Original contributionLoss of claudins-1 and -7 and expression of claudins-3 and -4 correlate with prognostic variables in prostatic adenocarcinomas
Introduction
The interrelationship of adjacent epithelial cells underlies overall tissue structure and polarized barrier formation [1]. Tight junctions (TJs) are one form of epithelial cell-cell adhesion, sealing the intercellular space between adjacent cells just below the apical surface [2]. TJs are composed of integral membrane proteins, including claudins, occludins, and junctional adhesion molecule and peripheral membrane proteins, including zonulae occludens, MAGI-1, Pilt, and others [3]. The resultant complexes have long been associated with segregation of the apical and basolateral compartments and paracellular permeability [4]. More recently, the TJ is better known as a sophisticated apparatus capable of recruiting signaling proteins, thereby regulating various cellular processes including cell growth and differentiation and tumorigenesis [5], [6]. Abnormal function of TJs and subsequent exchange of luminal and serosal fluid compartments may promote carcinogenesis by facilitating protein interactions [7].
Claudins, a complex network of TJ proteins working in collaboration with other TJ partners, have been the focus of a multitude of studies since the turn of the century. Since the identification and cloning of the claudin-1 gene, more than 20 claudin genes encoding a series of approximately 20 to 27 kDa integral membrane proteins have been identified [5], [8], [9]. Most tissues express multiple claudins, which can interact with one another with a given cell and with the claudins of adjacent cells [10].
The abnormal regulation of the claudin TJ proteins has been reported in various human epithelial cancers including both increased and decreased expression levels of specific claudins [10]. Differential expression of multiple claudins has been reported in several cancers including colorectal [11], [12], pancreatic [13], [14], breast [15], [16], [17], [18], [19], and ovarian [20], [21]. In prostate cancer, claudin-3 and claudin-4 expression were studied as potential targets for Clostridium perfringens enteroxin toxin-mediated therapy [22] and claudin-7 as a regulator of prostate specific antigen [23]. One additional study documented the expression of claudins-1, -2, -3, -4, -5, and -7 as potential markers of epithelial differentiation in several malignancies including 10 prostate carcinomas [24] and reports that the claudins evaluated in the current study are present in prostate cancer. However, the pattern of claudin protein expression and their correlation with prognostic variables have not yet been characterized in prostate cancer.
Abnormal claudin protein regulation as a critical step in cancer progression and as novel therapeutic targets [6], [10], [25], [26], [27] continues to gain interest. In the current study, we investigated the expression of claudins-1, -3, -4, -5, and -7 in both the benign and tumor components in prostatic adenocarcinomas (PACs) and correlated the results with clinicopathologic variables and disease outcome.
Section snippets
Specimen collection, tumor grading, and pathologic staging
One hundred forty-one patients who underwent radical prostatectomy for biopsy-proven PAC between 1987 and 1997 at the Albany Medical Center Hospital were randomly selected. Cases in which neoadjuvant hormone therapy was administered were excluded. Hematoxylin and eosin–stained slides from each radical prostatectomy case were reviewed, and a Gleason grade [28] and pathologic stage [29] were assigned. During review, multiple blocks were identified based on the presence of adequate tumor and the
Clinicopathologic data
Of the 141 PACs, there were 70 (49.6%) low-grade tumors (Gleason score ≤6) and 71 (50.4%) high-grade tumors (Gleason score ≥7). At prostatectomy, there were 84 (60%) organ-confined tumors (stages I and II) and 57 (40%) advanced-stage (III and IV) tumors. Follow-up information was available for all patients, of which 59 (42%) had biochemical postsurgical disease recurrence.
Claudin expression by immunohistochemistry
Variable membranous positivity was noted in the adjacent benign glands for all 5 proteins in all cases. Immunoreactivity in
Discussion
It is well documented that claudins, a large family of essential TJ proteins, are abnormally regulated in human carcinomas. A multitude of studies referenced previously in this article report down-regulation and up-regulation of various claudins in various cancers. Unraveling the impact of claudin dysregulation deserves attention, as it is now clear that these proteins play a role in tumorigenesis and represent promising new targets for cancer detection, diagnosis, and therapy [10], [25]. In
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