R-spondin family biology and emerging linkages to cancer

Abstract

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 MESSAGES 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.

Identification and Validation of Immune Implication of R-Spondin 1 and an R-Spondin 1-Related Prognostic Signature in Esophagus Cancer

“…Previous studies have shown that macrophages and dendritic cells are activated and positively correlated with ESCA progression [ 32 – 34 ], whereas resting mast cells are negatively correlated with ESCA progression [ 35 ]. Moreover, RSPO1 and RSPO3 expression exhibited significant correlations with immune checkpoint-related genes in various tumors [ 36 ], hinting at their potential for the development of immune checkpoint blockade therapy.…”

LGR5 Expression Predicting Poor Prognosis Is Negatively Correlated with WNT5A in Colon Cancer

“…Together with its ligand RSPO3, the LGR5 receptor promotes β-catenin signaling in cancer cells predominantly via membrane clearance of two endogenous negative regulators of β-catenin signaling: the transmembrane ubiquitin ligases ZNRF3 and RNF43 [17,21,31]. The fact that β-catenin signaling stimulates the colon cancer stem cell niche [32] explains why LGR5 has been recognized and used as a colon cancer stem cell marker [33].…”

Wnt/β-catenin signaling pathway in carcinogenesis and cancer therapy

“…These include Roof plate-specific spondins (R-spondins; RSPOs), Norrin, and Dickkopf (DKK), all of which are secreted proteins. R-spondins, consisting of four members (RSPO1-4), function as enhancers in the Wnt/β-catenin signaling pathway and are considered indispensable factors in carcinogenesis [ 58 ]. This effect was initially discovered in Xenopus embryos, and it was also observed that mouse R-spodin1-3 exhibits a similar effect [ 59 ].…”