Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS UMR 5089, 205 Route de Narbonne, 31077 Toulouse, France.
Service d'Anatomie Pathologique, CHRU de Tours, Inserm UMR 1069, 37000 Tours, France.
Int J Mol Sci. 2021 Feb 17;22(4):1994. doi: 10.3390/ijms22041994.
Bone metastasis remains the most frequent and the deadliest complication of prostate cancer (PCa). Mechanisms leading to the homing of tumor cells to bone remain poorly characterized. Role of chemokines in providing navigational cues to migrating cancer cells bearing specific receptors is well established. Bone is an adipocyte-rich organ since 50 to 70% of the adult bone marrow (BM) volume comprise bone marrow adipocytes (BM-Ads), which are likely to produce chemokines within the bone microenvironment. Using in vitro migration assays, we demonstrated that soluble factors released by primary BM-Ads are able to support the directed migration of PCa cells in a CCR3-dependent manner. In addition, we showed that CCL7, a chemokine previously involved in the CCR3-dependent migration of PCa cells outside of the prostate gland, is released by BM-Ads. These effects are amplified by obesity and ageing, two clinical conditions known to promote aggressive and metastatic PCa. In tumors, we found an enrichment of CCR3 in bone metastasis vs. primary tumors at mRNA levels using Oncomine microarray database. In addition, immunohistochemistry experiments demonstrated overexpression of CCR3 in bone versus visceral metastases. These results underline the potential importance of BM-Ads in the bone metastatic process and imply a CCR3/CCL7 axis whose pharmacological interest needs to be evaluated.
骨转移仍然是前列腺癌（PCa）最常见和最致命的并发症。导致肿瘤细胞归巢到骨骼的机制仍未得到很好的描述。趋化因子在为携带特定受体的迁移癌细胞提供导航线索方面的作用已得到充分证实。骨骼是富含脂肪细胞的器官，因为 50%至 70%的成人骨髓（BM）体积由骨髓脂肪细胞（BM-Ads）组成，这些细胞很可能在骨微环境中产生趋化因子。通过体外迁移实验，我们证明了原发性 BM-Ads 释放的可溶性因子能够以 CCR3 依赖的方式支持 PCa 细胞的定向迁移。此外，我们还表明，CCL7 是一种先前参与 PCa 细胞在前列腺外的 CCR3 依赖性迁移的趋化因子，由 BM-Ads 释放。肥胖和衰老这两种已知会促进侵袭性和转移性 PCa 的临床情况会放大这些影响。在肿瘤中，我们使用 Oncomine 微阵列数据库发现 CCR3 在骨转移瘤与原发性肿瘤中的 mRNA 水平上富集。此外，免疫组织化学实验表明 CCR3 在骨转移与内脏转移中的表达过度。这些结果强调了 BM-Ads 在骨转移过程中的潜在重要性，并暗示了 CCR3/CCL7 轴的药理学意义需要进行评估。
