Liver metastasis from colorectal cancer is a leading cause of cancer mortality. Myeloid cells play pivotal roles in the metastatic process, but their prometastatic functions in liver metastasis remain incompletely understood. To investigate their role, we simulated liver metastasis in C57BL/6 mice through intrasplenic inoculation of MC38 colon carcinoma cells. Among the heterogeneous myeloid infiltrate, we identified a distinct population of CD11b/Gr1 mid cells different from other myeloid populations previously associated with liver metastasis. These cells increased in number dramatically during establishment of liver metastases and were recruited from bone marrow by tumor-derived CCL2. Liver metastasis of Lewis lung carcinoma cells followed this pattern but this mechanism is not universal as liver colonization by B16F1 melanoma cells did not recruit similar subsets. Inhibition of CCL2 signaling and absence of its cognate receptor CCR2 reduced CD11b/Gr1 mid recruitment and decreased tumor burden. Depletion of the CD11b/Gr1 mid subset in a transgenic CD11b-diphtheria toxin receptor mouse model markedly reduced tumor cell proliferation. There was no evidence for involvement of an adaptive immune response in the prometastatic effects of CD11b/Gr1 mid cells. Additionally, an analogous myeloid subset was found in liver metastases of some colorectal cancer patients. Conclusion: Collectively, our findings highlight the importance of myeloid cells-in this case a selective CD11b/Gr1 mid subsetin sustaining development of colorectal cancer liver metastasis and identify a potential target for antimetastatic therapy. (HEPATOLOGY 2013;57:829-839) M etastatic colorectal cancer (CRC) is a prominent cause of cancer mortality worldwide. 1 Hepatic metastases are found in approximately 15% of CRC patients at primary diagnosis 2 with 14% subsequently developing metastases.3 Development of new treatment modalities for CRC liver metastasis is urgently required and a greater understanding of the biology of this process will help establish new therapeutics aimed at downstaging the disease, improving operability, and prolonging survival.Metastasis is a multistep process involving complex and continuous interactions between tumor cells and the host microenvironment.4 Several myeloid-derived cell types have been shown to play key roles in the metastatic cascade, including intravasation, extravasation, 5 and colonization at secondary sites by stimulating tumor cell proliferation and angiogenesis and suppressing antitumor immunity.6-8 However, delineation of their roles in metastasis is complicated by the heterogeneity of myeloid phenotypes that appears to be both tumor-and organ-selective. Vascular endothelial growth factor receptor 1 (VEGFR1) þ hematopoietic progenitor cells accumulated at premetastatic sites to promote adherence and growth of lung Lewis carcinoma (LLC) and B16F1 tumor cells, 9 while a Mac-1 þ myeloid population with different markers was

Because metastasis is associated with the majority of cancer-related deaths, its prevention is a clinical aspiration. Prostanoids are a large family of bioactive lipids derived from the activity of cyclooxygenase-1 (COX-1) and COX-2. Aspirin impairs the biosynthesis of all prostanoids through the irreversible inhibition of both COX isoforms. Long-term administration of aspirin leads to reduced distant metastases in murine models and clinical trials, but the COX isoform, downstream prostanoid, and cell compartment responsible for this effect are yet to be determined. Here, we have shown that aspirin dramatically reduced lung metastasis through inhibition of COX-1 while the cancer cells remained intravascular and that inhibition of platelet COX-1 alone was sufficient to impair metastasis. Thromboxane A 2 (TXA 2 ) was the prostanoid product of COX-1 responsible for this antimetastatic effect. Inhibition of the COX-1/TXA 2 pathway in platelets decreased aggregation of platelets on tumor cells, endothelial activation, tumor cell adhesion to the endothelium, and recruitment of metastasis-promoting monocytes/macrophages, and diminished the formation of a premetastatic niche. Thus, platelet-derived TXA 2 orchestrates the generation of a favorable intravascular metastatic niche that promotes tumor cell seeding and identifies COX-1/TXA 2 signaling as a target for the prevention of metastasis.

No abstract