Decreased Expression of α2,8 Sialyltransferase and Increased Expression of β1,4 N-Acetylgalactosaminyltransferase in Gastrointestinal Cancers

2002 ◽  
Vol 227 (3) ◽  
pp. 196-200 ◽  
Author(s):  
Yasuhiro Koh ◽  
Takuya Tsunoda ◽  
Makoto Iwahashi ◽  
Hiroki Yamaue ◽  
Kiwao Ishimoto ◽  
...  
Keyword(s):  
Antibody Therapy ◽  
Expression Level ◽  
Gastrointestinal Cancers ◽  
Antibody Treatment ◽  
Antitumor Effects ◽  
Gm2 Ganglioside ◽  
Normal Tissues ◽  
Cancer Group ◽  
Colorectal Cancer Patients

Gangliosides such as GD3, GM2, and GD2 are abundantly expressed on the cell surfaces of various malignant cells, suggesting the potential for anti-ganglioside antibody therapy for tumors. Anti-ganglioside GD2 antibody treatment is currently undergoing clinical trials for melanoma and neuroblastoma. We previously reported high in vivo antitumor effects of anti-GM2 ganglioside antibody against lung cancer. To determine whether anti-GM2 antibody may be clinically indicated for gastrointestinal cancers, we evaluated the mRNA expression of α2,8 sialyltransferase, a GD3 synthase, and β1,4 N-acetylgalactosaminyltransferase (β1,4 GalNAc-T), a GM2/GD2 synthase, in gastrointestinal cancers. We performed modified semi-quantitative RT-PCR, which reduces complexity incidental to radiolabeling on samples taken from small surgically removed clinical specimens. Stomach (19/22) and colorectal (21/30) cancers showed decreased expression of α2,8 sialyltransferase as compared with respective normal tissues (P < 0.05). In contrast, increased expression of β1,4 GalNAc-T was detected in both types of tumors. Clinicopathological analysis revealed significantly higher expression level of α2,8 sialyltransferase in the poorly differentiated than in the well-differentiated stomach cancer group (P < 0.05). Furthermore, the expression level of α2,8 sialyltransferase was significantly decreased in male as compared with female colorectal cancer patients (P < 0.05). These results suggest that expression level of GM2 ganglioside is elevated in gastrointestinal cancer, and that anti-GM2 antibody may be applicable to its treatment.

scholarly journals Downregulation of PD-L1 via FKBP5 by celecoxib augments antitumor effects of PD-1 blockade in a malignant glioma model

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Izumi Yamaguchi ◽  
Kohei Nakajima ◽  
Kenji Shono ◽  
Yoshifumi Mizobuchi ◽  
Toshitaka Fujihara ◽  
...  
Keyword(s):  
Antibody Therapy ◽  
High Expression ◽  
Antibody Treatment ◽  
Antitumor Effects ◽  
Fk506 Binding Protein ◽  
Cox 2 ◽  
Glioma Model ◽  
Human Gbm ◽  
Post Transcriptional Regulation

Abstract Background Antitumor therapies targeting programmed cell death-1 (PD-1) or its ligand-1 (PD-L1) are used in various cancers. However, in glioblastoma (GBM), the expression of PD-L1 varies between patients, and the relationship between this variation and the efficacy of anti-PD-1 antibody therapy remains unclear. High expression levels of PD-L1 affect the proliferation and invasiveness of GBM cells. As COX-2 modulates PD-L1 expression in cancer cells, we tested the hypothesis that the COX-2 inhibitor celecoxib potentiates anti-PD-1 antibody treatment via the downregulation of PD-L1. Methods Six-week-old male C57BL/6 mice injected with murine glioma stem cells (GSCs) were randomly divided into four groups treated with vehicle, celecoxib, anti-PD-1 antibody, or celecoxib plus anti-PD-1 antibody and the antitumor effects of these treatments were assessed. To verify the mechanisms underlying these effects, murine GSCs and human GBM cells were studied in vitro. Results Compared with that with each single treatment, the combination of celecoxib and anti-PD-1 antibody treatment significantly decreased tumor volume and prolonged survival. The high expression of PD-L1 was decreased by celecoxib in the glioma model injected with murine GSCs, cultured murine GSCs, and cultured human GBM cells. This reduction was associated with post-transcriptional regulation of the co-chaperone FK506-binding protein 5 (FKBP5). Conclusions Combination therapy with anti-PD-1 antibody plus celecoxib might be a promising therapeutic strategy to target PD-L1 in glioblastoma. The downregulation of highly-expressed PD-L1 via FKBP5, induced by celecoxib, could play a role in its antitumor effects.

