In Uveal Melanoma, Angiopoietin-2 but Not Angiopoietin-1 Is Increased in High-Risk Tumors, Providing a Potential Druggable Target
by
, and
Anna M.W. ten Voorde
1,†, 
Annemijn P.A. Wierenga
1,†,
Rogier J. Nell
1,
Pieter A. van der Velden
1,
Gregorius P.M. Luyten
1,
Robert M. Verdijk
2,3 and
Martine J. Jager
1,* 1
Department of Ophthalmology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
2
Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
3
Department of Pathology, Section Ophthalmic Pathology, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
*
Author to whom correspondence should be addressed.
†
Correspondence: A.M.W.t.V. and A.P.A.W. are joint first-authors.
Cancers 2021, 13(16), 3986; https://doi.org/10.3390/cancers13163986
Submission received: 17 June 2021
/
Revised: 28 July 2021
/
Accepted: 4 August 2021
/
Published: 7 August 2021
(This article belongs to the Special Issue Metastatic Uveal Melanoma)
Simple Summary
We hypothesize that proangiogenic factors such as angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2), two targetable cytokines, may play a role in tumor development in uveal melanoma. We determined the expression of these cytokines in both uveal melanoma tissue as well as in aqueous humor, which provides a unique combination of data. We observed that ANG-2, in contrast to ANG-1, showed more expression in high-risk tumors and was associated with the development of metastases. Its presence in aqueous humor correlated with expression in tumor tissue. Knowledge about the expression of these cytokines may help to identify targets for personalized treatment.
Abstract
Uveal melanoma (UM) metastasize haematogeneously, and tumor blood vessel density is an important prognostic factor. We hypothesized that proangiogenic factors such as angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2), two targetable cytokines, might play a role in tumor development and metastatic behavior. mRNA levels of ANG-1 and ANG-2 were determined in 64 tumors using an Illumina HT-12 v4 mRNA chip and compared to clinical, pathologic, and genetic tumor parameters. Tissue expression was also determined by immunohistochemistry (IHC). Samples of aqueous humor were collected from 83 UM-containing enucleated eyes and protein levels that were determined in a multiplex proximity extension assay. High tissue gene expression of ANG-2, but not of ANG-1, was associated with high tumor thickness, high largest basal diameter, involvement of the ciliary body, and with UM-related death (ANG-2 mRNA p < 0.001; ANG-2 aqueous protein p < 0.001). The presence of the ANG-2 protein in aqueous humor correlated with its mRNA expression in the tumor (r = 0.309, p = 0.03). IHC showed that ANG-2 was expressed in macrophages as well as tumor cells. The presence of ANG-2 in the tumor and in aqueous humor, especially in high-risk tumors, make ANG-2 a potential targetable cytokine in uveal melanoma.
Keywords:
eye disease; uveal melanoma; inflammation; oncology; angiogenesis
