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Epidermal Growth Factor, Neurotrophins and the Metastatic Cascade in Prostate Cancer

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Epidermal Growth Factor, Neurotrophins and the Metastatic Cascade in Prostate Cancer View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS 28643 FEBS Letters 571 (2004) 1–8 Minireview Epidermal growth factor, neurotrophins and the metastatic cascade in prostate cancer Ximena Montano*, Mustafa B.A. Djamgoz Department of Biological Sciences, Molecular Signalling Group, Neuroscience Solution to Cancer Research Group, Imperial College, London, Sir Alexander Fleming Building, Exhibition Road, London SW7 2AZ, UK Received 2 October 2003; revised 23 November 2003; accepted 28 June 2004 Available online 14 July 2004 Edited by Veli-Pekka Lehto in particular, during therapeutic CaP treatment where epige- Abstract Although cancer of the prostate (CaP) is the most commonly occurring cancer in males, there are major limitations netic deregulation of cell growth control can occur due to ac- in its diagnosis and long-term cure. Consequently, understanding quisition of androgen-independent autocrine growth factor the molecular mechanisms involved in the progression of CaP is stimulation [3–5]. Such stimulation has been implicated in of particular importance for production of pharmacological and tumour growth, angiogenesis and metastasis which, in turn, biological agents to manage the disease. The development of the involve cellular proliferation, adhesion, secretion and motility normal prostate is regulated by stromal–epithelial interactions [3–5]. Therefore, analysis of the deregulation of the functional via endocrine and paracrine factors, such as androgens and relationship between growth factors and their receptors is growth factors, which act as precise homeostatic regulators of central to determining the pathogenesis of CaP. cellular proliferation. Importantly, after a period of hormonal Current knowledge regarding the roles of epidermal growth therapy, CaP shifts from an androgen-dependent to an androgen- factor (EGF) and the neurotrophins – nerve growth factor independent state with a concomitant switch from paracrine to autocrine growth factor stimulation and subsequent upregulation (NGF), brain derived nerve growth factor (BDNF), neuro- of growth factor expression. Thus, growth factors and their trophin-3 (NT-3) and neurotrophin 4/5 (NT-4/5), as well as receptors have a pivotal role in CaP. This is emphasized by their tyrosine kinase receptors – epidermal growth factor re- current evidence obtained from clinical specimens as well as ceptor (EGFR) and members of the trk family (trk A, trk b several in vitro and in vivo models strongly suggesting that and trk c) – suggest strongly that these systems have a fun- epidermal growth factor and the neurotrophins (nerve growth damental role in stromal–epithelial interactions during the factor, brain derived neurotrophin factor, neurotrophin-3 and initiation and progression of CaP. neurotrophin-4/5) together with their tyrosine kinase receptors could play a very significant role in CaP progression. Ó 2004 Federation of European Biochemical Societies. Published 2. Basic cellular architecture of the human prostatic duct by Elsevier B.V. All rights reserved. The basic functional units of the normal adult prostate are Keywords: Prostate cancer; Metastatis; Neurotrophins; trk; ducts composed of epithelial cells associated with stromal cells. Epidermal growth factor receptor; Epidermal growth factor There are at least three different epithelial cell types which have been characterized by their morphology, functional properties and possible role in carcinogenesis (Fig. 1). The prevailing 1. Introduction epithelial cell type is the secretory luminal cell [6,7]. These are differentiated and androgen-dependent cells able to secrete Cancer of the prostate (CaP) is the most commonly diagnosed proteins such as growth factors. As well as androgen receptors, cancer in males, afflicting one man in nine over the age of 65 [1]. these cells express cytokeratins 8 and 18 and the cell surface In order to understand the initiation and progression of CaP, it marker CD57 [6–8]. The second epithelial cell type is the basal is necessary first to elucidate the molecular mechanisms in- cell. These cells are located primarily in the underlying base- volved in the development of the normal prostate gland. It is ment membrane and form a uniform continuous layer. Some well established that stromal–epithelial interactions, through basal cells may also be present among the luminal cells [6,7,9]. endocrine and paracrine factors, extracellular matrix compo- Basal cells, which appear not to be secretory, are characterized nents, cell–cell contact together with locally produced andro- by the expression of CD44, cytokeratins 5, 