Cancer Stem Cells in Pheochromocytoma and Paraganglioma

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.

Ultrasound-Targeted Microbubble Destruction-Mediated Downregulation of EZH2 Inhibits Stemness and Epithelial-Mesenchymal Transition of Liver Cancer Stem Cells

“…CSCs, with the biological characteristics of self-renewal, replication, and high tumorigenicity, are considered to be related to the occurrence, development, recurrence, metastasis and drug resistance of malignant tumors. 24,25 Some characteristic surface antigens have been found present on CSCs, such as CD13, CD44, and CD133. 26,27 It was reported that CD133 was widely expressed in leukemia, liver cancer, lung cancer, prostate cancer and other CSCs, and could be used to identify and isolate a variety of CSCs including liver CSCs.…”

Hypoxia pathway proteins regulate the synthesis and release of epinephrine in the mouse adrenal gland

“…In the physiological sympathoadrenal setting, pVHL has been shown to be essential during development and it is required by the peripheral oxygen-sensing system to ensure survival under hypoxic conditions [39]. Loss-of-function mutations in the VHL gene or gain-of-function mutations in HIF2α have been associated with the development of pheochromocytoma and paraganglioma [40]. However, this HIF-subunit is not essential for the development and functionality of the adrenal medulla, as mice deficient for HIF2α in THpositive medullary cells display no functional abnormalities [41].…”

HIF-Prolyl Hydroxylase Domain Proteins (PHDs) in Cancer—Potential Targets for Anti-Tumor Therapy?

“…CSCs have also been suggested as potential tumor therapy targets in PCC and PGL [ 154 ], and it is not surprising that cancer cells from cluster 1 pseudohypoxia-related tumors express CSC markers [ 155 ]. Targeting CSCs via surface markers or by inhibiting developmental stem cell pathways has been used in the clinic for the treatment of other tumors, such as in the lung [ 156 ], and given their promising outcome, CSC targeting might prove useful, even in PCCs and PGLs.…”