Format

Send to

Choose Destination
See comment in PubMed Commons below
Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):9710-5. doi: 10.1073/pnas.1509488112. Epub 2015 Jul 20.

The pH low insertion peptide pHLIP Variant 3 as a novel marker of acidic malignant lesions.

Author information

1
Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom;
2
Physics Department, University of Rhode Island, Kingston, RI 02881;
3
Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, Oxford OX3 9DS, United Kingdom;
4
Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, Oxford OX3 9DS, United Kingdom; Cancer Biology, Division of Cancer and Stem Cells, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom;
5
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520 ruth.muschel@oncology.ox.ac.uk donald.engelman@yale.edu.
6
Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom; ruth.muschel@oncology.ox.ac.uk donald.engelman@yale.edu.

Abstract

Current strategies for early detection of breast and other cancers are limited in part because some lesions identified as potentially malignant do not develop into aggressive tumors. Acid pH has been suggested as a key characteristic of aggressive tumors that might distinguish aggressive lesions from more indolent pathology. We therefore investigated the novel class of molecules, pH low insertion peptides (pHLIPs), as markers of low pH in tumor allografts and of malignant lesions in a mouse model of spontaneous breast cancer, BALB/neu-T. pHLIP Variant 3 (Var3) conjugated with fluorescent Alexa546 was shown to insert into tumor spheroids in a sequence-specific manner. Its signal reflected pH in murine tumors. It was induced by carbonic anhydrase IX (CAIX) overexpression and inhibited by acetazolamide (AZA) administration. By using (31)P magnetic resonance spectroscopy (MRS), we demonstrated that pHLIP Var3 was retained in tumors of pH equal to or less than 6.7 but not in tissues of higher pH. In BALB/neu-T mice at different stages of the disease, the fluorescent signal from pHLIP Var3 marked cancerous lesions with a very low false-positive rate. However, only ∼60% of the smallest lesions retained a pHLIP Var3 signal, suggesting heterogeneity in pH. Taken together, these results show that pHLIP can identify regions of lower pH, allowing for its development as a theranostic tool for clinical applications.

KEYWORDS:

carbonic anhydrase IX; early detection; in vivo fluorescence; invasive tumor; pHLIP

PMID:
26195776
PMCID:
PMC4534280
DOI:
10.1073/pnas.1509488112
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center