Original contributionUp-regulation of insulin-like growth factor axis components in human primary prostate cancer correlates with tumor grade☆
Introduction
Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer mortality in men in Western countries [1]. Early detection through serum testing for prostate-specific antigen (PSA) and improved procedures for surgical intervention and radiation therapy have recently reduced the number of fatalities significantly; nevertheless, prognosis of prostate cancer is still difficult to predict. Currently, tumor progression is assessed particularly by clinicopathologic parameters like staging and histopathologic grading [2], [3]. The present stage of knowledge, however, often does not permit a decision in which tumor, when diagnosed, will proceed to an aggressive cancer, and there is an urgent need to a better understanding of the biology and biochemistry of prostate cancer. The emergence of effective new prognostic markers and approaches for therapy will depend on the elucidation of the molecular and cellular mechanisms involved in initiation and progression of prostate cancer. It is therefore necessary to clarify the molecular changes involved in prostate cancer initiation and progression, accompanied by a precise understanding of the functional roles of candidate genes and regulatory pathways.
The insulin-like growth factor (IGF) axis has been attributed a critical role in the establishment and maintenance of the transformed phenotype in an increasing number of malignancies [4], [5], [6], [7]. IGFs are important mediators of growth, development, and survival. Their action is modulated by a complex network of molecules, including binding proteins, proteases, and receptors, which all comprise the IGF system [8], [9]. Expression and activity of components of this pathway have been found altered in a large number of human malignancies, including prostate cancer [6], [9], [10]. The IGF system consists of 2 ligands (IGF-I and IGF-II), 6 IGF binding proteins (IGFBP-1–6), and types I and II IGF receptors (IGF-IR and IGF-IIR). IGFs, which are primarily synthesized in the liver, have potent mitogenic and anti–apoptotic effects on prostate tissue [11], [12]. Reports on the significance of high serum levels of IGFs for prostate cancer risk are inconsistent [13], [14], [15], [16], [17], [18]. Recent controlled prospective studies did not find a correlation between IGF serum levels and prostate cancer risk, but suggest an association between IGF serum levels and pathogenesis and progression of the disease [17], [18], [19]. Information on IGF expression in prostatic tissue is limited. IGF-II messenger RNA expression was detected by in situ hybridization in human epithelial prostate cancer cells and rarely in benign epithelium [20].
IGFBPs may modulate IGF actions on cancer growth by reducing the level of free IGFs in the plasma and in the extracellular space. IGFBP-1, IGFBP-2, and IGFBP-3 plasma levels were found altered in prostate cancer patients, but a significant correlation of circulating levels of IGFBP and prostate cancer risk was not observed [13], [19]. However, a decrease in IGFBP-3 level was associated with advanced prostate cancer [17]. Because IGFBP-3 is a substrate for the serum protease PSA, it has been postulated that the rising PSA levels in patients with prostate cancer facilitate disease progression by proteolytic cleavage of IGFBP-3, thereby increasing the level of bioavailable IGF [21].
The biological functions of IGF-I and IGF-II are mediated primarily by the IGF-IR, a tyrosine kinase transmembrane receptor that binds IGF-I with higher affinity than IGF-II. The IGF-IIR that binds IGF-II has no apparent intracellular signaling activities but seems to function as a scavenger receptor that mediates the uptake and degradation of extracellular IGF-II [4]. A role of the IGF-IR for cell transformation and tumor progression has been established for a number of organs including the prostate. There are, however, contradictory reports regarding IGF-IR expression in benign and malignant prostatic epithelium. Although a few studies found no change in IGF-IR levels measured by immunostaining and immunoblotting, in malignant prostate tissue [22], IGF-IR was found decreased [23] or up-regulated [24] at the protein and messenger RNA levels in primary prostate cancer. Expression persisted in paired bone metastases [24] or was absent in bone metastases [22]. Expression of insulin receptor substrate-1 (IRS-1), which is a substrate for the IGF-IR, was not significantly changed in prostatic neoplasias [24].
