title: Development of a circulating miRNA assay to monitor tumor burden: From mouse to man.
abstract: Circulating miRNA stability suggests potential utility of miRNA based biomarkers to monitor tumor burden and/or progression, particularly in cancer types where serial biopsy is impractical. Assessment of miRNA specificity and sensitivity is challenging within the clinical setting. To address this, circulating miRNAs were examined in mice bearing human SCLC tumor xenografts and SCLC patient derived circulating tumor cell explant models (CDX). We identified 49 miRNAs using human TaqMan Low Density Arrays readily detectable in 10 μl tail vein plasma from mice carrying H526 SCLC xenografts that were low or undetectable in non-tumor bearing controls. Circulating miR-95 measured serially in mice bearing CDX was detected with tumor volumes as low as 10 mm(3) and faithfully reported subsequent tumor growth. Having established assay sensitivity in mouse models, we identified 26 miRNAs that were elevated in a stage dependent manner in a pilot study of plasma from SCLC patients (n = 16) compared to healthy controls (n = 11) that were also elevated in the mouse models. We selected a smaller panel of 10 previously reported miRNAs (miRs 95, 141, 200a, 200b, 200c, 210, 335#, 375, 429) that were consistently elevated in SCLC, some of which are reported to be elevated in other cancer types. Using a multiplex qPCR assay, elevated levels of miRNAs across the panel were also observed in a further 66 patients with non-small cell lung, colorectal or pancreatic cancers. The utility of this circulating miRNA panel as an early warning of tumor progression across several tumor types merits further evaluation in larger studies.
authors.affiliation: Clinical & Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK.
authors.forename: Alastair
authors.initials: A
authors.lastname: Greystoke
authors.affiliation: Clinical & Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK.
authors.forename: Mahmood
authors.initials: M
authors.lastname: Ayub
authors.affiliation: Clinical & Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK.
authors.forename: Dominic G
authors.initials: DG
authors.lastname: Rothwell
authors.affiliation: Clinical & Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK.
authors.forename: Dan
authors.initials: D
authors.lastname: Morris
authors.affiliation: Clinical & Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Burt
authors.affiliation: Clinical & Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK.
authors.forename: Cassandra L
authors.initials: CL
authors.lastname: Hodgkinson
authors.affiliation: Clinical & Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Morrow
authors.affiliation: Clinical & Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK.
authors.forename: Nigel
authors.initials: N
authors.lastname: Smith
authors.affiliation: Clinical & Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK; The Christie NHS Foundation Trust, UK.
authors.forename: Kyaw
authors.initials: K
authors.lastname: Aung
authors.affiliation: The Christie NHS Foundation Trust, UK; Institute of Cancer Sciences, University of Manchester, UK.
authors.forename: Juan
authors.initials: J
authors.lastname: Valle
authors.affiliation: Clinical & Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK; The Christie NHS Foundation Trust, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Carter
authors.affiliation: The Christie NHS Foundation Trust, UK; Institute of Cancer Sciences, University of Manchester, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Blackhall
authors.affiliation: Clinical & Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
authors.affiliation: Clinical & Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, UK. Electronic address: ged.brady@cruk.manchester.ac.uk.
authors.forename: Ged
authors.initials: G
authors.lastname: Brady
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D035683:MicroRNAs / Q000097:blood* / Q000378:metabolism; D060885:Multiplex Polymerase Chain Reaction / Q000379:methods*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D009360:Neoplastic Cells, Circulating / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010865:Pilot Projects; D060888:Real-Time Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D047368:Tumor Burden
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs
keywords: Blood biomarker; Cancer monitoring; miRNA