Enhanced Expression of CD13 in Vessels of Inflammatory and Neoplastic Tissues

Abstract

Aminopeptidase-N (CD13) is an important target of tumor vasculature-targeting drugs. The authors investigated its expression by immunohistochemistry with three anti-CD13 monoclonal antibodies (WM15, 3D8, and BF10) in normal and pathological human tissues, including 58 normal, 32 inflammatory, and 149 tumor tissue specimens. The three antibodies stained vessels in most neoplastic tissues, interestingly with different patterns. As a matter of fact, WM15 stained almost all intratumor and peritumor capillaries and only partially large vessels, whereas BF10 and 3D8 reacted with arteries and venules and to a lesser extent with capillaries. These antibodies also stained the stroma in about half of neoplastic tissues. In inflammatory lesions, the three antibodies stained vessels and stroma, whereas in normal tissues, they stained a small percentage of blood vessels. Finally, the three antibodies failed to stain endothelial cells of normal colon, whereas they reacted with activated human umbilical vein endothelial cells and with endothelial cells of colon adenocarcinoma vessels. Overall, WM15 was the most specific antibody for angiogenic tumor vessels, suggesting that it may be a good tool for detecting the CD13 form associated with the tumor vasculature. This finding may be relevant for CD13-mediated vascular targeting therapies.

Cooperative effects of aminopeptidase N (CD13) expressed by nonmalignant and cancer cells within the tumor microenvironment

“…We have previously reported that APN is expressed in tumor blood vessels and is necessary for pathological angiogenesis (15,18,19,23), a function also confirmed by others (8)(9)(10)(11)(12)(13)(14). Reduction in angiogenesis likely accounts for the tumor growth defect resulting from enzyme inactivation.…”

“…A body of indirect evidence suggests a role for APN in regulating these aspects of tumor progression. Indeed, APN is expressed by both cancer cells and nonmalignant cells such as environmental vascular endothelial cells, neutrophils, and stromal cells (8,14), but it remains unclear where and how APN acts to regulate tumor angiogenesis.We recently generated APN-null mice and found them to have impaired neovascularization in response to hypoxia or growth factor stimulation in the absence of tumor cells (23). We reasoned that the APN-null mouse combined with syngeneic tumor allografts would provide an ideal model system to sort out the roles of tumor and alternative sources of APN in tumor growth and metastasis.…”

“…A body of indirect evidence suggests a role for APN in regulating these aspects of tumor progression. Indeed, APN is expressed by both cancer cells and nonmalignant cells such as environmental vascular endothelial cells, neutrophils, and stromal cells (8,14), but it remains unclear where and how APN acts to regulate tumor angiogenesis.…”

“…It functions in the enzymatic cleavage of peptides, in endocytosis, and as a signaling molecule and has been implicated in the regulation of complex and diverse processes, including cell migration, cell survival, viral uptake, and angiogenesis (3). APN has also been linked specifically to cancer, having been identified as a cellsurface marker for malignant myeloid cells (4)(5)(6)(7) and reaching high levels of expression in association with the progression of tumors, including breast, ovarian, and prostate cancer (8)(9)(10)(11)(12)(13)(14). Indeed, vascular endothelial growth factor (VEGF), a key angiogenesis regulator, induces the expression of APN at an early stage of tumor growth (15), again highlighting the role of this enzyme in angiogenesis, a process crucial for sustained growth of most solid tumors (16).…”

Vasopeptidase-activated latent ligands of the histamine receptor-1

“…This vein also expresses ACE [2,15]. The ectopeptidase APN is present in the vascular smooth muscle cells of the umbilical artery [3,4] and at least in the endothelium of the umbilical vein [16,17].…”