scholarly journals EXTH-06. DOWN-REGULATION OF PD-L1 VIA FKBP5 LOWERED BY A CYCLOOXYGENASE-2 INHIBITOR IN GSCs AND GBM CELLS MAY BE ATTRIBUTABLE TO ENHANCE ANTITUMOR EFFECTS OF IMMUNOTHERAPY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi83-vi83
Author(s):  
Izumi Yamaguchi ◽  
Kohei Nakajima ◽  
Kenji Shono ◽  
Yoshifumi Mizobuchi ◽  
Toshitaka Fujihara ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Antibody Therapy ◽  
High Expression ◽  
Antibody Treatment ◽  
Antitumor Effects ◽  
Down Regulation ◽  
Fk506 Binding Protein ◽  
Cox 2 ◽  
Glioma Model ◽  
Human Gbm

Abstract BACKGROUND Antitumor therapies targeting programmed cell death-1 (PD-1)/its ligand-1 (PD-L1) are influential at present stage. However, in glioblastoma (GBM), the expression of PD-L1 is variable and the role of anti-PD-1 antibody therapy is still unclear. The high expression of PD-L1 affects cell proliferation and invasion in GBM cells. As COX-2 modulates PD-L1 expression in cancer cells, we tested our hypothesis that a COX-2 inhibitor, celecoxib may play a role on anti-PD-1 antibody treatment via down-regulation of PD-L1. METHODS Six weeks old male C57BL/6 mice subjected to intracranial injection of mice glioma stem cells (GSCs) were randomly divided into four treatment groups; vehicle control (VC), celecoxib, anti PD-1 antibody or the combination of celecoxib and anti-PD-1 antibody groups and examined antitumor effects. To verify the mechanisms underlying antitumor effects, mice GSCs and human GBM cells were used. RESULTS Compared to each single treatment in the glioma model, the combination therapy of anti PD-1 antibody and celecoxib significantly decreased the tumor volume and improved the survival period. Importantly, the high expression of PD-L1 in the glioma model, mice GSCs and human GBM cells was decreased by celecoxib. Interestingly, the reduction of PD-L1 was associated with post-transcriptional regulation of co-chaperone FK506-binding protein 5 (FKBP5) by celecoxib. The combination therapy of anti PD-1 antibody with celecoxib could be a promising therapeutic strategy targeting PD-L1 in GSCs and GBM. CONCLUSIONS Down-regulation of PD-L1 via FKBP5 by celecoxib may play a role on the antitumor effects under the overwhelmed expression of PD-L1.

scholarly journals Down-regulation of miRNA-30c predicts poor prognosis in Colorectal Cancer patients

2016 ◽  
Vol 24 (4) ◽  
pp. 369-375
Author(s):  
Liu Bin ◽  
Meng Zhang ◽  
Liu Lixia ◽  
Zang Aimin ◽  
Yang Hua ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Poor Prognosis ◽  
Univariate Analysis ◽  
Clinicopathological Features ◽  
Expression Level ◽  
Rt Pcr ◽  
Normal Tissues ◽  
Node Metastasis ◽  
Treatment Measures ◽  
Colorectal Cancer Patients

