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

Tapmeier, Thomas T.; Moshnikova, Anna; Beech, John; Allen, Danny; Kinchesh, Paul; Smart, Sean; Harris, Adrian; McIntyre, Alan; Engelman, Donald M.; Andreev, Oleg A.; Reshetnyak, Yana K.; Muschel, Ruth J.

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 31P 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.

• Journal Article Type: Article
• Acceptance Date: Jun 29, 2015
• Online Publication Date: Jul 20, 2015
• Publication Date: Aug 4, 2015
• Deposit Date: Jul 5, 2018
• Journal: Proceedings of the National Academy of Sciences
• Print ISSN: 0027-8424
• Publisher: National Academy of Sciences
• Peer Reviewed: Peer Reviewed
• Volume: 112
• Issue: 31
• Pages: 9710-9715
• DOI: https://doi.org/10.1073/pnas.1509488112
• Public URL: https://nottingham-repository.worktribe.com/output/1105153
• Publisher URL: https://www.pnas.org/content/112/31/9710
• PMID: 00035893