galectin-1 is a reliable prognostic biomarker in various cancers.

Galectin-1 is reported to be upregulated in various human cancers. However, the relationship between galectin-1 expression and cancer prognosis has not been systematically assessed. In this study, we searched PubMed, Web of Science, and Embase to collect all relevant studies and a meta-analysis was performed. We found that increased galectin-1 expression was associated with tumor size (odds ratio [OR] = 1.75; 95% confidence interval [CI]: 1.06-2.89; p = 0.029), clinical stage (OR = 3.89; 95% CI: 2.40-6.31; p < 0.001), and poorer differentiation (OR = 1.39; 95% CI: 1.14-1.69; p = 0.001), but not with age (OR = 1.07; 95% CI: 0.82-1.39; p = 0.597), sex (OR = 0.89; 95% CI: 0.74-1.07; p = 0.202), or lymph node metastasis (OR = 2.57; 95% CI: 0.98-6.78; p = 0.056). In addition, we found that high galectin-1 expression levels were associated with poor overall survival (HR = 2.12; 95% CI: 1.71-2.64; p < 0.001). The results were further validated using The Cancer Genome Atlas data set. Moreover, high galectin-1 expression was significantly associated with disease-free survival (hazard ratio [HR] = 1.60; 95% CI: 1.17-2.19; p = 0.003), progression-free survival (HR = 1.93; 95% CI: 1.65-2.25; p < 0.001), and cancer-specific survival (HR = 1.82; 95% CI: 1.30-2.55; p < 0.001). Our meta-analysis demonstrated that galectin-1 might be a useful common biomarker for predicting prognosis in patients with cancer.

Targeting Galectin-1 Impairs Castration-Resistant Prostate Cancer Progression and Invasion.

Purpose: The majority of patients with prostate cancer who are treated with androgen-deprivation therapy (ADT) will eventually develop fatal metastatic castration-resistant prostate cancer (mCRPC). Currently, there are no effective durable therapies for patients with mCRPC. High expression of galectin-1 (Gal-1) is associated with prostate cancer progression and poor clinical outcome. The role of Gal-1 in tumor progression is largely unknown. Here, we characterized Gal-1 functions and evaluated the therapeutic effects of a newly developed Gal-1 inhibitor, LLS30, in mCRPC.Experimental Design: Cell viability, colony formation, migration, and invasion assays were performed to examine the effects of inhibition of Gal-1 in CRPC cells. We used two human CRPC xenograft models to assess growth-inhibitory effects of LLS30. Genome-wide gene expression analysis was conducted to elucidate the effects of LLS30 on metastatic PC3 cells.Results: Gal-1 was highly expressed in CRPC cells, but not in androgen-sensitive cells. Gal-1 knockdown significantly inhibited CRPC cells' growth, anchorage-independent growth, migration, and invasion through the suppression of androgen receptor (AR) and Akt signaling. LLS30 targets Gal-1 as an allosteric inhibitor and decreases Gal-1-binding affinity to its binding partners. LLS30 showed in vivo efficacy in both AR-positive and AR-negative xenograft models. LLS30 not only can potentiate the antitumor effect of docetaxel to cause complete regression of tumors, but can also effectively inhibit the invasion and metastasis of prostate cancer cells in vivoConclusions: Our study provides evidence that Gal-1 is an important target for mCRPC therapy, and LLS30 is a promising small-molecule compound that can potentially overcome mCRPC. Clin Cancer Res; 24(17); 4319-31. ©2018 AACR.

