Elsevier

Human Pathology

Volume 36, Issue 11, November 2005, Pages 1186-1196
Human Pathology

Original contribution
Up-regulation of insulin-like growth factor axis components in human primary prostate cancer correlates with tumor grade

https://doi.org/10.1016/j.humpath.2005.07.023Get rights and content

Summary

There is an evidence that components of the insulin-like growth factor (IGF)–signaling pathway are involved in the development and progression of prostate cancer. The aim of the present study was to provide a comprehensive analysis of the expression levels of proteins of the IGF axis in prostate cancer. We studied expression of the ligands IGF-I and IGF-II, the inhibitory IGF binding protein–3, the type I IGF receptor (IGF-IR), and the downstream mediator insulin receptor substrate-1 by immunohistochemistry in 56 tissue specimens (28 low-grade and 28 high-grade prostate adenocarcinomas). Protein expression in tumor areas, prostatic intraepithelial neoplasias (PINs), and adjacent benign prostatic tissue were evaluated regarding staining intensity and fraction of positive cells. An immunoreactivity score was established from staining intensity and fraction of positive cells, and correlated with the prognostic clinicopathologic parameters prostate-specific antigen serum levels, Gleason score, and TNM stage. The expression levels of all proteins investigated, except IGF binding protein–3, were up-regulated in PIN and in cancer. IGF-I and IGF-II expression showed a higher expression in high-grade compared with low-grade tumor areas. IGF-I and IGF-II and insulin receptor substrate-1 immunoreactivity was higher in tumors from patients with preoperative prostate-specific antigen serum levels 10 ng/mL or greater, and IGF-II expression was correlated with Gleason score. The data indicate significant alterations in the IGF system as prostate cancer develops. Differential expression of growth-stimulating components of the IGF system may be associated with the malignant phenotype and more aggressive tumor behavior. Expression of IGFs, especially IGF-II, may be predictors of the outcome of prostate cancer.

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.

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