[en] 

Background

Despite developments in multidisciplinary treatment, the prognosis for advanced gallbladder cancer (GBC) still is poor because of its rapid progression. Epithelial–mesenchymal transition (EMT) plays a central role in promoting tumor invasion and metastasis in malignancies thorough signal transducer and activator of transcription-3 (STAT3) and nuclear factor κB (NF-κB) activation. Whereas Pin1 mediates STAT3 and NF-κB activation, the involvement of Pin1 in GBC progression is unclear.

Methods

Factors regulating Pin1-related STAT3 and NF-κB activation were evaluated using surgical specimens collected from 76 GBC patients, GBC cells, and orthotopic GBC xenograft mice.

Results

In the patients with GBC, high Pin1 expression in GBC was associated with aggressive tumor invasion and increased tumor metastasis, and was an independent factor for a poor prognosis. Pin1 expression was correlated with phosphorylation of STAT3(Ser727) and NF-κB-p65(Ser276), thereby activating STAT3 and NF-κB in GBC. Pin1-mediated STAT3 and NF-κB activation induced EMT in GBC. When Pin1 knockdown was performed in GBC cells, the phosphorylation of STAT3(Ser727) and NF-κB-p65(Ser276) was inhibited, and STAT3 and NF-κB activation was suppressed. Inactivation of STAT3 and NF-κB in Pin1-depleted cells decreased snail and zeb-2 expression, thereby reducing the rate of mesenchymal-like cells, suggesting that EMT was inhibited in GBC cells. PiB, a Pin1-specific inhibitor, inhibited EMT and reduced tumor cell invasion by inactivating STAT3 and NF-κB in vitro. Moreover, PiB treatment inhibited lymph node metastasis and intrahepatic metastasis in orthotopic GBC xenograft tumor in vivo.

Conclusions

Pin1 accelerates GBC invasion and metastasis by activating STAT3 and NF-κB. Therefore, Pin1 inhibition by PiB is an excellent therapy for GBC by safely inhibiting its metastasis.

[en] 

Purpose

: Recent studies suggest that the quality and quantity of visceral adipose tissue (VAT) play significant roles in adipocyte function, and are related to insulin resistance. We tested the hypothesis that high amounts of upper VAT (aVAT) and low-quality VAT worsen treatment outcomes via altered insulin metabolism.

Methods

: Cohort 1 included 106 women with breast cancer who were undergoing surgery. Homeostasis model assessment of insulin resistance (HOMA-R), insulin-like growth factor (IGF)-1, and IGF-binding protein 3 (IGFBP3) were measured before the initiation of treatment. aVAT was measured via computed tomography (CT). VAT quality was assessed using CT-determined Hounsfield units (VAT-HU). Associations between the variables investigated and VAT quality and quantity were analyzed. Cohort 2 included 271 patients who underwent chemotherapy. Associations between the variables investigated and survival outcomes after chemotherapy were analyzed via retrospective chart review.

Results

: In cohort 1, aVAT was significantly correlated with insulin and HOMA-R levels. As body mass index (BMI) class increased, mean IGF-1 increased and mean IGFBP3 decreased, but these trends were not statistically significant. In cohort 2, aVAT was significantly positively correlated with BMI. The patients in the third aVAT tertiles had significantly shorter distant disease-free survival (dDFS) after neoadjuvant chemotherapy setting. In multivariate analysis, aVAT and VAT-HU were significantly associated with shorter dDFS.

Conclusions

: High aVAT and low-quality VAT were associated with poor survival outcome, increased insulin levels, and insulin resistance. The present study suggests the importance of evaluating the quality and quantity of VAT when estimating insulin resistance and treatment outcomes.

[en] 

Purpose

: Although recent advances in molecular target therapy have improved the survival of breast cancer patients, high cost and frequent hospital visits result in both societal and individual burden. To reduce these problems, it has been proposed to produce antibodies in vivo. Here, we constructed gene-transduced human ceiling culture-derived proliferative adipocytes secreting anti-HER2 antibody (HER2-ccdPAs) and evaluated their ability to secrete antibody and mediate an anti-tumor effect.

Methods

: Plasmid lentivirus was used as a recipient for anti-HER2 antibody cDNA and transduced into human proliferative adipocyte. Secretory antibody expression was evaluated by ELISA and western blot. Specific binding of secretory antibody to HER2 was examined by immunofluorescence analysis. Direct and indirect anti-tumor effects of supernatants from HER2-ccdPAs were evaluated using BT474 (HER2+) and MDA-MB-231 (HER2−) breast cancer cell lines. Additionally, whether adipocyte differentiation affects antibody secretion was investigated using supernatant collected from different cell maturation states.

Results

: Anti-HER2 antibody was identified in the supernatant from HER2-ccdPAs and its production increased with the differentiation into mature adipocyte. Antibodies in supernatants from HER2-ccdPAs bound to HER2-positive breast cancer cells similar to trastuzumab. Supernatant from HER2-ccdPAs inhibited the proliferation of BT474 but not MDA-MB-231 cells, and downregulated AKT phosphorylation in BT474 cells compared with controls. Supernatants from HER2-ccdPAs also had an indirect anti-tumor effect on BT474 cells through ADCC. Additionally, Single inoculation of HER2-ccdPAs showed an anti-tumor effect in BT474 xenograft model.

Conclusions

: HER2-ccdPAs might be useful for cell-based gene therapy. This system could be a platform for various antibody therapies.