Abstract Background: MiRNA-30c was a tumor suppressor in several human cancers, however, its association with clinicopathological features and prognosis in colorectal cancer (CRC) is unclear. Materials and Methods: The expression level of miRNA-30c in 192 pairs of colorectal cancer and adjacent normal tissues was detected by Quantitative RT-PCR, the association between miRNA-30c expression and clinical characteristics and prognosis were statistically analyzed. Results: miRNA-30c was significantly lower in CRC tissues specimens compared with matched normal adjacent tissue (P<0.001). MiRNA-30c was positively correlated with tumor size (P=0.012), TMN stage (P=0.002) and lymph node metastasis (P=0.004). The univariate analysis showed CRC patients with low miRNA-30c had distinctly shorter overall survival (P<0.001) than patients with high miRNA-30c expression level. The multivariate analysis was performed and informed that low miRNA-30c expression (P<0.001) might be an independent prognostic predictor for poor prognosis. Conclusion: miRNA-30c could predict the prognosis of colorectal cancer which is helpful to choose reasonable treatment measures.

scholarly journals Defucosylated Mouse–Dog Chimeric Anti-EGFR Antibody Exerts Antitumor Activities in Mouse Xenograft Models of Canine Tumors

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3599
Author(s):  
Guanjie Li ◽  
Tomokazu Ohishi ◽  
Mika K. Kaneko ◽  
Junko Takei ◽  
Takuya Mizuno ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cell Line ◽  
Growth Factor Receptor ◽  
High Sensitivity ◽  
Osteosarcoma Cell ◽  
Antibody Treatment ◽  
Antitumor Effects ◽  
Vitro Analysis

The epidermal growth factor receptor (EGFR) contributes to tumor malignancy via gene amplification and protein overexpression. Previously, we developed an anti-human EGFR (hEGFR) monoclonal antibody, namely EMab-134, which detects hEGFR and dog EGFR (dEGFR) with high sensitivity and specificity. In this study, we produced a defucosylated mouse–dog chimeric anti-EGFR monoclonal antibody, namely E134Bf. In vitro analysis revealed that E134Bf highly exerted antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against a canine osteosarcoma cell line (D-17) and a canine fibroblastic cell line (A-72), both of which express endogenous dEGFR. Moreover, in vivo administration of E134Bf significantly suppressed the development of D-17 and A-72 compared with the control dog IgG in mouse xenografts. These results indicate that E134Bf exerts antitumor effects against dEGFR-expressing canine cancers and could be valuable as part of an antibody treatment regimen for dogs.

scholarly journals Neutralization of the induced VEGF-A potentiates the therapeutic effect of an anti-VEGFR2 antibody on gastric cancer in vivo

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tetsuo Mashima ◽  
Takeru Wakatsuki ◽  
Naomi Kawata ◽  
Myung-Kyu Jang ◽  
Akiko Nagamori ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Combination Treatment ◽  
Xenograft Model ◽  
Vegf Receptor ◽  
Antibody Treatment ◽  
Targeting Therapy ◽  
Normal Tissues ◽  
Anti Vegf ◽  
Mouse Xenograft Model

AbstractThe vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis is an essential regulator of angiogenesis and important therapeutic target in cancer. Ramucirumab is an anti-VEGFR2 monoclonal antibody used for the treatment of several cancers. Increased circulating VEGF-A levels after ramucirumab administration are associated with a worse prognosis, suggesting that excess VEGF-A induced by ramucirumab negatively affects treatment efficacy and that neutralizing VEGF-A may improve treatment outcomes. Here, we evaluated the effect of combination treatment with an anti-VEGFR2 antibody and anti-VEGF-A antibody on gastric tumor progression and normal tissues using a preclinical BALB/c-nu/nu mouse xenograft model. After anti-VEGFR2 antibody treatment in mice, a significant increase in plasma VEGF-A levels was observed, mirroring the clinical response. The elevated VEGF-A was host-derived. Anti-VEGF-A antibody co-administration enhanced the anti-tumor effect of the anti-VEGFR2-antibody without exacerbating the toxicity. Mechanistically, the combination treatment induced intra-tumor molecular changes closely related to angiogenesis inhibition and abolished the gene expression changes specifically induced by anti-VEGFR2 antibody treatment alone. We particularly identified the dual treatment-selective downregulation of ZEB1 expression, which was critical for gastric cancer cell proliferation. These data indicate that the dual blockade of VEGF-A and VEGFR2 is a rational strategy to ensure the anti-tumor effect of angiogenesis-targeting therapy.