14 and possible low gens and growth factors, are involved in normal prostate levels of androgen receptor [6,7,9]. Interestingly, analysis of the development and function [2–4]. There is also evidence that cytokeratin expression patterns suggested also the presence of regulation of prostatic growth is maintained by androgen de- transient populations of cells with basal/luminal properties pendent secretion of paracrine growth factors which, during that may be stem cells [10,11]. The third type of epithelial cell is normal development, behave as mitogens of prostatic epithelial the neuroendocrine cell [12]. These cells are a minor popula- cells [3,4]. Importantly, this balance is destabilized in CaP and, tion scattered throughout the basal layer and provide para- crine signals able to support the growth of luminal cells [12,13]. Neuroendocrine cells are androgen-independent but express * Corresponding author. Fax: +44-20-7584-2056. chromogranin A and serotonin [12,13]. The stroma is mainly E-mail address: [email protected] (X. Montano). composed of smooth muscle type cells, associated with a 0014-5793/$22.00 Ó 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.febslet.2004.06.088 2 X. Montano, M.B.A. Djamgoz / FEBS Letters 571 (2004) 1–8 Fig. 1. Schematic representation showing a typical normal human prostate duct. Within the adult duct, the positions of luminal, basal and neuroendocrine epithelial cells as well as the stroma can be ob- served. It should be noted that there is no morphological distinction between epithelial neuroendocrine and basal cells. matrix composed of fibrillar proteins (collagens and fibronec- tins), fibroblasts, adipocytes, lymphocytes, endothelial cells, pericytes and neuromuscular tissue [14–16]. The smooth muscle cells produce growth factors such as EGF and neuro- trophins such as NGF [15] and appear to play a significant role in prostate development and maintenance of homeostasis [15]. The current view is that the stroma is characterized by a constant modulation of different and individual cell pheno- types, which oscillate between those of fibroblastic origin to those of differentiated smooth muscle type and most likely others that still need to be identified [17]. 3. Prostate cancer and its progression Fig. 2 illustrates the main stages in the progression of CaP. Prostatic intraepithelial neoplasia (PIN) has been suggested to be the precursor of CaP [18,19]. PIN is a continuum from low- to high-grade lesions confined to the prostatic capsule/duct [18,19]. PIN can have allelic imbalance as well as architectural and cytological properties resembling invasive carcinoma, such as disruption of the basal layer and low levels of expression of markers (such as matrix metalloproteinase-2 and kallikreins) associated with early invasive carcinoma [18]. PIN can be Fig. 2. Schematic representation of human prostate cancer progres- followed by invasive carcinoma, characterized by loss of the sion. The integrity of normal adult duct is maintained by its androgen dependence. Subsequently, with the onset of prostatic intraepithelial basal lamina, over proliferation of basal and luminal cells and neoplasia (PIN), there is disorganization of luminal and basal epithe- full expression of matrix metalloproteinase-2 and kallikreins lial cells. PIN leads to invasive carcinoma and the full disarray of both [20]. Subsequently, invasive carcinoma may progress to a more luminal and basal cells with concomitant loss of the basal lamina. aggressive form capable of local invasion of the seminal vesi- Finally, during metastasis there is migration to other body sites of malignant epithelial cells which, when patients undergo androgen cles [20,21]. Finally, metastasis may occur primarily to bone withdrawal treatment, become androgen independent. and then to lung, and can be lethal. Importantly, in patients undergoing androgen ablation treatment, the transition from invasive carcinoma to metastasis is characterized by a shift xenografts, transgenic and knockout mice as well as model cell from an androgen-dependent to an androgen-independent lines. We should strongly emphasize, therefore, that although state [20,21]. The initial pathology of malignant cell migration it is possible that observations made on given cellular models within the prostate is predominantly by direct extension may not individually accurately represent human CaP, results around prostatic nerves. This invasion, via the micro-lym- obtained from different systems taken together could throw phatic system, follows the course of nerve branches to the light on the various clinical aspects of CaP progression. superior pedicle and inferior pedicle where capsule penetration is most common [20]. It is important to note that CaP rarely arises spontaneously 4. Tyrosine kinase receptors and their ligands in
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