Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1073/pnas.1509488112

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

04/08/2015

Volume

112

Pages

9710 - 9715

Keywords

carbonic anhydrase IX, early detection, in vivo fluorescence, invasive tumor, pHLIP, Acids, Amino Acid Sequence, Animals, Biomarkers, Tumor, Cell Line, Tumor, Disease Models, Animal, Humans, Hydrogen-Ion Concentration, Magnetic Resonance Spectroscopy, Membrane Proteins, Mice, Inbred BALB C, Molecular Sequence Data, Mutant Proteins, Neoplasm Invasiveness, Neoplasms, ROC Curve, Sensitivity and Specificity, Spheroids, Cellular