scholarly journals Local injection of CCL19-expressing mesenchymal stem cells augments the therapeutic efficacy of anti-PD-L1 antibody by promoting infiltration of immune cells

2020 ◽  
Vol 8 (2) ◽  
pp. e000582
Author(s):  
Yuichi Iida ◽  
Rintaro Yoshikawa ◽  
Akihiko Murata ◽  
Hitoshi Kotani ◽  
Yasuhiro Kazuki ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Therapeutic Efficacy ◽  
Antibody Therapy ◽  
Local Therapy ◽  
Anticancer Therapy ◽  
Interferon Γ ◽  
Local Injection ◽  
Antitumor Effects

BackgroundMesenchymal stem/stromal cells (MSC) accumulate and reside in tumor sites.MethodsTaking advantage of this feature in anticancer therapy, immortalized murine MSC (iMSC) were genetically altered to produce chemokine (C-C motif) ligand 19 (iMSC/CCL19), which attracts dendritic cells (DC) and T lymphocytes. Thereafter, iMSC/CCL19 were examined for their therapeutic efficacy using a syngeneic CT26 colon carcinoma cell line.ResultsCo-injection of iMSC/CCL19 into mice significantly suppressed the in vivo growth of CT26 cells compared with that of CCL19-expressing immortalized fibroblasts (iFib/CCL19). This anticancer effect was not observed when injected in CT26-bearing nude mice. Co-injected iMSC/CCL19 survived longer than iFib/CCL19 in the tumor sites. In a therapeutic model, local injection of iMSC/CCL19 suppressed the tumor growth, and increased IFN (interferon)-γ+ CD8+ T cells and CCR7+ DC infiltration in tumor site was observed when treated with iMSC/CCL19, but not with iMSC. This antitumor effect was completely negated by depletion of CD4+ cells and partially negated by depletion of CD8+ cells. Furthermore, the antitumor effects induced by local injection of iMSC/CCL19 were augmented by additional therapy with anti-programmed death (PD)-ligand 1 (PD-L1) antibody, but not with anti-PD-1 antibody. This combination therapy cured most of the tumors in CT26-bearing mice.ConclusionThese results suggest that local therapy with iMSC/CCL19 can suppress tumor growth via effective recruitment of CCR7+ DC into tumor sites and increase IFN-γ+ CD8+ T cells, and that combination with anti-PD-L1 antibody therapy can be a powerful anticancer therapy.

scholarly journals Long Non-Coding RNA SNHG12 Promotes Prostate Tumor Occurrence and Progression via AKT Regulation

2020 ◽  
Author(s):  
Zheng Chen ◽  
Tao Qi ◽  
Xiaoping Qin ◽  
Jue Wang ◽  
Zhangsen Huang ◽  
...  
Keyword(s):  
Underlying Mechanism ◽  
Prostate Tumor ◽  
Expression Level ◽  
Cell Cycle Distribution ◽  
Related Protein ◽  
Normal Tissues ◽  
Phosphorylated Akt ◽  
Tumorigenesis And Progression ◽  
Du145 Cells

