Abstract
Bone marrow-derived myeloid cells can form a premetastatic niche and provide a tumor–promoting microenvironment. However, subsets of myeloid cells have also been reported to have anti-tumor properties. It is not clear whether there is a transition between anti- and pro- tumor function of these myeloid cells, and if so, what are the underlying molecular mechanisms. Here we report platelet factor 4 (PF4), or CXCL4, but not the other family members CXCL9, 10, and 11, was produced at higher levels in the normal lung and early stage premetastatic lungs but decreased in later stage lungs. PF4 was mostly produced by Ly6G+CD11b+ myeloid cell subset. Although the number of Ly6G+CD11b+ cells was increased in the premetastatic lungs, the expression level of PF4 in these cells was decreased during the metastatic progression. Deletion of PF4 (PF4 knockout or KO mice) led an increased metastasis suggesting an inhibitory function of PF4. There were two underlying mechanisms: decreased blood vessel integrity in the premetastatic lungs and increased production of hematopoietic stem/progenitor cells (HSCs) and myeloid derived suppressor cells (MDSCs) in tumor-bearing PF4 KO mice. In cancer patients, PF4 expression levels were negatively correlated with tumor stage and positively correlated with patient survival. Our studies suggest that PF4 is a critical anti-tumor factor in the premetastatic site. Our finding of PF4 function in the tumor host provides new insight to the mechanistic understanding of tumor metastasis.
Highlights
Metastatic progression of epithelial tumor cells is influenced by host inflammatory or immune cells [1, 2]
Our studies show that platelet factor 4 (PF4) was produced by Ly6G+CD11b+ immature myeloid cells in the early stage premetastatic lungs, and decreased during metastatic progression
In examining the premetastatic lung microenvironment using a protein array of 100 cytokines, we found unexpectedly that PF4 was relatively high in normal lung and early stage, but decreased in late stage of premetastatic lung (Figure 1C)
Summary
Metastatic progression of epithelial tumor cells is influenced by host inflammatory or immune cells [1, 2]. Host bone marrow derived myeloid cells modulate host immune surveillance [3,4,5,6], and alter the tumor microenvironment [4, 5, 7,8,9]. Several studies report anti-tumor function of myeloid cell subsets such as type 1 polarized tumor-associated neutrophil [6, 14]. Gr-1+CD11b+ myeloid cells or myeloid derived suppressor cells (MDSCs) are largely composed of immature and heterogeneous myeloid progenitor cells [3]. It is not clear whether subsets of these myeloid cells have anti-tumor function, if so, what are the cellular and www.impactjournals.com/oncotarget molecular mechanisms.
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