McClelland Shauna, Maxwell Pamela J, Branco Cristina, Barry Simon T, Eberlein Cath, LaBonte Melissa J
Patrick G Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7AE, UK.
Bioscience Early Oncology, AstraZeneca, Cambridge CB2 0AA, UK.
Cancers (Basel). 2024 Aug 8;16(16):2797. doi: 10.3390/cancers16162797.
This review delves into the intricate roles of interleukin-8 (IL-8) and its receptors, CXCR1 and CXCR2, in prostate cancer (PCa), particularly in castration-resistant (CRPC) and metastatic CRPC (mCRPC). This review emphasizes the crucial role of the tumour microenvironment (TME) and inflammatory cytokines in promoting tumour progression and response to tumour cell targeting agents. IL-8, acting through C-X-C chemokine receptor type 1 (CXCR1) and type 2 (CXCR2), modulates multiple signalling pathways, enhancing the angiogenesis, proliferation, and migration of cancer cells. This review highlights the shift in PCa research focus from solely tumour cells to the non-cancer-cell components, including vascular endothelial cells, the extracellular matrix, immune cells, and the dynamic interactions within the TME. The immunosuppressive nature of the PCa TME significantly influences tumour progression and resistance to emerging therapies. Current treatment modalities, including androgen deprivation therapy and chemotherapeutics, encounter persistent resistance and are complicated by prostate cancer's notably "immune-cold" nature, which limits immune system response to the tumour. These challenges underscore the critical need for novel approaches that both overcome resistance and enhance immune engagement within the TME. The therapeutic potential of inhibiting IL-8 signalling is explored, with studies showing enhanced sensitivity of PCa cells to treatments, including radiation and androgen receptor inhibitors. Clinical trials, such as the ACE trial, demonstrate the efficacy of combining CXCR2 inhibitors with existing treatments, offering significant benefits, especially for patients with resistant PCa. This review also addresses the challenges in targeting cytokines and chemokines, noting the complexity of the TME and the need for precision in therapeutic targeting to avoid side effects and optimize outcomes.
本综述深入探讨了白细胞介素-8（IL-8）及其受体CXCR1和CXCR2在前列腺癌（PCa）中的复杂作用，特别是在去势抵抗性前列腺癌（CRPC）和转移性CRPC（mCRPC）中的作用。本综述强调了肿瘤微环境（TME）和炎性细胞因子在促进肿瘤进展以及对肿瘤细胞靶向药物反应中的关键作用。IL-8通过C-X-C趋化因子受体1型（CXCR1）和2型（CXCR2）发挥作用，调节多种信号通路，增强癌细胞的血管生成、增殖和迁移。本综述突出了PCa研究重点从单纯的肿瘤细胞向非癌细胞成分的转变，这些成分包括血管内皮细胞、细胞外基质、免疫细胞以及TME内的动态相互作用。PCa TME的免疫抑制特性显著影响肿瘤进展和对新兴疗法的耐药性。当前的治疗方式，包括雄激素剥夺疗法和化疗药物，面临持续的耐药性，并且由于前列腺癌显著的“免疫冷”特性而变得复杂，这限制了免疫系统对肿瘤的反应。这些挑战凸显了对新方法的迫切需求，这些新方法既要克服耐药性，又要增强TME内的免疫参与。研究探索了抑制IL-8信号传导的治疗潜力，结果显示PCa细胞对包括放疗和雄激素受体抑制剂在内的治疗的敏感性增强。诸如ACE试验等临床试验证明了将CXCR2抑制剂与现有治疗方法联合使用的疗效，带来了显著益处，尤其是对于耐药PCa患者。本综述还讨论了靶向细胞因子和趋化因子所面临的挑战，指出了TME的复杂性以及治疗靶向精确性的必要性，以避免副作用并优化治疗效果。