Abstract BackgroundIncreasing studies have shown that long noncoding RNAs (lncRNAs) participated in the development of prostate cancer (PCa). The small nucleolar RNA host gene 12 (SNHG12) has been reported to play an important role in the tumorigenesis and progression of PCa, but the functional underlying mechanism has not been studied clearly. MethodsWe detected the expression level of SNHG12 in PCa tissues and matched adjacent normal tissues that were collected from 85 patients. Then, colony formation assays, MTT experiments and flow cytometry were used to examine the effect of SNHG12 on proliferation, cell cycle distribution and apoptosis of DU145 cells. Further, Transwell invasion assay was utilized to assess whether SNHG12 participates in PCa cell invasion and affects the secretion of VEGF secretion in DU145 cells. Western blot analysis was applied to quantify the expression level of apoptosis-related and invasion-related proteins. Finally, we investigated the effect of SNHG12 on tumor growth in vivo. ResultsWe found that SNHG12 expression was upregulated in prostate tumor tissues compared with the matched adjacent normal tissues. SNHG12 knockdown increased the expression of apoptosis-related protein Caspase 3, whereas downregulated the expression of MMP9, which is an invasion-related protein. SNHG12 knockdown inhibited the expression of phosphorylated AKT. In vivo xenograft experiments showed that knockdown of SNHG12 suppressed the PCa growth. ConclusionsThe above-mentioned results revealed that SNHG12 promoted cell proliferation and suppressed apoptosis in PCa cells, which suggests that SNHG12 is probably a novel PCa biomarker and therapy target of PCa.

Non-coding microRNA hsa-let-7g as a novel chemoresponse biomarker for S-1 in colon cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13513-13513
Author(s):  
G. Nakajima ◽  
K. Uchida ◽  
K. Hayashi ◽  
Y. Xi ◽  
K. Takasaki ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Internal Control ◽  
Biological Significance ◽  
Wilcoxon Test ◽  
Expression Level ◽  
Pcr Analysis ◽  
Transcriptional Level ◽  
Normal Tissues ◽  
Tumor Tissues

13513 Background: MicroRNAs (miRNAs) are small non-cording RNAs (∼ 22 nucleotide) that regulate gene expression by suppressing their target mRNAs at post-transcriptional level. Previous studies from our group have identified a number of dis-regulated miRNAs due to the loss of p53 tumor suppressor in cancer cell lines. As part of the efforts to further investigate the in vivo biological significance of these miRNAs, the expression of both hsa-let-7g and hsa-miR-200c were investigated using formalin-fixed paraffin embedded (FFPE) colon cancer specimens to evaluate the potential correlation with chemosensitivity and tumorigenesis. Methods: Forty-six patients with recurrent or residual colon cancer lesion assessable were treated with 5-FU based antimetabolite S-1. This includes twenty-one pair of tumor and normal samples. Total RNAs were isolated from these samples FFPE specimens (contains either > 90% normal or > 90% tumor tissue). cDNAs were synthesized using primers specific for hsa-let-7g, hsa-miR-200c and internal control 5S. The expression levels of each particular miRNAs were quantified using real time qRT-PCR analysis. The expression level of each miRNAs was quantified by measuring the difference of threshold cycle (CT) of candidate miRNAs and internal control 5S (Δ-CT). Results: The expression level of hsa-let-7g was significantly higher in tumor tissues compare to normal tissues (p=0.0026; Wilcoxon test). In the forty-six tumor tissues, the expression level of hsa-let-7g in disease response group (patients group of complete response, partial response and no change after chemotherapy) was significantly lower than the disease progression group (p=0.03; Mann-Whitney test). The expression of hsa-miR-200c was significantly over-expressed in tumor tissues compare to normal tissues (p=0.0001; Wilcoxon test). Although hsa-let-7g is strongly associated with patient’s response to S-1 treatment, it is not a prognostic factor for predicting survival. Conclusion: hsa-let-7g and hsa-miR-200c may be associated with tumorigenesis in colon cancer. In addition, hsa-let-7g may be a significant indicator for chemoresponse to S-1 based chemotherapy. No significant financial relationships to disclose.