Although most reports describe changes in only 1 or 2 components of the IGF system related to prostate cancer, we decided to investigate the expression pattern of a whole panel of parameters to understand in more detail the role of the IGF axis in prostate cancer. We present data on IGF-I, IGF-II, IGFBP-3, IGF-IR, and IRS-1 expression at the protein level in a series of 56 prostate specimens comprising benign prostatic tissue (BPT), prostatic intraepithelial neoplasias (PINs), and prostatic adenocarcinomas of different grades (Gleason growth patterns 2-5). The expression of these parameters was correlated with the clinicopathologic parameters Gleason sum score, pathological tumor (pT) stage, and preoperative PSA serum level. We found that the IGF signaling components investigated, except IGFBP-3, were overexpressed in PIN and adenocarcinomas of the prostate and that overexpression of IGF-I and IGF-II correlated with tumor progression.
Section snippets
Tissues and clinical data
Prostate cancer specimens and serum samples were obtained with informed consent from 56 patients who underwent radical prostatectomy for prostate cancer between 1998 and 2001 at the University Hospital Mannheim, Heidelberg University, Heidelberg Germany. The patients did not receive hormonal or radiation therapy before prostatectomy and were not diagnosed for metastatic cancer. Clinicopathologic data are summarized in Table 1. PSA was measured by standard procedures. Two tumors were located in
Tissue characteristics
Protein expression was investigated in a total of 176 individual tissue areas observed in the 56 prostate specimens investigated, as defined in Materials and Methods. Fifty-three of the 56 prostate specimens displayed prostatic adenocarcinomas; in 8 sections, 2 different tumor growth patterns (primary and secondary Gleason patterns) were observed. Among the 61 tumor areas, we observed 9 areas with Gleason 2 pattern, 35 with Gleason 3 pattern, 11 with Gleason 4 pattern, and 6 with Gleason 5
Discussion
Disruptions in the balance of IGF system components leading to excessive proliferation and survival signals have been implicated in the development of benign prostatic hyperplasia and prostate cancer (summarized in Reference [10]). It has been generally accepted that circulating IGFs and IGFBPs influence the growth and behavior of IGF-IR–positive cancers; however, cancers may also be stimulated in an autocrine or paracrine manner by locally synthesized IGF-I or IGF-II. In this article, we
Acknowledgments
We thank Alexandra Kappeler, Dirk Maday, Regina Peichl, and Gabriele Rincke for valuable technical assistance.
References (35)
Histologic grading of prostate cancer: a perspective
Hum Path
(1992)The IGF-I receptor in cancer research
Exp Cell Res
(1999)- et al.
Insulin-like growth factors and cancer
Lancet Oncol
(2002) - et al.
The insulin-like growth factor system and cancer
Cancer Lett
(2003) - et al.
Tyrosine kinases expressed in vivo by human prostate cancer bone marrow metastases and loss of the type 1 insulin-like growth factor receptor
Am J Pathol
(1999) - et al.
Prediction of prognosis for prostatic adenocarcinoma by combined histological and clinical staging
J Urol
(1974) - et al.
Cancer statistics, 2003
CA Cancer J Clin
(2003) - et al.
Insulin-like growth factors and their binding proteins: biological actions
Endocr Rev
(1995) - et al.
Insulin-like growth factors and neoplasia
Nat Rev Cancer
(2004)
IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms
J Endocrinol
Insulin-like growth factor (IGF)-I, IGF-II and IGF type I receptor (IGFR-I) expression in prostate cancer
Anticancer Res
Insulin-like growth factors and risk of benign prostatic hyperplasia
Prostate
Engineered IGF-I expression induces glandular enlargement in the murine prostate
J Endocrinol
Insulin-like growth factor 1 and prostate cancer risk: a population-based, case-control study
J Natl Cancer Inst
Insulin-like growth factor I is not a useful marker of prostate cancer in men with elevated levels of prostate-specific antigen
J Clin Endocrinol Metab
Baltimore Longitudinal Study on Aging. Serum levels of insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein–3, and prostate-specific antigen as predictors of clinical prostate cancer
J Clin Endocrinol Metab
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The study was supported by grant 781010 from the Tumorzentrum Heidelberg/Mannheim. Y. Liao received a fellowship from the Akademisches Auslandsamt of Heidelberg University.
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Present address. Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.