Platelet factor 4 is produced by subsets of myeloid cells in premetastatic lung and inhibits tumor metastasis

Abstract

// Jiang Jian 1, 2, * , Yanli Pang 1, 3, * , H. Hannah Yan 1 , Yongfen Min 4 , Bhagelu R. Achyut 1, 5 , M. Christine Hollander 1 , P. Charles Lin 4 , Xinhua Liang 2 , Li Yang 1 1 Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA 2 Department of Oral and Maxillofacial Surgery, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, P. R. China 3 Current address: Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Peking University Third Hospital, Beijing, P. R. China 4 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH, Frederick, MD, USA 5 Tumor Angiogenesis Laboratory, Cancer Center, Georgia Regents University, Augusta, GA, USA * These authors contributed equally to this work Correspondence to: Li Yang, email: yangl3@mail.nih.gov Xinhua Liang, email: drliangxinhua@aliyun.com Keywords: PF4, metastasis, myeloid cells, premetastatic lung Received: January 15, 2016      Accepted: May 01, 2016      Published: May 19, 2016 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.