Sprouting Angiogenesis in Human Pituitary Adenomas

Jie Zhou; Yaomin Hu; Wende Zhu; Chuansheng Nie; Wenxiu Zhao; Alexander T Faje; Kay E Labelle; Brooke Swearingen; Hang Lee; E Tessa Hedley-Whyte; Xun Zhang; Pamela S Jones; Karen K Miller; Anne Klibanski; Yunli Zhou; Roy J Soberman

doi:10.3389/fonc.2022.875219

Sprouting Angiogenesis in Human Pituitary Adenomas

Front Oncol. 2022 May 5:12:875219. doi: 10.3389/fonc.2022.875219. eCollection 2022.

Authors

Affiliations

¹ Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
² Neurosurgery Department, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
³ Biostatistics Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
⁴ Department of Pathology (Neuropathology), Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
⁵ Nephrology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.

Abstract

Introduction: Angiogenesis in pituitary tumors is not fully understood, and a better understanding could help inform new pharmacologic therapies, particularly for aggressive pituitary tumors.

Materials and methods: 219 human pituitary tumors and 12 normal pituitary glands were studied. Angiogenic genes were quantified by an angiogenesis qPCR array and a TaqMan probe-based absolute qPCR. Angiogenesis inhibition in pituitary tumors was evaluated in vitro with the endothelial tube formation assay and in vivo in RbΔ19 mice.

Results: 71 angiogenic genes, 40 of which are known to be involved in sprouting angiogenesis, were differentially expressed in pituitary tumors. Expression of endothelial markers CD31, CD34, and ENG was significantly higher in pituitary tumors, by 5.6, 22.3, and 8.2-fold, respectively, compared to in normal pituitary tissue. There was no significant difference in levels of the lymphatic endothelial marker LYVE1 in pituitary tumors compared with normal pituitary gland tissue. Pituitary tumors also expressed significantly higher levels of angiogenesis growth factors, including VEGFA (4.2-fold), VEGFB (2.2), VEGFC (19.3), PGF (13.4), ANGPT2 (9.2), PDGFA (2.7), PDGFB (10.5) and TGFB1 (3.8) compared to normal pituitary tissue. Expression of VEGFC and PGF was highly correlated with the expression of endothelial markers in tumor samples, including CD31, CD34, and ENG (endoglin, a co-receptor for TGFβ). Furthermore, VEGFR inhibitors inhibited angiogenesis induced by human pituitary tumors and prolonged survival of RbΔ19 mice.

Conclusion: Human pituitary tumors are characterized by more active angiogenesis than normal pituitary gland tissue in a manner consistent with sprouting angiogenesis. Angiogenesis in pituitary tumors is regulated mainly by PGF and VEGFC, not VEGFA and VEGFB. Angiogenesis inhibitors, such as the VEGFR2 inhibitor cabozantinib, may merit further investigation as therapies for aggressive human pituitary tumors.

Keywords: Rb1 mice; VEGF inhibitor; angiogenesis inhibition; angiogenic gene expression; cabozantinib; endothelial marker; pituitary adenoma; sprouting angiogenesis.