Dopamine agonist resistance-related endocan promotes angiogenesis and cells viability of prolactinomas

Lin Cai, Zhi Gen Leng, Yu Hang Guo, Shao Jian Lin, Ze Rui Wu, Zhi Peng Su, Jiang Long Lu, Li Fei Wei, Qi Chuan Zhuge, Kunlin Jin, Zhe Bao Wu

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Abstract

Dopamine agonists (DAs) are the first-line treatment of prolactinomas. They function through the dopamine 2 receptor (D2R) in the tumor cells. Endocan, also called endothelial cell-specific molecule-1 (ESM1), has been described as a marker of neoangiogenesis. However, whether ESM1 promotes the resistance of prolactinomas to DA therapy is largely unknown. In our study, 25 patients with prolactinomas were divided into resistant- and sensitive- groups according to the clinical response to bromocriptine. We found that ESM1-microvessel density of resistant prolactinomas was significantly higher than that of sensitive prolactinomas (47.9 ± 11.6, n = 8, vs 13.1 ± 2.8, n = 17, p = 0.0006), indicating that ESM1 was a DA resistance-related gene. Immunostaining showed that ESM1 was expressed in tumor vessels and sporadic tumor cells, and ESM1 was overlapped with the Smooth Muscle Actin (SMA) and von Willebrand Factor (VWF) in the tumor vessels. Silencing of ESM1 markedly suppressed the viability of GH3 and MMQ cells in vitro, and furthermore, significantly increased the sensitivity of GH3 and MMQ cells to DA treatment. Additionally, silencing of ESM1 down-regulated the angiogenesis-associated genes, such as VEGFR2, FGF2, CD34, CD31, VWF, and EGFR. Knockdown of ESM1 decreased endothelial tube formation of HUVECs, and significantly increased the sensitivity of HUVECs to Avastin treatment. Therefore, we first demonstrate that DA resistance-related ESM1 promotes the angiogenesis and tumor cells growth of prolactinomas, suggesting that ESM1 may be a novel therapeutic target for prolactinomas.

Original languageEnglish
Pages (from-to)641-651
Number of pages11
JournalEndocrine
Volume52
Issue number3
DOIs
Publication statusPublished - 1 Jun 2016

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Keywords

  • Angiogenesis
  • Bromocriptine
  • Dopamine agonist
  • Endocan
  • Endothelial cell-specific molecule 1
  • Prolactinoma

Cite this

Cai, L., Leng, Z. G., Guo, Y. H., Lin, S. J., Wu, Z. R., Su, Z. P., ... Wu, Z. B. (2016). Dopamine agonist resistance-related endocan promotes angiogenesis and cells viability of prolactinomas. Endocrine, 52(3), 641-651. https://doi.org/10.1007/s12020-015-0824-2