Cancer Stem Cells in Pheochromocytoma and Paraganglioma

Laura D Scriba,Stefan R Bornstein,Graeme Eisenhofer,Cynthia L Andoniadou,Andreas Schedl,Charlotte Steenblock,Gregor Mueller,Julia Hauer,Angela Huebner,Ben Wielockx,Alice Santambrogio

doi:10.3389/fendo.2020.00079

Abstract

Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors associated with high cardiovascular morbidity and variable risk of malignancy. The current therapy of choice is surgical resection. Nevertheless, PCCs/PGLs are associated with a lifelong risk of tumor persistence or recurrence. A high rate of germline or somatic mutations in numerous genes has been found in these tumors. For some, the tumorigenic processes are initiated during embryogenesis. Such tumors carry gene mutations leading to pseudohypoxic phenotypes and show more immature characteristics than other chromaffin cell tumors; they are also often multifocal or metastatic and occur at an early age, often during childhood. Cancer stem cells (CSCs) are cells with an inherent ability of self-renewal, de-differentiation, and capacity to initiate and maintain malignant tumor growth. Targeting CSCs to inhibit cancer progression has become an attractive anti-cancer therapeutic strategy. Despite progress for this strategy for solid tumors such as neuroblastoma, brain, breast, and colon cancers, no substantial advance has been made employing similar strategies in PCCs/PGLs. In the current review, we discuss findings related to the identification of normal chromaffin stem cells and CSCs, pathways involved in regulating the development of CSCs, and the importance of the stem cell niche in development and maintenance of CSCs in PCCs/PGLs. Additionally, we examine the development and feasibility of novel CSC-targeted therapeutic strategies aimed at eradicating especially recurrent and metastatic tumors.

Highlights

The adrenal gland is composed of two main tissue types that establish a bidirectional connection; the catecholamine-producing chromaffin cells in the medulla and the primarily steroid-producing cells in the cortex
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are generally slow growing neural crest-derived tumors comprised of chromaffin cells arising at intra- and extra-adrenal locations, respectively [3]
Investigations into the homeostatic role of adult stem cells within the normal adrenal medulla in comparison to the tumor state may help understand the contribution of Cancer stem cells (CSCs) to PCCs/PGLs, which might lead to new therapies targeting CSCs in recurrent and metastatic PCCs/PGLs

Summary

Introduction

The adrenal gland is composed of two main tissue types that establish a bidirectional connection; the catecholamine-producing chromaffin cells in the medulla and the primarily steroid-producing cells in the cortex. Nestin appears to be linked to essential stem cell functions including selfrenewal/proliferation, differentiation and migration [29], and is expressed in progenitors of both the adrenal cortex and medulla [30, 31].

Results

Conclusion