Angiogenesis in the Normal Adrenal Fetal Cortex and Adrenocortical Tumors

Abstract

Angiogenesis plays an important role in several physiological and pathological processes. Pharmacological angiogenesis modulation has been robustly demonstrated to achieve clinical benefits in several cancers. Adrenocortical carcinomas (ACC) are rare tumors that often have a poor prognosis. In addition, therapeutic options for ACC are limited. Understanding the mechanisms that regulate adrenocortical angiogenesis along the embryonic development and in ACC could provide important clues on how these processes could be pharmacologically modulated for ACC treatment. In this report, we performed an integrative review on adrenal cortex angiogenesis regulation in physiological conditions and ACC. During embryonic development, adrenal angiogenesis is regulated by both VEGF and Ang-Tie signaling pathways. In ACC, early research efforts were focused on VEGF signaling and this pathway was identified as a good prognostic factor and thus a promising therapeutic target. However, every clinical trial so far conducted in ACC using VEGF pathway- targeting drugs, alone or in combination, yielded disappointing results. In contrast, although the Ang-Tie pathway has been pointed out as an important regulator of fetal adrenocortical angiogenesis, its role is yet to be explored in ACC. In the future, further research on the role and efficacy of modulating both Ang-Tie and VEGF pathways in ACC is needed.

Keywords: adrenal fetal cortex; adrenocortical carcinoma; adrenocortical tumors; angiogenesis; anti-angiogenic drugs.

Figure 1

Schematic illustration of the vessel stability regulation by Ang/Tie signaling. (a) Ang1 binds to Tie2 promoting vascular stability. (b) Ang2 has a dual function acting as a Tie2 agonist or antagonist to promote vascular stability or sprouting, respectively. (c) Tie1 forms a complex with Tie2. Upon Ang2 stimulation, Tie1 and Tie2 remain associated and Ang2 induces vascular sprouting. (d) Ang1 stimulation promotes Tie2 clustering leading to vascular stability. This schematic representation includes the most consensual theories; however, this pathway is not yet fully understood. Besides that, this figure is a schematic representation that is not intended to translate the real chemical conformation of the proteins.