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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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