Abstract
The risk factors for prostate cancer include a high-fat diet and obesity, both of which are associated with an altered cell environment including increased inflammation. It has been shown that chronic inflammation due to a high-fat diet or bacterial infection has the potential to accelerate prostate cancer as well as its precursor, prostatic intraepithelial neoplasia (PIN), development. However, the underlying mechanism of how chronic inflammation promotes prostate cancer development, especially PIN, remains unclear. In this study, we showed that more macrophages were present in PIN areas as compared to the normal areas of human prostate. When co-culturing PIN cells with macrophages in 3D, more PIN cells had nuclear localized cyclin D1, indicating that macrophages enhanced PIN cell proliferation. We identified ICAM-1 and CCL2 as chemoattractants expressed by PIN cells to recruit macrophages. Furthermore, we discovered that macrophage-secreted cytokines including C5a, CXCL1, and CCL2 were responsible for increased PIN cell proliferation. These three cytokines activated ERK and JNK signaling in PIN cells through a ligand-receptor interaction. However, only blockade of ERK abolished macrophage cytokines-induced cell proliferation of PIN. Overall, our results provide a mechanistic view on how macrophages activated through chronic inflammation can expedite PIN progression during prostate cancer development. The information from our work can facilitate a comprehensive understanding of prostate cancer development, which is required for improvement of current strategies for prostate cancer therapy.
Highlights
Over the years, prostate cancer has maintained its position as the second most commonly diagnosed form of cancer in men only succeeded by skin cancer
Xenografting of the immortalized nontumorigenic RWPE-1 cells with THP-1 monocytes in nude mice were able to develop tumors due to an epithelial–mesenchymal transition (EMT) of nontumorigenic prostate epithelial cells by the androgen receptor (AR) of THP-1 monocytes [46]
Our current work demonstrated that Raw264.7 macrophages promoted cell proliferation of murine Pr111 prostate intraepithelial neoplasia (PIN) cells that were established from low-grade PIN lesions in C3(1)/Tag transgenic model of prostate cancer in a 3D coculture (Fig. 1), providing the first direct evidence on the role of inflammation in PIN development and progression
Summary
Prostate cancer has maintained its position as the second most commonly diagnosed form of cancer in men only succeeded by skin cancer. The increase in fibroblasts and myofibroblasts causes heavy modification to the extracellular matrix, while simultaneous interaction of tumorous epithelial cells creates a safe microenvironment for tumor maturation [2,3,4]. This abnormal neoplastic, precancerous growth of the epithelial cells lining the internal and external surfaces of the prostate gland is known as prostatic intraepithelial neoplasia or PIN and is considered the precursor to prostate cancer [5,6]
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