870P - Expression of Galectin-1 Determines Tumor Recurrence and Cancer-specific Survival in Patients with pT3 Upper Urinary Tract Urothelial Carcinoma

Background: Upper urinary tract urothelial carcinoma (UTUC) is an aggressive and lethal disease. For patients with locally advanced UTUC, recurrence of tumor is frequent, and lacks of predictive biologic markers limited the choice of postoperative treatment. Galectin-1 (GAL1) is a β-galactoside-binding protein, participating in many parts of tumorigenesis, including cell proliferation, invasiveness, metastasis, and angiogenesis. However, the role of GAL1 in UTUC has not been fully investigated. The aim of this study was to examine the prognostic impact of GAL1 in patients with UTUC. Methods: The study enrolled 86 UTUC patients who underwent radical nephroureterectomy and bladder cuff excision with final pathologically diagnosed as pT3N0 stage between January 2005 and December 2012. Perioperative characteristics and pathologic features were recorded. Immunohistochemical staining of tumor specimens using anti-GAL1 antibody were performed. UTUC cell line (BFTC-909) was used for in vitro study of tumor invasiveness and migration. Kaplan-Meier analyses and Cox proportional regression models were used for univariate and multivariate survival analyses. Results: Using 10% expression of GAL1 protein as a cuff-off point, the study population could be classified as GAL1-high (GAL1 > 10%, n = 35) or GAL1-low (GAL1 ≤ 10%; n = 51) group. Basic clinicopathologic characteristics were comparable between two groups. In univariate analysis, high GAL1 expression was significantly associated with a worse recurrence-free survival (RFS; p = 0.028) and cancer-specific survival (CSS; p = 0.025). Multivariate analysis showed GAL1-high is an independent factor for RFS (HR 2.43; 95% CI 1.17-5.05, p = 0.018) and CSS (HR 4.04; 95% CI 1.25-13.03, p = 0.019). In vitro study, we found that knockdown of GAL1 reduced UTUC cancer cell migration and invasion significantly. Conclusions: Galectin-1 expression is a reliable prognostic factor for locally advanced UTUC. GAL1 inhibition may serve as a potential therapeutic target for patients with UTUC. Legal entity responsible for the study: Yu-Li Su Funding: None Disclosure: All authors have declared no conflicts of interest.

Galectin-1 promotes tumor progression via NF-κB signaling pathway in epithelial ovarian cancer.

Purpose: We previously reported that Galectin-1 (Gal-1) played a role in epithelial ovarian cancer (EOC) progression. In this study, we aimed to further investigate the association between Gal-1 expression and prognosis in EOC patients and tried to reveal some novel potential mechanisms of Gal-1 in EOC invasion and migration.Materials and Methods: Gal-1 and nucleus NF-κBp65 expression in 109 human epithelial ovarian cancer tissue specimens were evaluated by immunohistochemistry. The Cox model and survival curves were used to investigate the effect of Gal-1 on EOC prognosis. Correlation between Gal-1 expression and NF-κB activation in EOC patients was also analyzed. In vitro experiments were further performed to reveal the function and mechanisms of Gal-1 in invasion and migration of EOC cells.Results: Expression level of Gal-1 in EOC tissue was an independent prognostic factor on overall survival (p<0.05) and progression-free survival (p<0.05). Patients with high Galectin-1 expression had shorter overall survival (OS, p<0.05)) and progression-free survival (PFS, p<0.05). Immunohistochemistry revealed that expression of Gal-1 was positively associated with activation of NF-κBp65 in EOC tissues (Kappa coefficient=0.458, p<0.001). Patients with tumors concomitantly co-over-expressing Gal-1 and NF-κBp65 had the worse OS (p<0.001) and PFS (p<0.001). The abilities of migration and invasion for EOC cells were significantly reduced after Gal-1 knocked-down in human EOC cell line HO8910, which was accompanied with the suppression of NF-κb pathway activation and with the matrix metalloproteinase-2 and matrix metalloproteinase-9 down-regulation.Conclusions: Our results suggest that Gal-1 is associated with poor outcome in EOC and Galectin-1 promotes tumor progression via NF-κB pathway activation in EOC.

