Differential expression of interleukin-8 and its receptors in the neuroendocrine and non-neuroendocrine compartments of prostate cancer

Abstract

Hormonal therapy (androgen ablation and/or inhibition of androgen action) is the treatment of choice for advanced prostate cancer. After an initial response in most patients, tumors invariably progress to an androgen-independent state. It is unclear how prostate cancer cells proliferate without androgen. Recent studies suggest that interleukin-8 may promote androgen-independent proliferation, but the source of interleukin-8 in the prostate is unknown. Using immunohistochemistry, we show that interleukin-8 was expressed by the neuroendocrine tumor cells in human prostate cancer tissue. Expression of the interleukin-8 receptor CXCR1 was negative or low in benign prostatic tissue and was frequently increased in malignant cells of high-grade prostatic intraepithelial neoplasia and prostate cancer; however, CXCR1 was not detected in the neuroendocrine tumor cells, suggesting a paracrine mechanism by which interleukin-8 produced by neuroendocrine tumor cells stimulates androgen-independent proliferation of prostate cancer. Neuroendocrine tumor cells expressed another type of interleukin-8 receptor, CXCR2, suggesting an autocrine mechanism by which interleukin-8 regulates the differentiation or function of the neuroendocrine cells. These results, combined with previous reports that neuroendocrine differentiation is induced by hormonal therapy, suggest that neuroendocrine cells play an important role in promoting androgen-independent growth of prostate cancer through interleukin-8 signaling.

Figure 1

IL-8 is produced by NE cells of the prostate. Adjacent sections from the prostate tissue microarray were prepared. A and B were adjacent sections from one core and C and D were adjacent sections from another core. The first sections (A, C) were stained with a monoclonal anti-chromogranin A antibody to highlight the NE cells and the next sections were stained with a polyclonal antibody to IL-8 (B, D). The NE cells of PC (brown-stained cells in A and C) are positive for the expression of IL-8 (brown-stained cells in B and D). Immunohistochemical staining. Original magnifications, ×400.

Figure 2

CXCR1 is overexpressed in malignant cells of PC. The prostatic tissue microarray was stained with a monoclonal anti-CXCR1 antibody. Expression of CXCR1 is negative in benign epithelial cells (A) while its expression in PIN (B) and PC (C) was significantly increased. D was taken from an area with both benign prostatic glands (large arrows) and cancerous glands (small arrows) showing increased expression of CXCR1 in PC. Immunohistochemical staining. Original magnifications, ×400 (A–C); ×200 (D).

Figure 3

CXCR1 is expressed in non-NE tumor cells, not the NE tumor cells of PC. Adjacent sections from the prostate tissue microarray were prepared. A and B were adjacent sections from one core and C and D were adjacent sections from another core. The first sections (A, C) were stained with a monoclonal antibody for chromogranin A and the next sections (B, D) were stained with a monoclonal antibody for CXCR1. NE tumor cells (brown-stained cells in A and C, small arrows) are negative for CXCR1 (cells in B and D that do not show brown staining, small arrows). The non-NE tumor cells (cells in A and C that do not show brown staining, large arrows) are positive for CXCR1 (brown-stained cells in B and D, large arrows). Immunohistochemical staining. Original magnifications, ×400.

Figure 4

CXCR2 is only expressed in NE tumor cells of PC. Adjacent sections from the prostate tissue microarray were prepared. A and B were adjacent sections from one core and C and D were adjacent sections from another core. The first sections (A, C) were stained with a monoclonal anti-chromogranin A antibody to highlight the NE cells and the next sections (B, D) were stained with a monoclonal antibody to CXCR2. The NE cells of PC (brown-stained cells in A and C) are positive for the expression of CXCR2 (brown-stained cells in B and D). Immunohistochemical staining. Original magnifications, ×400.

Figure 5

A model of the function of NE differentiation and IL-8 and its receptors in promoting androgen-independent growth of PC. In this model, androgen deprivation induces NE differentiation of PC. The NE tumor cells produce IL-8, which acts on CXCR1 in the non-NE tumor cells to promote androgen-independent growth. The IL-8 also acts on CXCR2 in the NE tumor cells to regulate NE differentiation and/or function.