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

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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.

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Abbreviations

D2R:

Dopamine 2 receptor

D2S:

Dopamine 2 receptor short isoform

DA:

Dopamine agonist

ESM1:

Endothelial cell-specific molecule 1

MVD:

Microvessel density

HUVECs:

Human umbilical vein endothelial cells

SMA:

Smooth muscle actin

VWF:

Von Willebrand factor, or factor VIII-related antigen

Avastin:

Bevacizumab

VEGFR2:

Vascular endothelial growth factor receptor 2

FGF2:

Fibroblast grow factors 2

CD34:

Cluster of differentiation 34

CD31/PECAM-1:

Platelet endothelial cell adhesion molecule-1

EGFR:

Epidermal growth factor receptor

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Acknowledgments

We are grateful to Prof. Xun Zhang (Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114) for his critical evaluation and linguistic revision of this manuscript. This project was funded by grants from the National Natural Science Foundation of China (81271523 and 81471392 to Z.B.W) and from the Zhejiang Open Foundation of the Top Key Discipline (LKYJ015 to Z.B.W).

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    1. Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China

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

    2. Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

      Shao Jian Lin & Zhe Bao Wu

    3. Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA

      Kunlin Jin

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    Cai, L., Leng, Z.G., Guo, Y.H. et al. Dopamine agonist resistance-related endocan promotes angiogenesis and cells viability of prolactinomas. Endocrine 52, 641–651 (2016). https://doi.org/10.1007/s12020-015-0824-2

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