Nonapical and Cytoplasmic Expression of Interleukin-8, CXCR1, and CXCR2 Correlates with Cell Proliferation and Microvessel Density in Prostate Cancer

Abstract

Purpose: We characterized interleukin-8 (IL-8) and IL-8 receptor expression (CXCR1 and CXCR2) in prostate cancer to address their significance to this disease. Experimental Design: Immunohistochemistry was conducted on 40 cases of human prostate biopsy containing histologically normal and neoplastic tissue, excised from patients with locally confined or invasive androgen-dependent prostate cancer, and 10 cases of transurethral resection of the prostate material from patients with androgen-independent disease. Results: Weak to moderate IL-8 expression was strictly localized to the apical membrane of normal prostate epithelium. In contrast, membranous expression of IL-8, CXCR1, and CXCR2 was nonapical in cancer cells of Gleason pattern 3 and 4, whereas circumferential expression was present in Gleason pattern 5 and androgen-independent prostate cancer. Each of IL-8, CXCR1, and CXCR2 were also increasingly localized to the cytoplasm of cancer cells in correlation with advancing stage of disease. Cytoplasmic expression (but not apical membrane expression) of IL-8 in Gleason pattern 3 and 4 cancer correlated with Ki-67 expression (R = 0.79; P < 0.001), cyclin D1expression (R = 0.79; P < 0.001), and microvessel density (R = 0.81; P < 0.001). In vitro studies on androgen-independent PC3 cells confirmed the mitogenic activity of IL-8, increasing the rate of cell proliferation through activation of both CXCR1and CXCR2 receptors. Conclusions: We propose that the concurrent increase in IL-8 and IL-8 receptor expression in human prostate cancer induces autocrine signaling that may be functionally significant in initiating and promoting the progression of prostate cancer by underpinning cell proliferation and angiogenesis.

Impact of differential cyclin D1 expression and localisation in prostate cancer

“…The Gleason and cyclin D1 scores were assessed for each patient specimen ( Figure 1A). In agreement with the literature (Han et al, 1998;Aaltomaa et al, 1999;Murphy et al, 2005), cyclin D1 was absent in the majority of non-neoplastic prostate tissue (20/23) and of the three positive cases one exhibited weak/focal staining. These data are consistent with the low proliferative index of adult prostatic epithelia.…”

“…Here, nuclear cyclin D1 correlated with Gleason score and proliferation, as is also consistent with our results ( Figures 1C and 4C, respectively). A series of smaller studies have also reported cyclin D1 induction in tumours compared to normal specimens (Han et al, 1998;Kolar et al, 2000;Murphy et al, 2005) and at least one of these considered all cyclin D1 localisations (including cytoplasmic and perinuclear) as positive, although correlates according to localisation were not considered (Han et al, 1998). Thus, the data herein confirm that increased cyclin D1 is seen with high frequency in prostate cancer, and is the first to provide a detailed assessment of cyclin D1 localisation patterns and correlates in organ-confined disease.…”

Dexamethasone potentiates the antiangiogenic activity of docetaxel in castration-resistant prostate cancer

“…Consistent with this, studies in athymic mice have correlated the increased expression of IL-8 in implanted human CaP cells with increased vascularisation of the tumours and an enhanced tumourigenic and metastatic potential (Inoue et al, 2000;Kim et al, 2001). Other studies have determined the relevance of IL-8 signalling to the development of androgen-independence (Araki et al, 2007;Seaton et al, 2008), CaP cell proliferation (Murphy et al, 2005) and CaP cell survival in response to environmental and chemotherapy/biological agents (Maxwell et al, 2007;Wilson et al, 2008a, b).…”

“…CXC-chemokines including IL-8 have an established role in promoting the progression of CaP . Interleukin-8 expression has been shown to be elevated in CaP tissue by immunohistochemistry (Huang et al, 2005;Murphy et al, 2005) and by in situ hybridisation (Uehara et al, 2005), whereas overexpression of IL-8 has been detected in the serum of CaP patients (Veltri et al, 1999;McCarron et al, 2002). Furthermore, IL-8 expression in CaP tissue has been associated with increased biochemical recurrence (Caruso et al, 2008).…”

Chemokines in cancer related inflammation

“…CCR9 was associated with intestinal melanoma metastasis [112], and CCR10 with spread to LN [113]. CCR5 is expressed by Hodgkin lymphoma [114], in prostate cancer [115] and by mammary tumors [116].…”