Myeloid heme oxygenase-1 promotes metastatic tumor colonization in mice.
Bottom Line: Whether HO-1 has an effect on cancer progression through stromal compartments is less clear.Mechanistic studies revealed that HO-1 impacted chemoattractant-induced myeloid cell migration by modulating p38 kinase signaling.These data support a pathological role of myeloid HO-1 in metastasis and suggest a possibility of targeting myeloid HO-1 for cancer treatment.
Affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, China.Show MeSH
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Mentions: Myeloid cells, particularly inflammatory monocytes/macrophages, have been shown to promote tumor cell extravasation and survival during the early phase of metastasis.9,10 To assess the potential impact of myeloid HO-1 on these processes, we first examined the mobilization of monocytes/macrophages to lungs of WT and HO-1+/− mice after i.v. injection of CMTMR-labeled B16F10 cells. As demonstrated in Figure3(a,b), equivalent numbers of tumor cells were found in the lungs of WT and HO-1+/− mice at 4 h after B16F10 cell inoculation. After 24 h, tumor cells remaining in the lungs were significantly reduced. Nevertheless, more tumor cells were detected in the lungs of WT mice compared to HO-1+/− mice. An immunostaining experiment revealed the recruitment of significant numbers of F4/80+ macrophages to lungs of mice at 4 h post-B16F10 cell injection (Fig.3a,c). Notably, the macrophage infiltration was more prominent in WT mice. Although macrophages declined at a later time point (24 h), they remained higher in the WT mice than in their HO-1+/− counterparts. To examine whether tumor cell extravasation is correlated with macrophage infiltration, the lungs of mice subjected to infusion of CMFDA-labeled B16F10 cells for 4 h were incubated with red fluorescent dye-conjugated isolectin B4 to stain the vasculature, followed by examination with 3-D confocal microscopy. It was shown that significant percentages of B16F10 cells were present within the blood vessels in both groups of mice (Fig.4a,b). Nevertheless, the number of tumor cells located in the extravascular areas was much higher in WT mice compared to HO-1+/− mice (14.56 ± 1.26% vs 10.01 ± 1.51%, P = 0.019) at this early time point.
Affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, China.