Tumor-associated neutrophils secrete AGR2 to promote colorectal cancer metastasis via its receptor CD98hc–xCT
Gut Feb 01, 2022
Findings revealed a novel crosstalk between tumor-associated neutrophils (TANs) and colorectal cancer (CRC) cells implicating the secreted AGR2(anterior gradient-2)–CD98hc(heavy chain of CD98)–xCT axis that encourages metastasis and influences the outcomes of patients suffering from CRC.
This study included CRC patients, neutrophil-specific Agr2 knockout (Agr2 <sup>f/f</sup> ;Mrp-Cre) mice, and in vitro and in vivo analyses, to determine the cellular source for secreted AGR2 in the tumor microenvironment (TME) and underlying mechanisms mediating secreted AGR2’s effects.
TANs were identified as a main cell type for secreting AGR2 in the TME of CRC, and migration of CRC cells was promoted by TANs-secreted AGR2.
In mice, CRC liver metastases were relieved by neutrophils-specific ablation of Agr2.
CD98hc was the functional receptor for secreted AGR2.
Mechanistically, increase in xCT activity was brought about by secreted AGR2 in a CD98hc-dependent manner, subsequently activating Ras homologue family member A/Rho-related protein kinase 2 cascade.
Via the C-X-C motif chemokine 2, active recruitment of TANs by CRC cells occurred.
CRC-derived transforming growth factor beta 1 (TGF-β1) educated peripheral blood neutrophils to become AGR2 <sup>+</sup> TANs that secrete AGR2.
Factors correlated with poor prognosis of CRC patients were: abundant infiltration of AGR2 <sup>+</sup> TANs and high expression of TGF-β1 and CD98hc–xCT.
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