Department of Biological Sciences, Clark Atlanta University, GA, USA.
Center for Cancer Research and Therapeutic Development, Clark Atlanta University, GA, USA.
FEBS J. 2021 Mar;288(6):1871-1886. doi: 10.1111/febs.15541. Epub 2020 Sep 25.
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.
前列腺癌的风险因素包括高脂肪饮食和肥胖，两者都与改变的细胞环境有关，包括增加炎症。已经表明，高脂肪饮食或细菌感染引起的慢性炎症有可能加速前列腺癌及其前体前列腺上皮内瘤变（PIN）的发展。然而，慢性炎症如何促进前列腺癌的发展，特别是 PIN 的潜在机制仍不清楚。在这项研究中，我们发现与前列腺的正常区域相比，PIN 区域存在更多的巨噬细胞。当将 PIN 细胞与巨噬细胞在 3D 中共培养时，更多的 PIN 细胞具有核定位的细胞周期蛋白 D1，表明巨噬细胞增强了 PIN 细胞的增殖。我们确定了 ICAM-1 和 CCL2 作为 PIN 细胞表达的趋化因子来招募巨噬细胞。此外，我们发现巨噬细胞分泌的细胞因子，包括 C5a、CXCL1 和 CCL2，负责增加 PIN 细胞的增殖。这三种细胞因子通过配体-受体相互作用激活了 PIN 细胞中的 ERK 和 JNK 信号通路。然而，只有阻断 ERK 才能消除巨噬细胞细胞因子诱导的 PIN 细胞增殖。总的来说，我们的结果提供了一个关于巨噬细胞如何通过慢性炎症激活从而在前列腺癌发展过程中加速 PIN 进展的机制观点。我们工作的信息可以促进对前列腺癌发展的全面理解，这是改善当前前列腺癌治疗策略所必需的。
