Prostate cancer precursors, known as prostate intraepithelial neoplasia (PIN), require abnormal neoplastic cell proliferation to eventually develop into cancer cells. Our study indicated these precancerous lesions were able to recruit macrophages through expression of ICAM‐1 and CCR2. Once recruited, infiltrating macrophages secreted C5a, CXCL1, and CCL2 all of which activated ERK signaling in PIN cells to expedite cell proliferation of PIN.
Prostate cancer development and progression are associated with increased infiltrating macrophages. Prostate cancer is derived from prostatic intraepithelial neoplasia (PIN) lesions. However, the effects macrophages have on PIN progression remain unclear. Here, we showed that the recruited macrophages adjacent to PIN expressed M2 macrophage markers. In addition, high levels of Spp1 transcripts, also known as osteopontin, were identified in these macrophages. Extraneously added Spp1 accelerated PIN cell proliferation through activation of Akt and JNK in a 3D culture setting. We also showed that PIN cells expressed CD44, integrin αv, integrin β1, and integrin β3, all of which have been previously reported as receptors for Spp1. Finally, blockade of Akt and JNK activation through their specific inhibitor completely abolished macrophage Spp1-induced cell proliferation of PIN. Hence, our data revealed Spp1 as another macrophage cytokine/growth factor and its mediated mechanism to upregulate PIN cell growth, thus promoting prostate cancer development.
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