Inhibition of lymphoma vascularization and dissemination by estrogen receptor β agonists

• Published in: Blood 2014-03, Vol.123 (13), p.2054-2061
• Main Authors: Yakimchuk, Konstantin, Hasni, Mohammad Sharif, Guan, Jiyu, Chao, Mark P., Sander, Birgitta, Okret, Sam
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - therapeutic use; Animals; Cell Line, Tumor; Estrogen Receptor beta - agonists; Estrogen Receptor beta - genetics; Humans; Lymphoma - drug therapy; Lymphoma - genetics; Lymphoma - pathology; Male; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Neoplasm Metastasis; Neovascularization, Pathologic - drug therapy; Nitriles - therapeutic use; Propionates - therapeutic use; Tumor Microenvironment - drug effects; Xenograft Model Antitumor Assays
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2013-07-517292

Most lymphomas show an increased incidence and poorer prognosis in males vs females, suggesting endocrine regulation. We have previously shown that tumor growth in vivo of a murine T-cell–derived lymphoma is repressed following activation of estrogen receptor β (ERβ, ESR2). By using ERβ-deficient mice, we now demonstrate that this inhibition is mediated via a direct effect on the tumor cells and not on the microenvironment. Furthermore, we show that the growth-suppressing effects of ERβ agonist are also valid for human B-cell lymphomas as demonstrated in tumors derived from Granta-519 mantle cell lymphoma (MCL) and Raji Burkitt lymphoma (BL) cells. In Granta-519 MCL tumors, activation of ERβ reduced expression of BAFF and GRB7, 2 important molecules involved in B-cell proliferation and survival. Importantly, activation of ERβ inhibited angiogenesis and lymphangiogenesis, possibly mediated by impaired vascular endothelial growth factor C expression. Furthermore, using disseminating Raji BL cells, we show that ERβ activation reduces dissemination of grafted Raji BL tumors. We also show by immunohistochemistry that ERβ is expressed in primary MCL tissue. These results suggest that targeting ERβ with agonists may be valuable in the treatment of some lymphomas, affecting several aspects of the malignant process, including proliferation, vascularization, and dissemination. •Estrogen receptor β (ERβ) activation inhibits lymphoma growth, vascularization, and dissemination in vivo.•ERβ activation may mechanistically explain differences in gender incidence and prognosis and contribute to new therapies of lymphomas.