title: Antiphospholipid antibodies promote tissue factor-dependent angiogenic switch and tumor progression.
abstract: Progression to an angiogenic state is a critical event in tumor development, yet few patient characteristics have been identified that can be mechanistically linked to this transition. Antiphospholipid autoantibodies (aPLs) are prevalent in many human cancers and can elicit proangiogenic expression in several cell types, but their role in tumor biology is unknown. Herein, we observed that the elevation of circulating aPLs among breast cancer patients is specifically associated with invasive-stage tumors. By using multiple in vivo models of breast cancer, we demonstrated that aPL-positive IgG from patients with autoimmune disease rapidly accelerates tumor angiogenesis and consequent tumor progression, particularly in slow-growing avascular tumors. The action of aPLs was local to the tumor site and elicited leukocytic infiltration and tumor invasion. Tumor cells treated with aPL-positive IgG expressed multiple proangiogenic genes, including vascular endothelial growth factor, tissue factor (TF), and colony-stimulating factor 1. Knockdown and neutralization studies demonstrated that the effects of aPLs on tumor angiogenesis and growth were dependent on tumor cell-derived TF. Tumor-derived TF was essential for the development of pericyte coverage of tumor microvessels and aPL-induced tumor cell expression of chemokine ligand 2, a mediator of pericyte recruitment. These findings identify antiphospholipid autoantibodies as a potential patient-specific host factor promoting the transition of indolent tumors to an angiogenic malignant state through a TF-mediated pathogenic mechanism.
authors.affiliation: Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, New York, New York.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Wu
authors.affiliation: Department of Biological Sciences and Geology, The City University of New York, Queensborough Community College, Bayside, New York.
authors.forename: Andrew
authors.initials: A
authors.lastname: V Nguyen
authors.affiliation: Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, New York, New York.
authors.forename: Xiao-Xuan
authors.initials: XX
authors.lastname: Wu
authors.affiliation: Department of Biological Sciences and Geology, The City University of New York, Queensborough Community College, Bayside, New York.
authors.forename: Mingyu
authors.initials: M
authors.lastname: Loh
authors.affiliation: Department of Psychology, Boston College, Boston, Massachusetts.
authors.forename: Michelle
authors.initials: M
authors.lastname: Vu
authors.affiliation: Department of Medicine/Oncology, Einstein Cancer Center, Albert Einstein College of Medicine, New York, New York.
authors.forename: Yiyu
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, New York, New York.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Analytical Imaging Facility, Einstein Cancer Center, Albert Einstein College of Medicine, New York, New York.
authors.forename: Peng
authors.initials: P
authors.lastname: Guo
authors.affiliation: Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, New York, New York.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Surgery, Einstein Cancer Center, Albert Einstein College of Medicine, New York, New York.
authors.forename: Leslie L
authors.initials: LL
authors.lastname: Montgomery
authors.affiliation: Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, New York, New York.
authors.forename: Amos
authors.initials: A
authors.lastname: Orlofsky
authors.affiliation: Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, New York, New York.
authors.forename: Jacob H
authors.initials: JH
authors.lastname: Rand
authors.affiliation: Department of Medicine/Oncology, Einstein Cancer Center, Albert Einstein College of Medicine, New York, New York. Electronic address: line@ohsu.edu.
authors.forename: Elaine Y
authors.initials: EY
authors.lastname: Lin
mesh_terms: D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000737:chemistry*; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D018450:Disease Progression; D004731:Endotoxins / Q000737:chemistry; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D013925:Thromboplastin / Q000378:metabolism*
chemical_list: D017152:Antibodies, Antiphospholipid; D004731:Endotoxins; D007074:Immunoglobulin G; D013925:Thromboplastin