Myeloid cells are recruited by liver metastases and aid their development

Introduction: Myeloid cells aid the progression of various cancers. We identified a murine myeloid population recruited to the liver during the development of colorectal hepatic metastasis. Inhibition of myeloid recruitment through inhibition of the tumour-derived chemokine CCL2 delayed murine metastases and thus implicated a potential therapeutic target for patients with metastatic colorectal cancer. Methods: Murine hepatic metastases were induced by intrasplenic injection of MC38 colon cancer cells. Myeloid populations were identified by flow cytometry. Tumour-derived chemokines were detected in cell-conditioned medium by protein array. MC38-derived CCL2 was inhibited using shRNA. Serum CCL2 expression was quantified by ELISA in 130 colon cancer patients and metastatic colon cancer tissues were analysed immunohistochemically. Results: Cells co-expressing the myeloid markers Gr1 and CD11b and the chemokine receptor CCR2 (CD11b+/CCR2+) increased 6-fold in mouse liver bearing hepatic metastases compared with controls. MC38 cells expressed CCL2 and murine serum CCL2 concentration correlated with tumour burden and hepatic CD11b+/CCR2+ count suggesting a role for CCL2 in their recruitment. Consistent with this, inhibition of MC38-derived CCL2 reduced hepatic CD11b+/CCR2+ recruitment, delaying metastatic development. Serum CCL2 was elevated in patients with colon cancer compared to healthy controls. Furthermore, CCR2 and CD11b co-localised within human hepatic metastases indicating the presence of a myeloid population similar to that seen in metastasis-bearing mice. Conclusions: Recruitment of CD11b+/CCR2+ myeloid cells through the tumour-derived chemokine CCL2 aids the development of murine hepatic metastases. The development of therapeutics aimed at inhibiting myeloid cell trafficking may improve operability and survival for patients with metastatic colorectal cancer. Take-home message: A specific sub-set of myeloid cells are recruited to colon cancer metastases via the action of the tumour-derived chemokine CCL2. Inhibition of this process via manipulation of the chemokine pathway delays the development of hepatic metastasis.