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Role of pancreatic cancer-derived exosomes in salivary biomarker development.

ABSTRACT: Recent studies have demonstrated that discriminatory salivary biomarkers can be readily detected upon the development of systemic diseases such as pancreatic cancer, breast cancer, lung cancer, and ovarian cancer. However, the utility of salivary biomarkers for the detection of systemic diseases has been undermined due to the absence of the biological and mechanistic rationale as to why distal diseases from the oral cavity would lead to the development of discriminatory biomarkers in saliva. Here, we examine the hypothesis that pancreatic tumor-derived exosomes are mechanistically involved in the development of pancreatic cancer-discriminatory salivary transcriptomic biomarkers. We first developed a pancreatic cancer mouse model that yielded discriminatory salivary biomarkers by implanting the mouse pancreatic cancer cell line Panc02 into the pancreas of the syngeneic host C57BL/6. The role of pancreatic cancer-derived exosomes in the development of discriminatory salivary biomarkers was then tested by engineering a Panc02 cell line that is suppressed for exosome biogenesis, implanting into the C56BL/6 mouse, and examining whether the discriminatory salivary biomarker profile was ablated or disrupted. Suppression of exosome biogenesis results in the ablation of discriminatory salivary biomarker development. This study supports that tumor-derived exosomes provide a mechanism in the development of discriminatory biomarkers in saliva and distal systemic diseases.

SUBMITTER: Lau C

PROVIDER: S-EPMC3772238 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Role of pancreatic cancer-derived exosomes in salivary biomarker development.

Lau Chang C Kim Yong Y Chia David D Spielmann Nadine N Eibl Guido G Elashoff David D Wei Fang F Lin Yi-Ling YL Moro Aune A Grogan Tristan T Chiang Samantha S Feinstein Eric E Schafer Christopher C Farrell James J Wong David T W DT

The Journal of biological chemistry 20130723 37

Recent studies have demonstrated that discriminatory salivary biomarkers can be readily detected upon the development of systemic diseases such as pancreatic cancer, breast cancer, lung cancer, and ovarian cancer. However, the utility of salivary biomarkers for the detection of systemic diseases has been undermined due to the absence of the biological and mechanistic rationale as to why distal diseases from the oral cavity would lead to the development of discriminatory biomarkers in saliva. Her ...[more]

PMID: 23880764

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Project description:Exosomes are a subset of tiny extracellular vesicles manufactured by all cells and are present in all body fluids. They are produced actively in tumor cells, which are released and utilized to facilitate tumor growth. Their characteristics enable them to assist major cancer hallmarks, leveraged by cancer cells in fostering cancer growth and spread while implementing ways to escape elimination from the host environment. This review updates on the latest progress on the roles of cancer-derived exosomes, of 30-100 nm in size, in deregulating paracrine trafficking in the tumor microenvironment and circulation. Thus, exosomes are being exploited in diagnostic biomarker development, with its potential in clinical applications as therapeutic targets utilized in exosome-based nanoparticle drug delivery strategies for cancer therapy. Ongoing studies were retrieved from PubMed® and Scopus database and ClinicalTrials.gov registry for review, highlighting how cancer cells from entirely different cell lines rely on genetic information carried by their exosomes for homotypic and heterotypic intercellular communications in the microenvironment to favor proliferation and invasion, while establishing a pre-metastatic niche in welcoming cancer cells' arrival. We will elaborate on the trafficking of tumor-derived exosomes in fostering cancer proliferation, invasion, and metastasis in hematopoietic (leukemia and myeloma), epithelial (breast cancer), and mesenchymal (soft tissue sarcoma and osteosarcoma) cancers. Cancer-derived exosomal trafficking is observed in several types of liquid or solid tumors, confirming their role as cancer hallmark enabler. Their enriched genetic signals arising from their characteristic DNA, RNA, microRNA, and lncRNA, along with specific gene expression profiles, protein, or lipid composition carried by the exosomal cargo shed into blood, saliva, urine, ascites, and cervicovaginal lavage, are being studied as a diagnostic, prognostic, or predictive cancer biomarker. We reveal the latest research efforts in exploiting the use of nanoparticles to improve the overall cancer diagnostic capability in the clinic.

Project description:PurposePancreatic cancer frequently causes diabetes. We recently proposed adrenomedullin as a candidate mediator of pancreatic β-cell dysfunction in pancreatic cancer. How pancreatic cancer-derived adrenomedullin reaches β cells remote from the cancer to induce β-cell dysfunction is unknown. We tested a novel hypothesis that pancreatic cancer sheds adrenomedullin-containing exosomes into circulation, which are transported to β cells and impair insulin secretion.Experimental methodsWe characterized exosomes from conditioned media of pancreatic cancer cell lines (n = 5) and portal/peripheral venous blood of patients with pancreatic cancer (n = 20). Western blot analysis showed the presence of adrenomedullin in pancreatic cancer-exosomes. We determined the effect of adrenomedullin-containing pancreatic cancer exosomes on insulin secretion from INS-1 β cells and human islets, and demonstrated the mechanism of exosome internalization into β cells. We studied the interaction between β-cell adrenomedullin receptors and adrenomedullin present in pancreatic cancer-exosomes. In addition, the effect of adrenomedullin on endoplasmic reticulum (ER) stress response genes and reactive oxygen/nitrogen species generation in β cells was shown.ResultsExosomes were found to be the predominant extracellular vesicles secreted by pancreatic cancer into culture media and patient plasma. Pancreatic cancer-exosomes contained adrenomedullin and CA19-9, readily entered β cells through caveolin-mediated endocytosis or macropinocytosis, and inhibited insulin secretion. Adrenomedullin in pancreatic cancer exosomes interacted with its receptor on β cells. Adrenomedullin receptor blockade abrogated the inhibitory effect of exosomes on insulin secretion. β cells exposed to adrenomedullin or pancreatic cancer exosomes showed upregulation of ER stress genes and increased reactive oxygen/nitrogen species.ConclusionsPancreatic cancer causes paraneoplastic β-cell dysfunction by shedding adrenomedullin(+)/CA19-9(+) exosomes into circulation that inhibit insulin secretion, likely through adrenomedullin-induced ER stress and failure of the unfolded protein response.

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Role of pancreatic cancer-derived exosomes in salivary biomarker development.

Publications

Role of pancreatic cancer-derived exosomes in salivary biomarker development.

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