Lipocalin2 Promotes Invasion, Tumorigenicity and Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma

Leung, Lisa; Radulovich, Nikolina; Zhu, Chang-Qi; Organ, Shawna; Bandarchi, Bizhan; Pintilie, Melania; To, Christine; Panchal, Devang; Tsao, Ming‐Sound

doi:10.1371/journal.pone.0046677

Cited by 64 publications

(73 citation statements)

References 30 publications

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“…However, activity in these tissues is most probably related to one or more of the multifaceted functions of this molecule identified in other tissues. These include promoting angiogenesis [21] and enhancing matrix degradation through interactions with MMP9 [16]. With respect to the latter activity, dimerization of Lcn2 with proMMP9 appears to enhance activation of the enzyme by plasma kallikrein and protects the enzyme from degradation [22].…”

Section: Discussionmentioning

confidence: 99%

Nerve growth factor increases MMP9 activity in annulus fibrosus cells by upregulating lipocalin 2 expression

et al. 2014

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Purpose Nerve growth factor (NGF) expression and activity is important in chronic lower back pain but may also act as a pro-catabolic factor in the pathogenesis of intervertebral disc (IVD) degeneration. Lipocalin 2 (Lcn2) expression in IVD was upregulated by NGF stimulation in our previous study. The current study was undertaken to identify potential mechanisms of the latter effect including potential interactions between Lcn2 and matrix metalloproteinase 9 (MMP9). Methods Rat annulus fibrosus (AF) cells were stimulated by NGF and subjected to microarray analysis, subsequent real-time PCR, western immunoblotting, and immunofluorescence. Cells were treated with NGF in the absence or presence of the NGF inhibitor Ro 08-2750. Zymography and functional MMP9 assays were used to determine MMP9 activity, whilst the dimethyl-methylene blue assay was used to quantify the release of glycosaminoglycans (GAGs) reflecting catabolic effects following NGF treatment. Immunoprecipitation with immunoblotting was used to identify interactions between MMP9 and Lcn2. Results Increased expression of Lcn2 gene and protein following NGF stimulation was confirmed by microarray analysis, real-time PCR, western blot and immunofluorescence. Zymography showed that NGF enhanced 125-kDa gelatinase activity, identified as a Lcn2/MMP9 complex by immunoprecipitation and immunoblotting. Functional assays showed increased MMP9 activity and GAG release in the presence of NGF. The effects of NGF were neutralized by the presence of Ro 08-2750. Conclusions NGF upregulates Lcn2 expression and increases MMP9 activity in AF cells; processes which are likely to potentiate degeneration of AF tissue in vivo. Anti-NGF treatment may have benefit for management of pain Electronic supplementary material The online version of this article

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Section: Discussionmentioning

confidence: 99%

Nerve growth factor increases MMP9 activity in annulus fibrosus cells by upregulating lipocalin 2 expression

et al. 2014

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“…Lenti-X 293T cells were transfected with the respective expression vectors coding for the tribody [(Her2) 2 (29). The tribody was purified from supernatant as described (29,30).…”

Section: Expression and Purification Of The Antibody Derivativesmentioning

confidence: 99%

“…Approximately 80% of the patients have an advanced disease with distant metastases at diagnosis, and only 10% to 20% are accessible for surgical resection (1). Occasional resistance of PDAC to chemotherapy demanded alternative therapeutic approaches (2,3). An increasing number of novel therapeutic strategies, including targeted therapy or immunotherapy alone or in combination with chemotherapy, have been described but still failed to considerably improve survival times of the patients (4,5).…”

Section: Introductionmentioning

confidence: 99%

Novel Bispecific Antibodies Increase γδ T-Cell Cytotoxicity against Pancreatic Cancer Cells

