Progression-linked overexpression of c-Met in prostatic intraepithelial neoplasia and latent as well as clinical prostate cancers
Introduction
While prostate cancer is one of the most common malignant diseases in American men, it is not frequent in Japan [1], [2], although its incidence has been increasing recently [3]. The similar incidence of latent prostate cancers between Japanese and Americans suggests that the difference in clinical disease is due to variation in the factors responsible for progression [4], [5].
The hepatocyte growth factor (HGF) is an acidic protein growth factor whose functions encompass stimulation of cell motility and scattering, mitogenesis, morphogenesis and invasion, as well as paradoxical inhibition of tumor growth [6], [7], [8], [9], [10], [11]. However, HGF has been reported to provoke prostate epithelial cell proliferation [12]. The c-Met receptor for HGF is a tyrosine kinase comprising disulfide-linked 50-kDa α-chain and 145-kDa β-chain subunits [13]. It has been reported to be overexpressed in carcinomas of the gastrointestinal tract, thyroid cancers and in malignant melanomas. Recent studies have also revealed c-met gene amplification in various human cancers [14], [15], [16], [17] and interestingly, this was associated with advanced tumor stage [14].
To our knowledge, there have only been a few studies of c-Met expression in prostate cancers [18], [19], [20], [21]; prostatic intraepithelial neoplasia (PIN) and clinical prostate cancers were investigated but not latent carcinomas. In the present study, we focused on latent cancer and PIN, and examined 22 PIN, 15 latent, 14 clinical cancers and seven metastatic lesions using an immunohistochemical method with c-Met antibodies to clarify their levels of c-Met expression.
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Tissue samples
A total of 36 tumor samples were available for this study, including 15 latent and 14 clinical prostate cancers, and seven metastatic lesions. The specimens were obtained by surgical resection or autopsy at Mie University Hospital between 1992 and 1995. Metastatic lesions were resected from the lungs and/or bone marrow at autopsy. Unfortunately, their primary lesions were not available because of previous resections. Of the 14 clinical prostate cancers two were stage B1, one stage B2, six stage
Pathological findings of prostate cancers
Classification of the lesions examined was made according to ‘The General Rules for Clinical and Pathological Studies on Prostatic Cancer’, the Gleason system, and the WHO histological subtyping criteria. Twelve PIN (80%) were detected in latent cancer samples and 10 (71%) in clinical samples. Of these, 16 were diagnosed as low-grade PIN and six as high grade. Of the 15 latent prostate cancers, 13 were graded as well differentiated, and two as poorly differentiated. The 15 cancers comprised 12
Discussion
Previous reports have indicated an involvement of HGF and c-Met in progression of tumor cells to a more malignant phenotype [10], [14], [15]. The present results are also of interest in this context: immunoreactivity significantly increased with the Gleason score and was particular strong in metastases.
The significant association of c-Met expression with prostate tumor progression observed in this study is in line with findings for malignant melanomas and thyroid cancers [15], [16]. In the rat
Acknowledgements
The expert technical advice of Dr. J. Morita, Department of Pathology, Mie University School of Medicine, is greatly appreciated.
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