Elsevier

Human Pathology

Volume 42, Issue 12, December 2011, Pages 1946-1952
Human Pathology

Original contribution
Low activated leukocyte cell adhesion molecule expression is associated with advanced tumor stage and early prostate-specific antigen relapse in prostate cancer,☆☆

https://doi.org/10.1016/j.humpath.2011.02.017Get rights and content

Summary

Activated leukocyte cell adhesion molecule (CD166) is a member of the immunoglobulin superfamily and is aberrantly expressed in different tumors, including prostate cancer. To learn more on the prevalence and clinical significance of activated leukocyte cell adhesion molecule expression in prostate cancer, a tissue microarray containing 3261 primary prostate cancers treated by radical prostatectomy was used. A total of 2390 different prostate cancers were analyzed by immunohistochemistry in a tissue microarray format. Activated leukocyte cell adhesion molecule immunostaining in cancers was compared with clinical follow-up, which was available for 1746 patients. Membranous activated leukocyte cell adhesion molecule immunostaining was recorded in 1663 (69.6%) of cases. High activated leukocyte cell adhesion molecule expression levels were significantly associated with favorable tumor features (pT: P = .0015; pN: P = .0008; preoperative prostate-specific antigen: P = .0057) and a lower risk of a biochemical recurrence (P = .0067). Cytoplasmatic activated leukocyte cell adhesion molecule staining was usually associated with membranous staining. The small number of cancers with pure cytoplasmatic staining did not reveal any particularities with respect to clinical outcome or tumor phenotype. It is concluded that activated leukocyte cell adhesion molecule protein is almost always expressed in prostate cancer and that decreased levels of activated leukocyte cell adhesion molecule expression may lead to an aggressive behavior of tumor cells. The abundant presence of activated leukocyte cell adhesion molecule and its membranous localization in prostate cancer epithelium make activated leukocyte cell adhesion molecule a potentially attractive structure for targeted therapy.

Introduction

Activated leukocyte cell adhesion molecule (ALCAM; CD166) is a member of the immunoglobulin superfamily. ALCAM is a cell adhesion molecule expressed by epithelial cells in several organs and is involved in embryogenesis, angiogenesis, hematopoiesis [1], and immune response [2]. Alterations in expression of ALCAM have been reported in different malignancies including melanoma [3], bladder cancer [4], breast cancer [5], [6], colorectal cancer [7], [8], esophageal squamous cell cancer [9], pancreatic cancer [10], oral squamous cell cancer [11], ovarian cancer [12], neuroblastoma [13], and prostate cancer [14], [15], [16], [17]. ALCAM expression is increased in some tumors and down-regulated in others. An association between high ALCAM expression and unfavorable prognosis has been shown for colorectal cancer [7], pancreatic cancer [10], esophageal squamous cell cancer [9], and neuroblastoma [13]. In contrast, several studies on breast cancer suggested that reduced ALCAM expression is associated with poor prognosis [5].

ALCAM expression occurs in normal prostate epithelium [16], [17]. The role of ALCAM in prostate cancer is unclear. An increased ALCAM expression in low-grade as compared with high-grade prostate cancer was described in a study analyzing 54 cancers by immunohistochemistry [16] However, the same group found a significant association between high cytoplasmatic ALCAM staining and early biochemical recurrence in a series of 42 patients [17]. In addition to its prognostic role, ALCAM represents a potential future target for therapy. The utility of ALCAM as a drug target structure may be further enhanced by ligand-induced endocytosis [18]. Moreover, in a recently described internalizing single-chain antibody [18], [19], targeting ALCAM has been suggested for potential intracellular delivery of various therapeutic agents to prostate cancer cells.

The aim of our study was to clarify the prevalence and prognostic role of ALCAM expression in prostate cancer by using a preexisting tissue microarray (TMA) including more than 3000 prostate cancers mostly with clinical follow-up data. The data show that ALCAM expression is abundant in prostate cancer and that high-level ALCAM expression is associated with favorable tumor phenotype and good prognosis.

Section snippets

Patients

Radical prostatectomy specimens were available from 3261 patients, consecutively treated at the Department of Urology, University Medical Center Hamburg-Eppendorf, between 1992 and 2005 (Table 1). Follow-up data were available for 2385 patients, ranging from 1 to 144 months (mean, 34 months). None of the patients received neoadjuvant therapy. Additional (salvage) therapy was initiated in case of a biochemical relapse (BCR). In all patients, prostate-specific antigen (PSA) values were measured

Technical issues

A total of 2390 (73.3%) of tumor samples were interpretable in our TMA analysis. Reasons for noninformative cases (821; 26.7%) included complete lack of tissue samples or absence of unequivocal cancer tissue in the TMA section.

Immunohistochemistry

ALCAM immunostaining always showed strong membrane predominance in our tissues. Although some cytoplasmatic staining was seen, this was always significantly associated with a strong membranous staining (P < .0001). Only 72 of 1392 cytoplasmatic positive cases revealed a

Discussion

The results of this study show that ALCAM is expressed in almost all prostate cancers. Expression differences that were perceivable at bright field immunohistochemistry were only found after marked dilution of the antibody in our protocol development efforts. A dilution series was performed to find experimental conditions that differentiate between low and high ALCAM expressers. Although almost all tumors were ALCAM positive at a dilution of 1:450, the fraction of positive cases reduced to 70%

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    This project was supported by the German Federal Ministry of Education and Science in the framework of the program for medical genome research, Germany (FKZ: 01GS08189).

    ☆☆

    There is no conflict of interest to disclose.

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