Aminopeptidase N/CD13 as a potential therapeutic target in malignant pleural mesothelioma

Abstract

Angiogenesis is a crucial factor in the progression of malignant pleural mesothelioma (MPM) and antiangiogenic strategies might be effective against MPM. Aminopeptidase N (APN)/CD13 promotes tumour angiogenesis and is associated with poor prognosis; however, its clinical significance in MPM remains unclear.In 37 consecutive patients with surgically resected MPM, we evaluated the association between immunohistochemical APN/CD13 expression in resected tumours and survival. Additionally, the antitumour and antiangiogenic effects of MT95-4, a fully humanised anti-APN/CD13 monoclonal antibody, were evaluated in mice orthotopically implanted with EHMES-10 (abundantly expressing APN/CD13) and MSTO-211H (scarcely expressing APN/CD13) MPM cells.High tumour APN/CD13 expression was associated with poor prognosis in MPM patients (p=0.04), and MT95-4 treatment reduced tumour growth and angiogenesis in mice harbouring EHMES-10 but not MSTO-211H cells. Furthermore, in mice harbouring EHMES-10 cells, MT95-4 combined with cisplatin more effectively suppressed tumour progression than cisplatin alone.Taken together, these results suggest that APN/CD13 is implicated in the aggressiveness of MPM. Here, MT95-4 treatment reduced tumour progression likely by inhibiting angiogenesis, suggesting APN/CD13 as a potential molecular target for MPM treatment. Additionally, combination treatment with MT95-4 and cisplatin could represent a promising approach to treating MPM exhibiting high APN/CD13 expression.

In Vivo Imaging of Hypoxia and Neoangiogenesis in Experimental Syngeneic Hepatocellular Carcinoma Tumor Model Using Positron Emission Tomography

“…Hypoxia influences tumor resistance to radio-or chemotherapy; moreover, hypoxia is a major stimulator of expression of different neoangiogenic molecules, e.g., VEGF and CD13, in tumors [32]. Neovascularization of malignant tumors plays an important role in tumor growth, tumor progression, and the efficacy of antitumor therapies based on antiangiogenic molecules [33][34][35].…”

CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110

“…Indeed, there is a very active research on tumor stratification based on CD13 expression, and there are many reports in the literature indicating that CD13 expression is an unfavorable prognosis factor in a variety of cancers. Those tumors include pancreas [10] and colon cancers [11], non-small cell lung cancer [12,13], malignant pleural mesothelioma [14], hepatoblastoma [15], hepatocellular carcinoma [35], clear cell papillary renal cell carcinoma [36], scirrhous gastric cancer [37], lymphoplasmatic lymphoma [38], and soft tissue sarcoma [16]. Some of these tumors are rare and/or have poor prognosis, and new therapeutic approaches are urgently needed to increase patient's survival.…”

“…In addition, there is evidence showing a critical role of CD13-positive bone marrow-derived myeloid cells in supporting tumor growth, angiogenesis, and metastasis [8], thus highlighting CD13 as a potential antitumor target [9]. Besides, high expression of CD13 in cancer cells is associated with bad prognosis and poor patient survival in pancreas [10] and colon cancers [11], non-small cell lung cancer [12,13], malignant pleural mesothelioma [14], hepatoblastoma [15], and soft tissue sarcoma [16] among others. In addition, CD13 has been shown to be a target for myeloid malignancies [17].…”

Aminopeptidase antibodies in mesothelioma: new wine deserves new sacks

“…by inhibition of both the pemetrexed/cisplatin-induced stimulation of the AKT pathway, or would CD13's role be more related to inhibition of angiogenesis? Of note, since MT95-4 does not recognise murine APN/CD13, the anti-tumour and anti-angiogenic effects of MT95-4 described by OTSUKI et al [1] were achieved by inhibiting the activity of APN/CD13 expressed only in tumour cells. However, when used for patients with MPM, MT95-4 may exert stronger anti-tumour effects through inhibition of APN/CD13 activity in both tumour and stromal cells.…”

“…In this issue of the European Respiratory Journal, OTSUKI et al [1] postulate that antibody targeting of aminopeptidase N (APN)/CD13 by MT95-4 might be a potential therapeutic approach for malignant pleural mesothelioma (MPM). Aminopeptidases have several functions, but their main role is breakdown of small peptides [2].…”