The Role of the Ectopeptidase APN/CD13 in Cancer

Abstract

APN/CD13 is expressed in a variety of cells/tissues and is therefore associated with diverse physiological functions, including proliferation, differentiation, migration, angiogenesis, invasion, metastasis, vasoconstriction, and the regulation of normal and impaired immune function. Increased expression or activity of APN/CD13 has been described for various tumors, such that APN/CD13 is in most cases associated with reduced disease-free and overall survival. The mechanisms that mediate these cellular effects of APN/CD13 have been largely determined and are described here. APN/CD13-regulated signaling pathways include integrin recycling, the regulation of small GTPase activities, cell–ECM interactions, and Erk1/2, PI3K, and Wnt signaling. APN/CD13 is a neo-angiogenesis marker that is not found on normal endothelia, but it is found on neo-angiogenetically active endothelia. Therefore, APN/CD13 represents a specific receptor for so-called “tumor-homing peptides” (NRG peptides). Peptides containing the NRG motif show high-affinity binding to APN/CD13. APN/CD13 thus represents a versatile target for the inhibition of tumor-induced angiogenesis through the tumor-selective administration of, e.g., cytotoxic substances. Furthermore, it enables the molecular imaging of tumor masses and the assessment of (neo)angiogenesis in animal models and in patients. Pharmacological inhibitors of APN/CD13 have been proven to reduce tumor growth and tumor progression in various APN/CD13-positive tumors.

The DNA repair kinase ATM regulates CD13 expression and cell migration

“…However, this may also be attributed to indirect signaling effects. It is important to note that the CD13 inhibitor used in this study is not entirely selective and inhibits other proteases ( Lendeckel et al, 2023 ).…”

“…However, this may Frontiers in Cell and Developmental Biology frontiersin.org also be attributed to indirect signaling effects. It is important to note that the CD13 inhibitor used in this study is not entirely selective and inhibits other proteases (Lendeckel et al, 2023). Ataxia telangiectasia patients, along with more classical traits, have vasculature abnormalities (Meshulam et al, 2012).…”

NGR-Based Radiopharmaceuticals for Angiogenesis Imaging: A Preclinical Review

“…A high level of receptor expression was found in a broad range of cancers, such as breast, prostate, ovarian, thyroid, pancreatic, colorectal, non-small cell lung cancer, and malignant pleural mesothelioma [ 7 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Although prior literature data state that APN/CD13 cannot be encountered on the surface of normal vasculature [ 9 , 20 ], Curnis et al reported the existence of different isoforms of CD13 in healthy epithelial cells as well as normal blood vessel endothelium and cancer-linked newly formed vasculature [ 21 ].…”