Cancer-associated fibroblasts promote angiogenesis in gastric cancer through galectin-1 expression

Galectin-1, an evolutionarily conserved glycan-binding protein with angiogenic potential, was recently identified as being overexpressed in cancer-associated fibroblasts (CAFs) of gastric cancer. The role of endogenous CAF-derived galectin-1 on angiogenesis in gastric cancer and the mechanism involved remain unknown. Immunohistochemical staining was used to investigate the correlation between galectin-1 and vascular endothelial growth factor (VEGF) and CD31 expression in gastric cancer tissues and normal gastric tissues. Galectin-1 was knocked down in CAFs isolated from gastric cancer using small interfering ribonucleic acid (RNA), or overexpressed using recombinant lentiviruses, and the CAFs were co-cultured with human umbilical vein endothelial cells (HUVECs) or cancer cells. Subsequently, proliferation, migration, tube formation, and VEGF/VEGF receptor (VEGFR) 2 expression were detected. The role of CAF-derived galectin-1 in tumor angiogenesis in vivo was studied using the chick chorioallantoic membrane (CAM) assay. Galectin-1 was highly expressed in the CAFs and was positively associated with VEGF and CD31 expression. In the co-culture, high expression of galectin-1 in the CAFs increased HUVEC proliferation, migration, tube formation, and VEGFR2 phosphorylation and enhanced VEGF expression in gastric cancer cells. The CAM assay indicated that high expression of galectin-1 in the CAFs accelerated tumor growth and promoted angiogenesis. In contrast, galectin-1 knockdown in the CAFs significantly inhibited this effect. CAF-derived galectin-1 significantly promotes angiogenesis in gastric cancer and may be a target for angiostatic therapy.

Apoptosis and anergy of T cell induced by pancreatic stellate cells-derived galectin-1 in pancreatic cancer.

Galectin-1, a β-galactoside-binding protein implicated in cancer cell immune privilege, was highly expressed in activated pancreatic stellate cells (PSCs). This study was designed to investigate the relationship between PSC-derived galectin-1 and tumor immunity in pancreatic cancer. Isolated PSCs were identified as normal pancreas cells (hNPSCs) or pancreatic cancer cells (hCaPSCs) by immunohistochemical staining for α-SMA and vimentin, and galectin-1 expression was evaluated by Western blotting and quantitative RT-PCR. Apoptosis, caspase activity, and cytokine production (IL-6, IL-10, TNF-β, and IFN-γ) of T cells co-cultured with PSCs were evaluated, and immunohistochemical staining of galectin-1 was correlated with CD3 and clinicopathological variables in 66 pancreatic cancer and 10 normal pancreatic tissue samples. hCaPSCs exhibited higher galectin-1 expression than did hNPSCs, and hCaPSCs induced higher levels of apoptosis in T cells following co-culture. hCaPSCs activated caspase-9 and caspase-3 in the mitochondrial apoptotic pathway and stimulated secretion of Th2 cytokines (IL-6 and IL-10) but decreased secretion of Th1 cytokines (TNF-β and IFN-γ), compared with hNPSCs. Immunohistochemical staining indicated that galectin-1 and CD3 were more highly expressed in pancreatic cancer tissue. Galectin-1 expression was highest in poorly differentiated pancreatic cancer cells and lowest in well-differentiated pancreatic cancer cells and was associated with tumor size, lymph node metastasis, differentiation, and UICC stage. However, CD3 expression showed the opposite trend and was highest in well-differentiated pancreatic cancer cells and was associated with tumor differentiation and UICC stage. High expression of galectin-1 was associated with short survival, as was low expression of CD3. hCaPSC-derived galectin-1 enhanced apoptosis and anergy of T cells in pancreatic cancer, which contributes to the immune escape of pancreatic cancer cells.

Knockdown of galectin-1 suppresses the growth and invasion of osteosarcoma cells through inhibition of the MAPK/ERK pathway.

