Mice with highly metastatic breast cancer transfer express exosomes in serum which increase metastatic capacity of a poorly metastatic tumor

Abstract

Abstract Altered interaction between CD200 and CD200R, represents an example of “checkpoint blockade” disrupting an effective, tumor-directed, host response in murine breast cancer cells. In CD200R1KO mice, long-term cure of EMT6 breast cancer, including metastatic spread to lung and liver, was achieved in BALB/c mice. The reverse was observed with 4THM tumors, an aggressive, inflammatory breast cancer, with increased tumor metastasis in CD200R1KO. To explore possible explanations for this difference we measured the frequency of circulating tumor cells (CTCs) in peripheral blood of tumor bearers, as well as in lung/liver and draining lymph nodes, and in addition infused exosomes from non-tumor controls, or tumor bearers, with/without additional infusions of anti-cytokine antibodies into tumor bearing mice. The measured frequency of circulating tumor cells (CTCs) in peripheral blood was equivalent in the two models in both WT and CD200R1KO mice. Increased metastasis in EMT6 tumor bearers was seen following adoptive transfer of serum, or serum-derived exosomes, from 4THM tumor bearers, an effect which was attenuated by anti-IL-6, and anti-IL-17, but not anti-TNFa, antibody. Anti-IL-6 also attenuated enhanced migration of EMT6 cells in vitro induced by 4THM serum or exosomes, or recombinant IL-6. Exosome cytokine proteomic profiles responses in 4THM and EMT6 tumor bearer mice were regulated by CD200:CD200R interactions, with attenuation of both IL-6 and IL-17 in 4THM CD200tg mice, and enhanced levels in 4THM CD200R1KO mice. We hypothesize that these cytokines act on the microenvironment at sites within the host, and/or directly on tumor cells themselves, to increase metastatic potential.