Pancreatic Cancer–Derived Exosomes Cause Paraneoplastic β-cell Dysfunction

Javeed, Naureen; Sagar, Gunisha; Dutta, Shamit K.; Smyrk, Thomas C.; Lau, Julie S.; Bhattacharya, Santanu; Truty, Mark J.; Petersen, Gloria M.; Kaufman, Randal J.; Chari, Suresh T.; Mukhopadhyay, Debabrata

doi:10.1158/1078-0432.ccr-14-2022

Cited by 162 publications

(124 citation statements)

References 37 publications

(50 reference statements)

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“…Our group has previously shown that pancreatic tumors shed more exosomes than any other EV, and that these tumor-derived exosomes can mediate b-cell dysfunction and induce lipolysis in both in vitro and in vivo models of new-onset diabetes for PC. 8,9 This work suggests that tumorderived exosomes are mediators of paraneoplastic syndromes in PC. Therefore, we sought to examine the role of PC-derived exosomes (PC-Exo) in immunity for PC.…”

Section: Introductionmentioning

confidence: 81%

“…8,9 These important cellular cargos can aid in metabolic alterations that can help facilitate tumor growth. Exosomes have been strongly implicated in tumor immunity as mediators of both immune activation and suppression.…”

Section: Discussionmentioning

confidence: 99%

“…The isolation procedure was adapted from Javeed et al 8 Exosome internalization into CD14 C monocytes Exosomes were isolated from PANC-1 CM 72 h post-incubation with MV-free media as described above. The resulting exosomes were dyed with the green fluorescent linker PKH67 (Sigma-Aldrich, no.…”

Section: Cd14 C Monocyte Isolationmentioning

confidence: 99%

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Immunosuppressive CD14⁺HLA-DR^lo/negmonocytes are elevated in pancreatic cancer and “primed” by tumor-derived exosomes

et al. 2016

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Immunological strategies to treat pancreatic cancer offer new therapeutic approaches to improve patient outcomes. Understanding alterations in the immune systems of pancreatic cancer patients will likely lead to advances in immunotherapy for the disease. We profiled peripheral blood leukocytes from pancreatic cancer patients (n D 22) and age-matched controls (n D 20) using flow cytometry. Immune profiling of pancreatic cancer patients identified phenotypic changes in various immune cell populations, including a population of immunosuppressive monocytes (CD14 C HLA-DR lo/neg ), which were shown to be increased in these patients. There was a correlation between the levels of CD14 C monocytes and the levels of CD14 C HLA-DR lo/neg monocytes in peripheral blood from pancreatic cancer patients. HLA-DR downregulation of monocytes was shown to occur through pancreatic cancer-derived exosome interactions with monocytes. In an in vitro model, exosomes from patient-derived xenograft cell lines and patient plasma decreased HLA-DR expression on CD14 C monocytes. Additionally, tumor-derived exosomes caused immune suppression in monocytes through altered STAT3 signaling, induction of arginase expression, and reactive oxygen species. These findings provide novel insights into the mechanisms that govern immunosuppression in pancreatic cancer. Understanding monocyte-exosome interactions could lead to novel immunotherapies for this disease.

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Section: Introductionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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Immunosuppressive CD14⁺HLA-DR^lo/negmonocytes are elevated in pancreatic cancer and “primed” by tumor-derived exosomes

et al. 2016

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“…A study by Javeed et al showed that pancreatic cancer-derived exosomes, containing cancer antigen 19-9 (CA19-9) and Adrenomedullin (AM), which interacts adrenomedullin receptors (ADMRs) on β-cells, readily enter with β-cells via caveolin-mediated endocytosis or micropinocytosis. This exosomal uptake leads to the upregulation of endoplasmic reticular stress genes, such as Bip and Chop, which increases reactive oxygen/nitrogen species (ROS/RNS) production, resulting in failure of the unfolded protein response, inhibition of insulin secretion, and increased β-cell death [40]. Another study revealed a novel mechanism of exosome-induced lipolysis in pancreatic cancer.…”

