PO.CL07.01 · 临床研究
CCL5激活替代受体与非小细胞肺癌的差异相关
Activation of alternative receptor by CCL5 is associated with non-small cell lung cancer disparities
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景与意义：肺癌仍是美国癌症相关死亡的主要原因，非裔美国人（AAs）的生存率持续低于欧裔美国人（EAs）。新出现的证据表明，趋化因子受体-配体网络中与种族相关的分子差异可能是这些差异的基础。通过CC趋化因子受体5（CCR5）及其配体CCL5的趋化因子信号传导已被证实与肿瘤生长和免疫调节有关；然而，趋化因子配体常表现出受体混杂性。因此，在本研究中，我们证明了当CCL5无法激活CCR5时其他趋化因子受体的激活，以及其与NSCLC差异的关联。
方法：采用ELISA法定量CCL5，采用PCR免疫沉淀继而Western blot评估CCL5、CCR5、CCR3和CCR1的mRNA转录本和蛋白表达。在功能实验中，使用抗CCR5抗体和/或CCR5小分子抑制剂，在有或无CCL5刺激的情况下进行，并阻断同样以CCL5为配体的其他受体。
结果：我们的研究结果揭示，NSCLC中CCL5驱动的信号传导并不局限于CCR5，替代受体的结合（如CCR3激活）可能维持促肿瘤通路。趋化因子受体在AA来源与EA来源肺癌细胞中的差异表达提示，配体-受体选择性和代偿性信号传导可能促成肺癌生物学和结局中的种族差异。针对CCR3的持续研究将确定当CCR5不可用时该受体是否介导逃逸信号，从而识别出破坏强化肿瘤进展和疾病负担不平等的冗余趋化因子回路的精准治疗策略。
结论与意义：这些发现凸显了肺癌中趋化因子信号传导的复杂性，其中配体混杂性和受体冗余可维持癌细胞的增殖和迁移。CCR3、CCR5和GPR75表达、癌症相关基因活性以及AA和EA来源细胞迁移行为的差异提示，趋化因子受体利用的差异可能在塑造促成肺癌结局种族差异的分子图景和细胞行为中发挥关键作用。
查看英文原文 English abstract
Background and Significance: Lung cancer remains the leading cause of cancer-related mortality in the United States, with persistently lower survival rates among African Americans (AAs) compared to European Americans (EAs). Emerging evidence suggests that race-associated molecular differences in chemokine receptor-ligand networks may underlie these disparities. Chemokine signaling through CC chemokine receptor 5 (CCR5) and its ligand CCL5 has been implicated in tumor growth and immune modulation; however, chemokine ligands often exhibit receptor promiscuity. Hence, in this study, we have demonstrated the activation of other chemokine receptors when CCL5 is unable to activate CCR5, as well as its association with disparities in NSCLC.
Methods: An ELISA assay was used to quantify CCL5, and PCR Immunoprecipitation followed by Western blot was used to evaluate mRNA transcripts and protein expression of CCL5, CCR5, CCR3, and CCR1. An anti-CCR5 antibody and/or a small molecule inhibitor of CCR5 were used during the functional assay, with or without CCL5 stimulation, and blocking other receptors that also share CCL5 as a ligand.
Results: Our findings reveal that CCL5-driven signaling in NSCLC is not restricted to CCR5 and that alternative receptor engagement, such as CCR3 activation, may sustain tumor-promoting pathways. The differential expression of chemokine receptors in AA- versus EA-derived lung cancer cells suggests that ligand-receptor selectivity and compensatory signaling could contribute to racial disparities in lung cancer biology and outcomes. Ongoing work targeting CCR3 will determine whether this receptor mediates escape signaling when CCR5 is unavailable, thereby identifying precision-based therapeutic strategies to disrupt redundant chemokine circuits that reinforce tumor progression and inequities in disease burden.
Conclusions and Implications: These findings highlight the complexity of chemokine signaling in lung cancer, where ligand promiscuity and receptor redundancy can sustain the proliferation and migration of cancer cells. Differences in CCR3, CCR5, and GPR75 expression, cancer-related gene activity, and migratory behavior in AA and EA-derived cells suggest that differences in chemokine receptor utilization may play a crucial role in shaping the molecular landscape and cellular behaviors that contribute to racial disparities in lung cancer outcomes
利益披露 Disclosure
B. A. Brock, None..
S. Singh, None.