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Early dissemination highly enhances liver metastasis development during intestinaltumorigenesis
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The ability of yet benign tumor cells to disseminate from the primary tumor before transforming to their full metastatic potential has recently received increasing attention. So far, the existence of such function of cells at early benign stages of intestinal tumorigenesis could not be demonstrated. Here, we introduced and characterized a genetic mouse model with specific tamoxifen-driven induction of tumorigenesis in intestinal tdTomato expressing cells. This model enabled us, already at the adenoma stage, to detect the sparse but obvious presence of intestinal disseminated cells in the liver. In parallel, an elevated plasma level of TIMP1, most prominently, as well as TNFα, SDF-1, CXCL2, and M-CSF was detected, a pattern, which was also observed in blood of patients with benign intestinal polyps. In the liver, the presence of early disseminated cells, in synergy with the detected systemic factors, was accompanied by severe infiltration of myeloid cells including macrophages and neutrophils. This enrichment facilitated metastatic growth in this organ when challenged with carcinoma cell inoculation. This study expands the concept of the impact of early disseminated intestinal cells in synergy with circulating factors on the creation of a pre-metastatic niche to promote distant metastases.
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