Role of Pancreatic Cancer-derived Exosomes in Salivary Biomarker Development

Lau, Chang Shun; Kim, Yong; Chia, David; Spielmann, Nadine; Eibl, Guido; Elashoff, David; Fang, Wei; Lin, Yi-Ling; Moro, Aune; Grogan, Tristan; Chiang, Samantha H.; Feinstein, Eric; Schafer, Christopher A.; Farrell, James J.; Wong, David T.

doi:10.1074/jbc.m113.452458

Cited by 223 publications

(175 citation statements)

References 29 publications

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“…Moreover, we did not observe differences in the total protein concentration or ␣-amylase activity between wild-type and PAP Ϫ/Ϫ mice. However, we cannot disregard potential differences in the particular composition of the saliva, considering that systemic diseases can induce alterations in the profile of components that are secreted into the saliva (15,30).…”

Section: Discussionmentioning

confidence: 99%

Prostatic acid phosphatase is the main acid phosphatase with 5′-ectonucleotidase activity in the male mouse saliva and regulates salivation

Araujo

Quintero

Kipar

et al. 2014

American Journal of Physiology-Cell Physiology

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Araujo CL, Quintero IB, Kipar A, Herrala AM, Pulkka AE, Saarinen L, Hautaniemi S, Vihko P. Prostatic acid phosphatase is the main acid phosphatase with 5=-ectonucleotidase activity in the male mouse saliva and regulates salivation. Am J Physiol Cell Physiol 306: C1017-C1027, 2014. First published April 9, 2014; doi:10.1152/ajpcell.00062.2014.-We have previously shown that in addition to the well-known secreted isoform of prostatic acid phosphatase (sPAP), a transmembrane isoform exists (TMPAP) that interacts with snapin (a SNARE-associated protein) and regulates the endo-/exocytic pathways. We have also shown that PAP has 5=-ectonucleotidase and thiamine monophosphatase activity and elicits antinociceptive effects in mouse models of chronic inflammatory and neuropathic pain. Therefore, to determine the physiological role of PAP in a typical exocrine organ, we studied the submandibular salivary gland (SMG) of PAP Ϫ/Ϫ and wild-type C57BL/6J mice by microarray analyses, microRNA sequencing, activity tests, immunohistochemistry, and biochemical and physiological analyses of saliva. We show that PAP is the main acid phosphatase in the wild-type male mouse saliva, accounting for 50% of the total acid phosphatase activity, and that it is expressed only in the granular convoluted tubules of the SMGs, where it is the only 5=-ectonucleotidase. The lack of PAP in male PAP Ϫ/Ϫ mice was associated with a significant increase in the salivation volume under secretagogue stimulation, overexpression of genes related to cell proliferation (Mki67, Aurkb, Birc5) and immune response (Irf7, Cxcl9, Ccl3, Fpr2), and upregulation of miR-146a in SMGs. An increased and sustained acinar cell proliferation was detected without signs of glandular hyperplasia. Our results indicate that in PAP Ϫ/Ϫ mice, SMG homeostasis is maintained by an innate immune response. Additionally, we suggest that in male mice, PAP via its 5=-ectonucleotidase activity and production of adenosine can elicit analgesic effects when animals lick their wounds. acid phosphatase; transmembrane prostatic acid phosphatase; 5=-ectonucleotidase activity; TMPase activity; submandibular salivary gland PROSTATIC ACID PHOSPHATASE (PAP, E.C. 3.1.3.2) is a tartratesensitive histidine acid phosphatase enzyme with two known isoforms, the secreted (sPAP) and the type-I transmembrane (TMPAP) isoform, originating from alternative splicing of the same gene (Acpp) (45). Both isoforms are widely expressed in human and mouse tissues. In humans, PAP is predominately expressed in the prostate gland. TMPAP contains an extracellular NH 2 -terminal catalytic domain and a cytosolic COOHterminal domain, carrying a tyrosine-based endosomal/lysosomal targeting motif (Yxx) (45). In addition, TMPAP is an integral membrane protein of cells and is located in the plasma and vesicular membranes, from where it cycles through the endocytic/exocytic pathway via endosomes, multivesicular endosomes, lysosomes, and exosomes (46). Unlike the activity of other acid phosphatases, such as those derived from erythroc...

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Section: Discussionmentioning

confidence: 99%

Prostatic acid phosphatase is the main acid phosphatase with 5′-ectonucleotidase activity in the male mouse saliva and regulates salivation

Araujo

Quintero

Kipar

et al. 2014

American Journal of Physiology-Cell Physiology

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“…47 Using a rodent pancreatic cancer model, we have demonstrated that tumor-specific mRNA markers are shed from the pancreatic tumor cells, packaged in exosome and shuttled to salivary gland. 48 …”

Section: Future Perspectivesmentioning

confidence: 99%

Saliva diagnostics – Current views and directions

Kaczor‐Urbanowicz

Carreras‐Presas

Aro

et al. 2016

Exp Biol Med (Maywood)

358

271

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The purpose of this mini-review is to make an update about the present and future applications of saliva as a diagnostic biofluid in many fields of science such as dentistry, medicine and pharmacotherapy. Using saliva as a fluid for diagnostic purposes would be a huge breakthrough for both patients and healthcare providers since saliva collection is easy, non-invasive and inexpensive. We will go through the current main diagnostic applications of saliva, and provide a highlight on the emerging, newly developing technologies and tools for cancer screening, detection and monitoring. AbstractIn this review, we provide an update on the current and future applications of saliva for diagnostic purposes. There are many advantages of using saliva as a biofluid. Its collection is fast, easy, inexpensive, and non-invasive. In addition, saliva, as a ''mirror of the body,'' can reflect the physiological and pathological state of the body. Therefore, it serves as a diagnostic and monitoring tool in many fields of science such as medicine, dentistry, and pharmacotherapy. Introduced in 2008, the term ''Salivaomics'' aimed to highlight the rapid development of knowledge about various ''omics'' constituents of saliva, including: proteome, transcriptome, micro-RNA, metabolome, and microbiome. In the last few years, researchers have developed new technologies and validated a wide range of salivary biomarkers that will soon make the use of saliva a clinical reality. However, a great need still exists for convenient and accurate point-of-care devices that can serve as a non-invasive diagnostic tool. In addition, there is an urgent need to decipher the scientific rationale and mechanisms that convey systemic diseases to saliva. Another promising technology called liquid biopsy enables detection of circulating tumor cells (CTCs) and fragments of tumor DNA in saliva, thus enabling non-invasive early detection of various cancers. The newly developed technology-electric field-induced release and measurement (EFIRM) provides near perfect detection of actionable mutations in lung cancer patients. These recent advances widened the salivary diagnostic approach from the oral cavity to the whole physiological system, and thus point towards a promising future of salivary diagnostics for personalized individual medicine applications including clinical decisions and post-treatment outcome predictions.

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“…Salivary miRNA biomarkers have recently become an emerging field for monitoring oral diseases and systemic diseases Lau et al, 2013;Yoshizawa et al, 2013). In carcinogenesis, overexpression of certain miRNAs could result in downregulation of tumor suppressor genes, while underexpression of certain miRNAs could cause oncogene upregulation (Chen, 2005).…”

Section: Introductionmentioning

confidence: 99%