R-spondin family biology and emerging linkages to cancer

The R-spondin protein family comprises four members (RSPO1-4), which are agonists of the canonical Wnt/β-catenin pathway. Emerging evidence revealed that RSPOs should not only be viewed as agonists of the Wnt/β-catenin pathway but also as regulators for tumor development and progression. Aberrant expression of RSPOs is related to tumorigenesis and tumor development in multiple cancers and their expression of RSPOs has also been correlated with anticancer immune cell signatures. More importantly, the role of RSPOs as potential target therapies and their implication in cancer progressions has been studied in the preclinical and clinical settings. These findings highlight the possible therapeutic value of RSPOs in cancer medicine. However, the expression pattern, effects, and mechanisms of RSPO proteins in cancer remain elusive. Investigating the many roles of RSPOs is likely to expand and improve our understanding of the oncogenic mechanisms mediated by RSPOs. Here, we reviewed the recent advances in the functions and underlying molecular mechanisms of RSPOs in tumor development, cancer microenvironment regulation, and immunity, and discussed the therapeutic potential of targeting RSPOs for cancer treatment. In addition, we also explored the biological feature and clinical relevance of RSPOs in cancer mutagenesis, transcriptional regulation, and immune correlation by bioinformatics analysis.KEY MESSAGESAberrant expressions of RSPOs are detected in various human malignancies and are always correlated with oncogenesis.Although extensive studies of RSPOs have been conducted, their precise molecular mechanism remains poorly understood.Bioinformatic analysis revealed that RSPOs may play a part in the development of the immune composition of the tumor microenvironment. Aberrant expressions of RSPOs are detected in various human malignancies and are always correlated with oncogenesis. Although extensive studies of RSPOs have been conducted, their precise molecular mechanism remains poorly understood. Bioinformatic analysis revealed that RSPOs may play a part in the development of the immune composition of the tumor microenvironment.

R-spondin（R-spondin, RSPO）蛋白家族共有四个成员（RSPO1至RSPO4），作为经典Wnt/β-连环蛋白（canonical Wnt/β-catenin）通路的激动剂。越来越多的研究证据表明，RSPOs不仅可被视作Wnt/β-连环蛋白通路的激动剂，同时也是肿瘤发生与进展的调控因子。RSPOs的异常表达与多种癌症的肿瘤发生及发展密切相关，其表达水平还与抗癌免疫细胞特征存在关联。更重要的是，RSPOs作为潜在治疗靶点的作用及其在癌症进展中的影响已在临床前与临床研究中得到探索。上述研究结果凸显了RSPOs在肿瘤医学中的潜在治疗价值。然而，RSPO蛋白在癌症中的表达模式、生物学效应及分子机制仍有待阐明。探究RSPOs的多重功能，有望拓展并加深我们对RSPOs介导的致癌机制的理解。本文综述了RSPOs在肿瘤发生、肿瘤微环境调控及免疫调节中的功能与潜在分子机制的最新研究进展，并探讨了靶向RSPOs用于癌症治疗的治疗潜力。此外，本文还通过生物信息学分析，探究了RSPOs在癌症诱变、转录调控及免疫相关性中的生物学特征与临床相关性。
核心要点：
RSPOs的异常表达在多种人类恶性肿瘤中均有检出，且始终与肿瘤发生密切相关。
尽管针对RSPOs已开展了大量研究，但其确切的分子机制仍未被充分阐明。
生物信息学分析显示，RSPOs可能参与肿瘤微环境免疫组成的塑造。
RSPOs的异常表达在多种人类恶性肿瘤中均有检出，且始终与肿瘤发生密切相关。
尽管针对RSPOs已开展了大量研究，但其确切的分子机制仍未被充分阐明。
生物信息学分析显示，RSPOs可能参与肿瘤微环境免疫组成的塑造。