Galectin-1 (GAL1), a widely expressed β‑galacto-side-binding protein, exerts pleiotropic biological functions. GAL1 has been found to be upregulated in many malignancies; yet the role of GAL1 in the pathophysiology of human osteosarcoma (OS) remains uncertain. The present study was carried out to investigate the expression of GAL1 in human OS tissues and to explore its effects on the growth and invasion of OS cells. OS and corresponding adjacent non-cancerous tissues (ANCT) were collected from 30 consecutive cases. The expression of GAL1 was detected by immunohistochemical assay through tissue microarray procedure. Using small hairpin RNA (shRNA)-mediated GAL1 knockdown (Lv-shGAL1) in OS (MG-63 and U-2 OS) cells, we observed the changes in the malignant phenotype in OS cells invitro and invivo. As a consequence, the positive expression of GAL1 was significantly higher in OS tissues than that in the ANCT (63.3 vs. 36.7%, P=0.029), and was positively correlated with distant metastasis in the OS patients (P=0.022). Knockdown of GAL1 suppressed cell proliferative activities and invasive potential and induced apoptosis in OS cells with decreased expression of p38MAPK, p-ERK, Ki-67 and matrix metallopeptidase-9 (MMP-9) and increased expression of caspase-3. In addition, the tumor volume in the MG-63 subcutaneous tumor models treated with Lv-shGAL1 was significantly smaller than that in the negative control (NC) group (P<0.01). Altogether, our findings indicate that high expression of GAL1 is associated with distant metastasis of OS patients, and knockdown of GAL1 inhibits growth and invasion of OS cells possibly through inhibition of the MAPK/ERK pathway, suggesting that GAL1 may represent a potential target for the treatment of cancer.

P-0032 - Apoptosis and Anergy of T Cell Induced by Pancreatic Stellate Cells Derived Galectin-1 in Pancreatic Cancer

Galectin-1, a β-galactoside-binding protein implicated in cancer cell immune privilege, was highly expressed in activated pancreatic stellate cells (PSCs). This study was designed to investigate the relationship between PSC-derived galectin-1 and tumor immunity in pancreatic cancer. Isolated PSCs were identified as normal pancreas cells (hNPSCs) or pancreatic cancer cells (hCaPSCs) by immunohistochemical staining for α-SMA and vimentin, and galectin-1 expression was evaluated by Western blotting and quantitative RT-PCR. Apoptosis, caspase activity, and cytokine production (IL-6, IL-10, TNF-β, and IFN-γ) of T cells co-cultured with PSCs were evaluated, and immunohistochemical staining of galectin-1 was correlated with CD3 and clinicopathological variables in 66 pancreatic cancer and 10 normal pancreatic tissue samples. hCaPSCs exhibited higher galectin-1 expression than did hNPSCs, and hCaPSCs induced higher levels of apoptosis in T cells following co-culture. hCaPSCs activated caspase-9 and caspase-3 in the mitochondrial apoptotic pathway and stimulated secretion of Th2 cytokines (IL-6 and IL-10) but decreased secretion of Th1 cytokines (TNF-β and IFN-γ), compared with hNPSCs. Immunohistochemical staining indicated that galectin-1 and CD3 were more highly expressed in pancreatic cancer tissue. Galectin-1 expression was highest in poorly differentiated pancreatic cancer cells and lowest in well-differentiated pancreatic cancer cells and was associated with tumor size, lymph node metastasis, differentiation, and UICC stage. However, CD3 expression showed the opposite trend and was highest in well-differentiated pancreatic cancer cells and was associated with tumor differentiation and UICC stage. High expression of galectin-1 was associated with short survival, as was low expression of CD3. hCaPSC-derived galectin-1 enhanced apoptosis and anergy of T cells in pancreatic cancer, which contributes to the immune escape of pancreatic cancer cells.

