University of Pennsylvania, Philadelphia, PA, 19104, USA.
Robert H Lurie Cancer Center, Northwestern University, Chicago, IL, 60611, USA.
Breast Cancer Res. 2022 May 23;24(1):35. doi: 10.1186/s13058-022-01528-w.
CCR5 is a motility chemokine receptor implicated in tumor progression, whose activation and subsequent endocytosis may identify highly aggressive breast cancer cell subtypes likely to spread into the circulatory system.
The MDA-MB-231 cell line was used to model and visualize CCR5 activation by stimulation with RANTES, in an effort to quantify CCR5 endocytosis from the cell surface to the perinuclear space. CCR5 expression was then examined in tumor-associated cells (TACs), consisting of circulating tumor cells and circulating stromal cells, isolated from the peripheral blood of 54 metastatic breast cancer (mBC) patients to evaluate these CCR5 pooling patterns as they relate to progression and survival over 2 years.
In MB231 experiments, it was observed that CCR5 formed ~ 1 micron clusters identified as "CCR5 pools" on the surface of the cell, which in the presence of RANTES were endocytosed and translocated to the cell cytoplasm. When TACs from patients were analyzed, CCR5 pools were observed on the cell surface and translocating to the nuclear area, with CCR5 also having a positive statistical correlation between increased numbers of TACs and increased CCR5 pools on the cells. Further, it was determined that patients with very high numbers of CCR5 (> 10 CCR5 pools), specifically in the circulating stromal cells, were associated with worse progression-free survival (hazard ratio = 4.5, p = 0.002) and worse overall survival (hazard ratio = 3.7, p = 0.014).
Using a liquid biopsy approach, we evaluated two populations of tumor-associated cells emanating from primary tumors, with data suggesting that upregulation of the motility chemokine CCR5 in TACs provides clinically relevant opportunities for treating and tracking drug targetable receptors in mBC.
趋化因子受体 5（CCR5）是一种与肿瘤进展有关的运动趋化因子受体，其激活和随后的内吞作用可能识别出具有高度侵袭性、可能扩散到循环系统的乳腺癌细胞亚群。
使用 MDA-MB-231 细胞系模拟和可视化 CCR5 被 RANTES 刺激后的激活情况，以定量测量 CCR5 从细胞表面到核周空间的内吞作用。然后，在从 54 名转移性乳腺癌（mBC）患者外周血中分离出的肿瘤相关细胞（TAC）中检查 CCR5 的表达，以评估这些 CCR5 聚集模式与 2 年以上的进展和生存相关。
在 MB231 实验中，观察到 CCR5 在细胞表面形成了大约 1 微米的簇，被鉴定为“CCR5 池”，在 RANTES 的存在下，这些簇被内吞并转移到细胞质中。当分析患者的 TAC 时，观察到 CCR5 池在细胞表面并转移到核区，并且 CCR5 与 TAC 数量的增加和细胞上 CCR5 池的增加之间存在正统计相关性。此外，确定具有非常高数量的 CCR5（>10 个 CCR5 池）的患者，特别是在循环基质细胞中，与无进展生存期（风险比=4.5，p=0.002）和总生存期（风险比=3.7，p=0.014）更差相关。
使用液体活检方法，我们评估了源自原发肿瘤的两种肿瘤相关细胞群，数据表明，TAC 中运动趋化因子 CCR5 的上调为治疗和跟踪 mBC 中的药物靶向受体提供了具有临床意义的机会。
