Michael Geng

Introduction: Colorectal cancer (CRC) is the third most common cancer and second most lethal cancer globally.^1,3,4 Twenty percent of patients present with metastatic CRC when diagnosed, and an additional 25% of patients who present with local disease will develop metastatic CRC during their treatment course.¹ In recent decades, increasing evidence has shown the promise of tailoring the treatment of metastatic CRC based on screening tumor biomarkers and oncogene mutations.^1,3,4 CXC Chemokine Receptor 2 (CXCR2) is a chemokine receptor with several associated ligands of the CXC chemokine ligand (CXCL) class.  CXCR2 and its associated ligands are known to mediate neutrophil recruitment and angiogenesis, and increasing evidence has implicated them in the proliferation and metastasis of various cancers.⁸ Studies have found a significant link between the upregulation of various myeloid-derived cells and the metastasis of CRC through a CXCR2-dependent manner.^5-8 Other studies linked the CRC migratory effects of Fusobacterium nucleatum through upregulation of CXCL1 and CXCL8.² Recent studies have also shown the ability of CXCL1/5 to induce resistance to cetuximab (EGFR antibody) in CRC cell lines.⁷ These findings show the potential for CXCR2 to be both a therapeutic target and a prognostic biomarker in the management of CRC.  Methods: Mouse models, colorectal resections, blood samples, and human colon cancer cell lines were used. Western blots and RNA-Seq analyses were commonly employed to measure gene expression. Transwell assays were used to assay migratory response. Flow cytometry methods were employed to quantify cell populations, and immunohistochemistry methods were used to analyze tumor stroma cell populations. Results: Several myeloid-derived cells including neutrophils, myeloid-derived suppressor cells (MDSCs), dendritic cells, and macrophages had CXCR2-dependent mechanisms in the metastasis and proliferation of primary colorectal tumors. F. nucleatum-invaded cells induced migration of unexposed CRC cells. CXCL1/5 enabled EGFR activation through a CXCR2/MMP1/HB-EGF axis, conferring cetuximab resistance. Conclusion: Several myeloid-derived cells promote tumor migration through a CXCR2-mediated mechanism. F. nucleatum invasion was shown to promote tumor spread, and bacterial interactions serve as a comparatively understudied field. CXCR2-antagonism has been shown to hinder tumor proliferation through several proposed mechanisms involving tumor-associated immune cells in vitro, and alongside its promise as a therapeutic target, CXCR2 also has the potential to serve as a prognostic biomarker in the management of CRC.

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