Oberg¹,

Peipp²,

Kellner³

et al. 2014

Cancer Research

124

160

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The ability of human gd T cells from healthy donors to kill pancreatic ductal adenocarcinoma (PDAC) in vitro and in vivo in immunocompromised mice requires the addition of gd T-cell-stimulating antigens. In this study, we demonstrate that gd T cells isolated from patients with PDAC tumor infiltrates lyse pancreatic tumor cells after selective stimulation with phosphorylated antigens. We determined the absolute numbers of gd T-cell subsets in patient whole blood and applied a real-time cell analyzer to measure their cytotoxic effector function over prolonged time periods. Because phosphorylated antigens did not optimally enhance gd T-cell cytotoxicity, we designed bispecific antibodies that bind CD3 or Vg9 on gd T cells and Her2/neu (ERBB2) expressed by pancreatic tumor cells. Both antibodies enhanced gd T-cell cytotoxicity with the Her2/Vg9 antibody also selectively enhancing release of granzyme B and perforin. Supporting these observations, adoptive transfer of gd T cells with the Her2/Vg9 antibody reduced growth of pancreatic tumors grafted into SCID-Beige immunocompromised mice. Taken together, our results show how bispecific antibodies that selectively recruit gd T cells to tumor antigens expressed by cancer cells illustrate the tractable use of endogenous gd T cells for immunotherapy.

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“…There has been some research on the resistance aspects of gemcitabine and 5-FU. Leung et al found that suppression of Lipocalin2 (LCN2) in PC cells increased their sensitivity to gemcitabine in vitro, and in vivo (43). Awasthi et al reported that insulin-like growth factor (IGF) signaling proteins are frequently overexpressed in pancreatic duct adenocarcinoma (PDAC), and using a small molecular inhibitor of IGF receptor (BMS-754807) was able to enhance gemcitabine response in PC (44).…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance and therapeutic implications of peroxisome proliferator-activated receptor γ overexpression in human pancreatic carcinoma

Zhang

Luo

Liu

et al. 2014

International Journal of Oncology

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Abstract. Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor which has been implicated in carcinogenesis and angiogenesis in a wide range of cancers, including pancreatic carcinoma (PC). We aimed to characterize the prognosis and potential therapeutic implications of PPARγ in PC. Real-time RT-PCR and western blotting were used to quantify PPARγ expression in immortalized pancreatic epithelial cells, PC cell lines and freshly isolated matched tumor and non-tumor tissues. PPARγ protein expression was analyzed by immunohistochemistry (IHC) in archived tumor tissues from 101 PC patients. Furthermore, the effect of PPARγ on the cytotoxic action of gemcitabine (Gem) and 5-fluorouracil (5-FU) in PC cell lines was investigated in vitro using RNA interference techniques. Both PPARγ protein and mRNA were expressed at markedly higher levels in all of the PC cell lines and freshly isolated PC tissues, compared to normal immortalized pancreatic epithelial cells and the matched adjacent non-tumor tissues. High levels of PPARγ expression correlated significantly with tumor-nodemetastasis (TNM) staging (P<0.001) and poor overall survival (P<0.001), especially in patients with advanced disease who received postoperative chemotherapy. While silencing of PPARγ significantly inhibit the cytotoxic effects of both gemcitabine and 5-fluorouracil in PC cells in vitro. This study suggests that high levels of PPARγ expression are associated with poor overall survival in PC. Additionally, PPARγ promotes chemoresistance in PC cells, indicating that PPARγ may represent a novel therapeutic target for PC.

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Lipocalin2 Promotes Invasion, Tumorigenicity and Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma

Cited by 64 publications

References 30 publications

Nerve growth factor increases MMP9 activity in annulus fibrosus cells by upregulating lipocalin 2 expression

Nerve growth factor increases MMP9 activity in annulus fibrosus cells by upregulating lipocalin 2 expression

Novel Bispecific Antibodies Increase γδ T-Cell Cytotoxicity against Pancreatic Cancer Cells

Prognostic significance and therapeutic implications of peroxisome proliferator-activated receptor γ overexpression in human pancreatic carcinoma

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