Myosin IIa activation is crucial in breast cancer derived galectin-1 mediated tolerogenic dendritic cell differentiation

BackgroundTolerogenic dendritic cells (tDCs) play important roles in immune tolerance, autoimmune disease, tissue transplantation, and the tumor micro-environment. Factors that induce tDCs have been reported, however the intracellular mechanisms involved are rarely discussed. MethodsCirculating CD14+CD16+ of breast cancer patients and induced CD14+CD16+ DCs were identified as tDCs by treating CD14+ monocytes with galectin-1 and cancer cell-derived medium combined with IL-4 and GM-CSF. In addition, the 4T1 breast cancer syngeneic xenograft model was used to investigate the effect of galectin-1 in vivo. ResultsThe CD14+CD16+ tDC population in the breast cancer patients was comparatively higher than that in the healthy donors, and both the MDA-MB-231 conditioned medium and galectin-1 could induce tDC differentiation. In a BALB/c animal model, the 4T1 breast cancer cell line enhanced IL-10 expression in CD11c+ DCs which was down-regulated after knocking down the galectin-1 expression of 4T1 cells. Analysis of galectin-1 interacting proteins showed that myosin IIa was a major target of galectin-1 after internalization through a caveolin-dependent endocytosis. Myosin IIa specific inhibitor could diminish the effects of galectin-1 on monocyte-derived tDCs and also block the 4T1 cell induced CD11c+/Ly6G+/IL-10+ in the BALB/c mice. ConclusionsGalectin-1 can induce tDCs after internalizing into CD14+ monocytes through the caveolae-dependent pathway and activating myosin IIa. For the breast cancer patients with a high galectin-1 expression, blebbistatin and genistein show potential in immune modulation and cancer immunotherapy. General significanceMyosin IIa activation and galectin-1 endocytosis are important in tumor associated tDC development.

Apoptosis and anergy of T cell induced by galectin-1 derived from pancreatic stellate cells in pancreatic cancer

Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China Background: Galectin-1 is an immunoregulatory protein which was expressed in the activated pancreatic stellate cells (PSCs). Aim: This study was to investigate the relationships between galectin1 expressed in PSCs and T cells in pancreatic cancer. Methods: Immunohistochemistry was performed in 66 pancreatic cancer and 10 normal pancreas tissues to detect the galectin-1 and CD3 expression. The relationship between galectin-1, CD3 and clinicopathologic variables was assessed. Expression of galectin-1 in freshly isolated PSCs fromhumannormal pancreas (hNPSCs) and human pancreatic cancer tissues (hCaPSCs) were evaluated bywestern blot and quantitative RT-PCR. The apoptosis of Tcells coculturedwith these PSCswere detected byflowcytometry and Tcell IL-2, IL-4, IL-5 and INF-g production levels were quantified by ELISA. Results: Galectin-1 was higher expressed in pancreatic cancer compared to normal pancreas (P<0.05). Galectin-1 expression was gradually increased in well, moderately, poorly differentiated pancreatic cancer (P<0.05, separately), while the CD3 expression is decreased (P<0.05, P<0.01). Galectin-1 expression was associated with tumor size (p1⁄40.007), lymph node metastasis (p1⁄40.019), differentiation (p1⁄40.021) and UICC stage (p1⁄40.01). CD3 expression was associated with tumor differentiation (p1⁄40.009) and UICC stage (p1⁄40.018). Expression of Galectin-1 (p<0.001) and CD3 (p1⁄40.002) were associated with short patient survival. In vitro coculture experiments showed that, compared with hNPSCs, hCaPSCs inducedmore apoptosis of CD3 Tcells, more secretion of Th2 cytokines (IL4 and IL-5) and less secretion of Th1 cytokines (IL-2 and INF-g) (p<0.01). Conclusions: The high expression of galectin-1 in hCaPSCs enhance the apoptosis and anergy of T cells in pancreatic cancer, and thus may play a role in immune evasion of pancreatic cancer.