Section: To Change the Metabolism Of Pancreatic Cancer Patientsmentioning

confidence: 99%

Exosomes: Navigating a New Route in Pancreatic Cancer

Zhang¹,

Wang²,

Xu³

et al. 2017

J Biomol Res Ther

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Pancreatic cancer is a fatal disease, and even with an increased commitment to pancreatic cancer research, the 5-year survival rate remains at approximately 6%. However, in the last decade, there has been a rising interest in the role of small extracellular vesicles called exosomes in the cancer field. Accumulating evidence shows that exosomes participate in early processes of tumorigenesis, tumor progression, and metastasis by mediating communication between cells or between cells and their surrounding microenvironment. In pancreatic cancer, exosomes play key roles in building pre-metastatic niches in the liver, inducing immune evasion, changing metabolism, mediating crosstalk between tumor and stromal cells, and causing low chemosensitivity. Although research exploring the roles of exosomes in pancreatic cancer is still in its infancy, the studies presented in this review highlight their potential value in developing novel tools, such as lipid biomarkers, treatment targets, and efficient drug delivery devices, for cancer diagnosis and therapy.

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“…3 Compelling data also support the concept that pancreatic cancer itself can induce diabetes, which may precede the actual onset of pancreatic cancer symptoms by months. 4,5 The complexity of these relationships is outlined in Figure 1. Interestingly, antidiabetic therapy modulates the risk of developing pancreatic cancer; those treated with insulin or insulin secretagogues are at a higher risk, whereas patients treated with metformin have a significantly lower risk of pancreatic cancer.…”

Section: Relationship Between Diabetes and Pancreatic Cancermentioning

confidence: 99%

Clinical Insights Into the Biology and Treatment of Pancreatic Cancer

Mettu

Abbruzzese

2016

JOP

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Pancreatic cancer is a devastating disease with a universally poor prognosis. In 2015, it is estimated that there will be 48,960 new cases of pancreatic cancer and that 40,560 people will die of the disease. The 5-year survival rate is 7.2% for all patients with pancreatic cancer; however, survival depends greatly on the stage at diagnosis. Unfortunately, 53% of patients already have metastatic disease at diagnosis, which corresponds to a 5-year survival rate of 2.4%. Even for the 9% of patients with localized disease confined to the pancreas, the 5-year survival is still modest at only 27.1%. These grim statistics highlight the need for ways to identify cohorts of individuals at highest risk, methods to screen those at highest risk to identify preinvasive pathologic precursors, and development of effective systemic therapies. Recent clinical and translational progress has emphasized the relationship with diabetes, the role of the stroma, and the interplay of each of these with inflammation in the pathobiology of pancreatic cancer. In this article, we will discuss these relationships and how they might translate into novel management strategies for the treatment of this disease.

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Pancreatic Cancer–Derived Exosomes Cause Paraneoplastic β-cell Dysfunction

Cited by 162 publications

References 37 publications

Immunosuppressive CD14⁺HLA-DR^lo/negmonocytes are elevated in pancreatic cancer and “primed” by tumor-derived exosomes

Immunosuppressive CD14⁺HLA-DR^lo/negmonocytes are elevated in pancreatic cancer and “primed” by tumor-derived exosomes

Exosomes: Navigating a New Route in Pancreatic Cancer

Clinical Insights Into the Biology and Treatment of Pancreatic Cancer

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Pancreatic Cancer–Derived Exosomes Cause Paraneoplastic β-cell Dysfunction

Cited by 162 publications

References 37 publications

Immunosuppressive CD14+HLA-DRlo/negmonocytes are elevated in pancreatic cancer and “primed” by tumor-derived exosomes

Immunosuppressive CD14+HLA-DRlo/negmonocytes are elevated in pancreatic cancer and “primed” by tumor-derived exosomes

Exosomes: Navigating a New Route in Pancreatic Cancer

Clinical Insights Into the Biology and Treatment of Pancreatic Cancer

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Immunosuppressive CD14⁺HLA-DR^lo/negmonocytes are elevated in pancreatic cancer and “primed” by tumor-derived exosomes

Immunosuppressive CD14⁺HLA-DR^lo/negmonocytes are elevated in pancreatic cancer and “primed” by tumor-derived exosomes