High intratumoral homogeneity and tumor specificity makes uroplakin 3b (Upk3b) a promising therapeutic targetin malignant mesothelioma

Uroplakin 3B (Upk3b) is one out of 5 known uroplakin (Upk) proteins that cooperatively form the apical asymmetrical unit membrane (AUM) plaques which play a pivotal role in the stabilization and strengthening of epithelial cells that line organs exposed to mechanical stress. In a previous study involving 608 normal tissues and 17,693 cancers we had found that Upk3b expression was limited to membranes of only three cell types which are all subjected to periodical massive distension. These include the apical membrane of the most superficial cell layer of the urothelium (umbrella cells), amnion cells covering the membrane that forms a part of the amniotic sac surrounding the developing fetus in the uterus during pregnancy, and mesothelial cells. Among cancers, Upk3b expression was largely limited to malignant mesothelioma and - less commonly - ovarian carcinomas. The combination of membranous expression in tumor cells and a lack of expression in drug-accessible vital normal cells makes Upk3b a potential therapeutic drug target in malignant mesothelioma. For targeted therapy, both the therapeutic success and the quality of the diagnostic assessment are likely to critically depend on the degree of heterogeneity of target protein expression in individual cancers. Cancers with Upk3b expression in all cancer cells are most likely to be correctly diagnosed as “Upk3b positive” in small biopsies and these tumors may also respond optimally to therapy as all tumor cells carry the drug target. To study the extent of intratumoral heterogeneity of Upk3b expression in malignant mesothelioma, all tumor containing tissue blocks from 58 consecutive patients with a diagnosis of malignant mesothelioma were examined for Upk3b expression by immunohistochemistry. A total of 109 tissue blocks was analyzed (average 2.02 per patient, range 1 - 9). With respect to their Upk3b staining 39 patients (72.2%) were homogeneously positive, 4 (7.4%) were heterogeneously positive and 11 (20.4%) were homogeneously negative. It is concluded from our data that a homogeneous Upk3b expression occurs in about 70.0% of patients with a malignant mesothelioma. This finding supports the notion that UpK3b may represent a promising therapeutic target for malignant mesothelioma, warranting further efforts in drug development.