title: Platelet factor 4 is produced by subsets of myeloid cells in premetastatic lung and inhibits tumor metastasis.
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.
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.|Department of Oral and Maxillofacial Surgery, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, P. R. China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Jian
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.|Current address: Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Peking University Third Hospital, Beijing, P. R. China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Pang
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: H Hannah
authors.initials: HH
authors.lastname: Yan
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH, Frederick, MD, USA.
authors.forename: Yongfen
authors.initials: Y
authors.lastname: Min
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.|Tumor Angiogenesis Laboratory, Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Bhagelu R
authors.initials: BR
authors.lastname: Achyut
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: M Christine
authors.initials: MC
authors.lastname: Hollander
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH, Frederick, MD, USA.
authors.forename: P Charles
authors.initials: PC
authors.lastname: Lin
authors.affiliation: Department of Oral and Maxillofacial Surgery, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, P. R. China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Liang
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology*; D039481:CD11b Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D002469:Cell Separation; D054370:Chemokine CXCL9 / Q000378:metabolism; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055786:Gene Knockout Techniques; D006801:Humans; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000473:pathology* / Q000556:secondary; D051379:Mice; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000378:metabolism*; D000072737:Myeloid-Derived Suppressor Cells / Q000378:metabolism; D010978:Platelet Factor 4 / Q000235:genetics / Q000378:metabolism*; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D000950:Antigens, Ly; D039481:CD11b Antigen; D054370:Chemokine CXCL9; D010978:Platelet Factor 4
keywords: PF4; metastasis; myeloid cells; premetastatic lung