Construction of DCTPP1 Regulated ceRNA Network and it can be Used as a Potential Prognostic Marker for B7-H3 Antibody Therapy in Breast Cancer

2021 ◽  
Author(s):  
Jiayin Zhang ◽  
Yuan Qu ◽  
Tingting Hou ◽  
Wanbao Ge ◽  
Shanyong Zhang
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Prognostic Marker ◽  
Antibody Therapy ◽  
The Cancer Genome Atlas ◽  
Antibody Treatment ◽  
Immune Infiltration ◽  
Normal Tissues ◽  
Basal Like Breast Cancer ◽  
Cancer Tissues

Abstract Background：Breast cancer is the most common female cancer in the world. Many scholars have devoted themselves to elucidating the pathogenesis of Breast cancer. In the past, dCTP pyrophosphatase 1 (DCTPP1) was thought to be overexpressed in several cancers. However, The mechanism by which DCTPP1 is regulated by non-coding RNA in Breast cancer and its relationship with immune infiltration have not been elucidated.Results：In this study, reliable databases from the Cancer Genome Atlas (TCGA) and Gene Expression Integration (GEO) showed that the expression of DCTPP1 in Breast cancer tissues was higher than in normal tissues. Bioinformatics analysis showed that DCTPP1 was negatively correlated with the expression of hsa-miR-125b-5p in BRCA,The expression of LncRNA LGALS8-AS1 is positively correlated with the expression of DCTPP1, and negatively correlated with the expression of hsa-miR-125b-5p. Therefore, we speculate that lncRNA LGALS8-AS1 promotes tumor progression through sponge hsa-miR-125b-5p and maintains the overexpression of DCTPP1 in Breast cancer. The survival analysis of 3 genes showed that the overexpression of DCTPP1 and LGALS8-AS1 is related to the poor prognosis of patients. By analyzing the relationship between DCTPP1 and immune infiltration, we found that the high copy of DCTPP1 is related to the infiltration of CD8+ T cells, and the high expression of DCTPP1 is related to the infiltration of CD4+ T cells in basal-like Breast cancer. DCTPP1 is positively correlated with the expression of immune checkpoint B7-H3.Conclusion: LNC LGALS8-AS1 can upregulate DCTPP1 by sponging with hsa-miR-125b-5p. DCTPP1 can be used as a new prognostic marker for B7-H3 antibody treatment of breast cancer.

Clinical Evaluation of Radio-Labelled Bleomycin for Tumor Detection

1978 ◽  
Vol 17 (06) ◽  
pp. 238-248
Author(s):  
H. Beekhuis ◽  
M.A.P.C. van de Poll ◽  
A. Versluis ◽  
H. Jurjens ◽  
M.G. Woldring ◽  
...  
Keyword(s):  
Clinical Evaluation ◽  
Acidic Solution ◽  
Tumor Detection ◽  
Neutral Solution ◽  
Normal Tissues ◽  
Patients With Cancer ◽  
Tumor Bearing

Investigations with bleomycin labelled with radionuclides other than 57Co in patients with cancer and in tumor-bearing animals are described. In patients 57Co-bleo appears to be a better tumor-seeking radiopharmaceutical than 111In-bleo, 99mTc-bleo or 197Hg-bleo. This can be explained by a higher stability in vivo and a better tumor-seeking property of 57Co-bleo and less disturbing activity in the cardiac pool and in bone and other normal tissues when assessing the scintigram.Results with 111In-bleo labelled in acidic solution are not essentially different from those with 111In-bleo labelled in neutral solution.Results of 197Hg-bleo are almost identical with those of 197HgCl2 regarding the tumor-seeking effect as well as the distribution in normal tissues and organs. Probably the complex of 197Hg to bleomycin is not stable in vivo. The superiority of 57Co-bleo over 99mTc-bleo, 197Hg-bleo and also over 67Cu-bleo is confirmed by experiments on tumor bearing animals.We may conclude that the indication for use of bleomycin as a tumor-seeking pharmaceutical labelled with 111In, 99mTc, 197Hg or 67Cu seems to be very limited.

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