R-spondins are secretory proteins localized in the endoplasmic reticulum and Golgi bodies and are processed through the secretory pathway. Among the R-spondin family

RSPO2 has emanated as a novel regulator of Wnt signaling

which has now been acknowledged in numerous

in vitro

and

in vivo

studies. Cancer is an abnormal growth of cells that proliferates and spreads uncontrollably due to the accumulation of genetic and epigenetic factors that constitutively activate Wnt signaling in various types of cancer. Colorectal cancer (CRC) begins when cells in the colon and rectum follow an indefinite pattern of division due to aberrant Wnt activation as one of the key hallmarks. Decades-long progress in research on R-spondins has demonstrated their oncogenic function in distinct cancer types

particularly CRC. As a critical regulator of the Wnt pathway

it modulates several phenotypes of cells

such as cell proliferation

invasion

migration

and cancer stem cell properties. Recently

RSPO mutations

gene rearrangements

fusions

copy number alterations

and altered gene expression have also been identified in a variety of cancers

including CRC. In this review

we addressed the recent updates regarding the recurrently altered R-spondins with special emphasis on the RSPO2 gene and its involvement in potentiating Wnt signaling in CRC. In addition to the compelling physiological and biological roles in cellular fate and regulation

we propose that RSPO2 would be valuable as a potential biomarker for prognostic

diagnostic

and therapeutic use in CRC.