Meta-analysis of studies comparing laparoscopic and open left pancreatectomy

Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China Background: Galectin-1 is an immunoregulatory protein which was expressed in the activated pancreatic stellate cells (PSCs). Aim: This study was to investigate the relationships between galectin1 expressed in PSCs and T cells in pancreatic cancer. Methods: Immunohistochemistry was performed in 66 pancreatic cancer and 10 normal pancreas tissues to detect the galectin-1 and CD3 expression. The relationship between galectin-1, CD3 and clinicopathologic variables was assessed. Expression of galectin-1 in freshly isolated PSCs fromhumannormal pancreas (hNPSCs) and human pancreatic cancer tissues (hCaPSCs) were evaluated bywestern blot and quantitative RT-PCR. The apoptosis of Tcells coculturedwith these PSCswere detected byflowcytometry and Tcell IL-2, IL-4, IL-5 and INF-g production levels were quantified by ELISA. Results: Galectin-1 was higher expressed in pancreatic cancer compared to normal pancreas (P<0.05). Galectin-1 expression was gradually increased in well, moderately, poorly differentiated pancreatic cancer (P<0.05, separately), while the CD3 expression is decreased (P<0.05, P<0.01). Galectin-1 expression was associated with tumor size (p1⁄40.007), lymph node metastasis (p1⁄40.019), differentiation (p1⁄40.021) and UICC stage (p1⁄40.01). CD3 expression was associated with tumor differentiation (p1⁄40.009) and UICC stage (p1⁄40.018). Expression of Galectin-1 (p<0.001) and CD3 (p1⁄40.002) were associated with short patient survival. In vitro coculture experiments showed that, compared with hNPSCs, hCaPSCs inducedmore apoptosis of CD3 Tcells, more secretion of Th2 cytokines (IL4 and IL-5) and less secretion of Th1 cytokines (IL-2 and INF-g) (p<0.01). Conclusions: The high expression of galectin-1 in hCaPSCs enhance the apoptosis and anergy of T cells in pancreatic cancer, and thus may play a role in immune evasion of pancreatic cancer.

Middle segment pancreatectomy: Experience from a high-volume center in China

Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China Background: Galectin-1 is an immunoregulatory protein which was expressed in the activated pancreatic stellate cells (PSCs). Aim: This study was to investigate the relationships between galectin1 expressed in PSCs and T cells in pancreatic cancer. Methods: Immunohistochemistry was performed in 66 pancreatic cancer and 10 normal pancreas tissues to detect the galectin-1 and CD3 expression. The relationship between galectin-1, CD3 and clinicopathologic variables was assessed. Expression of galectin-1 in freshly isolated PSCs fromhumannormal pancreas (hNPSCs) and human pancreatic cancer tissues (hCaPSCs) were evaluated bywestern blot and quantitative RT-PCR. The apoptosis of Tcells coculturedwith these PSCswere detected byflowcytometry and Tcell IL-2, IL-4, IL-5 and INF-g production levels were quantified by ELISA. Results: Galectin-1 was higher expressed in pancreatic cancer compared to normal pancreas (P<0.05). Galectin-1 expression was gradually increased in well, moderately, poorly differentiated pancreatic cancer (P<0.05, separately), while the CD3 expression is decreased (P<0.05, P<0.01). Galectin-1 expression was associated with tumor size (p1⁄40.007), lymph node metastasis (p1⁄40.019), differentiation (p1⁄40.021) and UICC stage (p1⁄40.01). CD3 expression was associated with tumor differentiation (p1⁄40.009) and UICC stage (p1⁄40.018). Expression of Galectin-1 (p<0.001) and CD3 (p1⁄40.002) were associated with short patient survival. In vitro coculture experiments showed that, compared with hNPSCs, hCaPSCs inducedmore apoptosis of CD3 Tcells, more secretion of Th2 cytokines (IL4 and IL-5) and less secretion of Th1 cytokines (IL-2 and INF-g) (p<0.01). Conclusions: The high expression of galectin-1 in hCaPSCs enhance the apoptosis and anergy of T cells in pancreatic cancer, and thus may play a role in immune evasion of pancreatic cancer.