Antiphospholipid antibodies promote tissue factor-dependent angiogenic switch and tumor progression

Yuan Yuan Wu, Andrew V. Nguyen, Xiao Xuan Wu, Mingyu Loh, Michelle Vu, Yiyu Zou, Qiang Liu, Peng Guo, Yanhua Wang, Leslie L. Montgomery, Amos Orlofsky, Jacob H. Rand, Elaine Y. Lin

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3359-3375
Number of pages17
JournalAmerican Journal of Pathology
Volume184
Issue number12
DOIs
StatePublished - Dec 1 2014

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Wu, Y. Y., Nguyen, A. V., Wu, X. X., Loh, M., Vu, M., Zou, Y., Liu, Q., Guo, P., Wang, Y., Montgomery, L. L., Orlofsky, A., Rand, J. H., & Lin, E. Y. (2014). Antiphospholipid antibodies promote tissue factor-dependent angiogenic switch and tumor progression. American Journal of Pathology, 184(12), 3359-3375. https://doi.org/10.1016/j.ajpath.2014.07.027