Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins

The L1 adhesion molecule plays an important role in axon guidance and cell migration in the nervous system. L1 is also expressed by many human carcinomas. In addition to cell surface expression, the L1 ectodomain can be released by a metalloproteinase, but the biological function of this process is unknown. Here we demonstrate that membrane-proximal cleavage of L1 can be detected in tumors and in the developing mouse brain. The shedding of L1 involved a disintegrin and metalloproteinase (ADAM)10, as transfection with dominant-negative ADAM10 completely abolishes L1 release. L1-transfected CHO cells (L1-CHO) showed enhanced haptotactic migration on fibronectin and laminin, which was blocked by antibodies to αvβ5 and L1. Migration of L1-CHO cells, but not the basal migration of CHO cells, was blocked by a metalloproteinase inhibitor, indicating a role for L1 shedding in the migration process. CHO and metalloproteinase-inhibited L1-CHO cells were stimulated to migrate by soluble L1-Fc protein. The induction of migration was blocked by αvβ5-specific antibodies and required Arg-Gly-Asp sites in L1. A 150-kD L1 fragment released by plasmin could also stimulate CHO cell migration. We propose that ectodomain-released L1 promotes migration by autocrine/paracrine stimulation via αvβ5. This regulatory loop could be relevant for migratory processes under physiological and pathophysiological conditions

L1CAM Expression is Related to Non-Endometrioid Histology, and Prognostic for Poor Outcome in Endometrioid Endometrial Carcinoma

The majority of endometrial carcinomas are classified as Type I endometrioid endometrial carcinomas (EECs) and have a good prognosis. Type II non-endometrioid endometrial carcinomas (NEECs) have a significant worse outcome. Yet, 20 % of the EECs are associated with an unexplained poor outcome. The aim of this study was to determine if L1CAM expression, a recently reported biomarker for aggressive tumor behavior in endometrial carcinoma, was associated with clinicopathological features of EECs. A total of 103 patients diagnosed as EEC at the Radboud University Medical Centre, based on the pathology report were selected. L1CAM status of these tumors was determined, and histologic slides were reviewed by two expert pathologists. L1CAM-positivity was observed in 17 % (18/103). Review of the diagnostic slides revealed that 11 out of these 18 L1CAM-positive tumors (61 %) contained a serous- or mixed carcinoma component that was not initially mentioned in the pathology report. L1CAM-expression was associated with advanced age, poor tumor grade, and lymphovascular space invasion. A worse five year progression free survival rate was observed for patients with L1CAM-positive tumors (55.6 % for the L1CAM-positive group, compared to 83.3 % for the L1CAM-negative group P = 0.01). L1CAM expression carries prognostic value for histologically classified EEC and supports the identification of tumors with a NEEC component. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12253-016-0047-8) contains supplementary material, which is available to authorized users

Undisclosed Antiretroviral Drug Use in a Multinational Clinical Trial (HIV Prevention Trials Network 052)

The HIV Prevention Trials Network 052 study enrolled serodiscordant couples. Index participants infected with human immunodeficiency virus reported no prior antiretroviral (ARV) treatment at enrollment. ARV drug testing was performed retrospectively using enrollment samples from a subset of index participants. ARV drugs were detected in 45 of 96 participants (46.9%) with an undetectable viral load, 2 of 48 (4.2%) with a low viral load, and 1 of 65 (1.5%) with a high viral load (P < .0001); they were also detected in follow-up samples from participants who were not receiving study-administered treatment. ARV drug testing may be useful in addition to self-report of ARV drug use in some clinical trial settings

Alpha smooth muscle actin (α-SM actin) in normal human ovaries, in ovarian stromal hyperplasia and in ovarian neoplasms

An immunohistochemical investigation of alpha-smooth muscle actin (α-SM actin) using the monoclonal anti-α-SM-1 antibody was carried out in 15 normal ovaries, in three ovaries with stromal hyperplasia and in 27 neoplastic ovaries. In selected cases the pattern of actin isoforms was examined by means of 2 D-gel electrophoresis. In addition, the tissues were stained for vimentin and desmin. In normal ovaries α-SM actin was found in the inner cortex and in the theca externa. In ovarian stromal hyperplasia expression of α-SM actin was minimal or absent. In primary and metastatic epithelial tumors there was positive stromal staining for α-SM actin, especially in the vicinity of epithelial elements. This tended to be more widespread in malignant neoplasms. Thecomas did not express α-SM-actin and could thus be differentiated from leiomyomas which stained intensely for α-SM actin. Only focal stromal staining of α-SM actin was observed in granulosa and germ cell tumors. In all the tissues studied blood vessels were strongly positive for α-SM actin. Desmin, although present in the stroma of most of the specimens, was less abundant than α-SM actin. We concluded that α-SM actin is a component of the normal human ovary where it may contribute to the contractility of its stroma. Its absence in the normal outer cortex and theca interna, and in stromal hyperplasia and thecoma implies that sex hormones do not constitute a stimulus for α-SM actin production in the ovary. Among neoplasms it is most widely represented in the stroma of epithelial tumors in which it may reflect stromal stimulation mediated by neoplastic epithelium. © 1989 Springer-Verlag