Fig. 8. TIE2 inhibitor rebastinib eliminates the prometastatic effects of paclitaxel. TIE2 inhibitor rebastinib eliminates the prometastatic effects of.

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Fig. 8. TIE2 inhibitor rebastinib eliminates the prometastatic effects of paclitaxel. TIE2 inhibitor rebastinib eliminates the prometastatic effects of paclitaxel. (A) Experimental design and chemotherapy scheme. (B) Mouse models of breast carcinoma and cohort sizes. (C and D) TMEM scores in the PyMT transplantation model (C) and the HT17 xenograft model (D), treated with vehicle control, rebastinib, paclitaxel, or a combination of rebastinib with paclitaxel. Mann-Whitney U test. (E and F) Perivascular TIE2hi/VEGFhi macrophages quantified in 10 HPFs in the PyMT transplantation model (E) or in the HT17 xenograft model (F), treated with vehicle control rebastinib, paclitaxel, or a combination of rebastinib with paclitaxel. Mann-Whitney U test. (G and H) CTCs per milliliter of blood collected before sacrifice (day 15) of mice [PyMT transplantation (G); HT17 xenograft (H)]. Values normalized to the control group in each case to account for intercohort variability. Mann-Whitney U test. (I) Incidence of bursting (at least one complete event during 4.5 hours of imaging per mouse) in paclitaxel-treated MMTV-PyMT/Dendra2 cfms-CFP mice that either received or did not receive rebastinib. (J) Frequency of bursting in paclitaxel-treated MMTV-PyMT/Dendra2 cfms-CFP mice that either received or did not receive rebastinib. Mann-Whitney U test. (K) Proposed model of chemotherapy-induced prometastatic changes and cancer cell dissemination. Chemotherapy treatment increases the density of TIE2hi/VEGFhi macrophages within the primary tumor. In addition to inducing angiogenesis, these macrophages assemble active TMEM structures. Chemotherapy treatment also increases expression of the actin-regulatory protein MENAINV isoform in tumor cells due to their contact with infiltrating macrophages, which makes these cancer cells highly migratory and invasive. Upon arriving at the blood vessels, some of the MENAINV-expressing cancer cells assemble active TMEM sites, which other MENAINV-expressing cells then use to intravasate. Together, chemotherapy-mediated MENAINV overexpression and TMEM assembly in breast cancer contribute to TMEM-dependent cancer cell dissemination and distant metastasis. Targeting the function of TMEM-associated macrophage subpopulation by a TIE2 inhibitor counteracts TMEM-mediated cancer cell dissemination induced by chemotherapy treatment. George S. Karagiannis et al., Sci Transl Med 2017;9:eaan0026 Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works