A PAUF-neutralizing antibody targets both carcinoma and endothelial cells to impede pancreatic tumor progression and metastasis

Kim, Su Jin; Chang, Suhwan; Lee, Yangsoon; Kim, Na Young; Hwang, Youngbae; Min, Hye Jin; Yoo, Kyung-Sook; Park, Eun Hye; Kim, Seokho; Chung, Young‐Hwa; Park, Young Woo; Koh, Sang Seok

doi:10.1016/j.bbrc.2014.10.056

Cited by 11 publications

(10 citation statements)

References 33 publications

(40 reference statements)

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“…Previously, PMAb83, a human monoclonal antibody against PAUF, was a novel targeted therapeutic intervention for pancreatic cancer treatment [30]. To ascertain the influence of neutralized PAUF on MDSCs, we utilized PMAb83 for evaluating the function and migration of MDSCs.…”

Section: Resultsmentioning

confidence: 99%

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Pancreatic adenocarcinoma up-regulated factor (PAUF) enhances the accumulation and functional activity of myeloid-derived suppressor cells (MDSCs) in pancreatic cancer

et al. 2016

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Pancreatic cancer is characterized by an immunosuppressive tumor microenvironment (TME) with a profound immune infiltrate populated by a significant number of myeloid-derived suppressor cells (MDSCs). MDSCs have been increasingly recognized for their role in immune evasion and cancer progression as well as their potential as a target for immunotherapy. However, not much is known about the mechanisms regulating their behavior and function in the pancreatic TME. Here we report that pancreatic adenocarcinoma up-regulated factor (PAUF), a soluble protein involved in pancreatic tumorigenesis and metastasis, plays a role as an enhancer of tumor-infiltrating MDSC and its functional activity. We show that PAUF enhanced the accumulation of MDSCs in the spleen and tumor tissues of PAUF-overexpressing tumor cell-injected mice. In addition, PAUF was found to enhance the immunosuppressive function of MDSCs via the TLR4-mediated signaling pathway, which was demonstrated by PAUF-induced increased levels of arginase, nitric oxide (NO), and reactive oxygen species (ROS). The role of PAUF in modulating the functional properties of MDSCs was further demonstrated by the use of a PAUF-neutralizing antibody that caused a decreased number of tumor-infiltrating MDSCs and reduced MDSC immunosuppressive activity. The observations made in mice were confirmed in human pancreatic cancer patient-derived MDSCs, supporting the clinical relevance of our findings. Collectively, we conclude that the PAUF is a powerful and multifunctional promoter of tumor growth through increase and functional activation of MDSCs, suggesting therapeutic potential for targeting PAUF in pancreatic cancers.

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Section: Resultsmentioning

confidence: 99%

“…rPAUF, and PMAb83 (a monoclonal antibody against human PAUF) were generated as previously described [24, 30]. rPAUF treatment was performed at a concentration of 0.5 μg/ml.…”

Section: Methodsmentioning

confidence: 99%

Pancreatic adenocarcinoma up-regulated factor (PAUF) enhances the accumulation and functional activity of myeloid-derived suppressor cells (MDSCs) in pancreatic cancer

et al. 2016

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“…It is also known to have function in promoting angiogenesis and vascular permeability [7]. Data showing PAUF increases proliferation by up-regulating β-catenin, at least in pancreatic cancer, are important because this may be an avenue for pharmaceutical inhibition [8][9][10]. The aim of this study was to examine the clinical correlation and prognostic significance of PAUF protein expression by immunohistochemistry (IHC) in a large cohort.…”

Section: Introductionmentioning

confidence: 99%

Pancreatic adenocarcinoma up-regulated factor expression is associated with disease-specific survival in cervical cancer patients

Choi¹,

Chung²,

Park³

et al. 2015

Human Pathology

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Pancreatic adenocarcinoma up-regulated factor (PAUF) is a novel soluble protein involved in tumor development and metastases. This study was to investigate the PAUF expression and its prognostic value in cervical cancer patients. The expression of PAUF was immunohistochemically determined in 345 formalin-fixed, paraffin-embedded cervical cancer tissues and 107 normal cervical epitheliums. Subsequently, its associations with clinicopathological characteristics and patient survival were assessed. PAUF protein was expressed both in cytoplasm and nucleus, and cytoplasmic expression was more frequent in cancers than normal tissues (32% versus 17%, P = .002), and the difference was prominent in glandular cells. Notably, the expression was more frequent in adenocarcinoma than in squamous cell carcinoma (57% versus 25%, respectively; P < .001), and the differential expression was also seen at the messenger RNA level (P = .014). Cox regression analysis showed that the cytoplasmic expression of PAUF protein was independently associated with poor disease-free (hazard ratio = 2.3; 95% confidence interval, 1.2-4.3; P = .008) and overall survival (hazard ratio = 2.9; 95% confidence interval, 1.2-7.5; P = .020). Detection of PAUF expression may aid current evaluation of prognosis in cervical adenocarcinoma.

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“…PAUF promotes C–X–C chemokine receptor type 4 (CXCR4)‐mediated metastasis and tumour progression in pancreatic cancer . It accelerates tumour angiogenesis and activates TLR‐mediated ERK signalling to produce oncogenic cytokines and escape from innate immune surveillance in a paracrine manner . Immunostaining for PAUF is also detected in colorectal adenocarcinoma, cervical adenocarcinoma and SCC .…”

Section: Discussionmentioning

confidence: 99%

“…Recently, PAUF has been found to decrease the sensitivity of pancreatic cancer cells to gemcitabine . Cisplatin‐based therapy combined with other anticancer agents is employed frequently in first‐line chemotherapy for OSCC .…”

Section: Introductionmentioning

confidence: 99%

Pancreatic adenocarcinoma up‐regulated factor has oncogenic functions in oral squamous cell carcinoma

et al. 2016

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A PAUF-neutralizing antibody targets both carcinoma and endothelial cells to impede pancreatic tumor progression and metastasis

Cited by 11 publications

References 33 publications

Pancreatic adenocarcinoma up-regulated factor (PAUF) enhances the accumulation and functional activity of myeloid-derived suppressor cells (MDSCs) in pancreatic cancer

Pancreatic adenocarcinoma up-regulated factor (PAUF) enhances the accumulation and functional activity of myeloid-derived suppressor cells (MDSCs) in pancreatic cancer

Pancreatic adenocarcinoma up-regulated factor expression is associated with disease-specific survival in cervical cancer patients

Pancreatic adenocarcinoma up‐regulated factor has oncogenic functions in oral squamous cell carcinoma

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