The Molecular Landscape of Hürthle Cell Thyroid Cancer Is Associated with Altered Mitochondrial Function-A Comprehensive Review

Abstract

Hürthle cell thyroid carcinoma (HTC) accounts for 3-5% of all thyroid malignancies. Widely invasive HTC is characterized by poor prognosis and limited responsiveness to standard therapy with radioiodine. The molecular landscape of HTC is significantly different from the genetic signature seen in other forms of thyroid cancer. We performed a comprehensive literature review on the association between the molecular features of HTC and cancer metabolism. We searched the Pubmed, Embase, and Medline databases for clinical and translational studies published between 1980 and 2020 in English, coupling "HTC" with the following keywords: "genomic analysis", "mutations", "exome sequencing", "molecular", "mitochondria", "metabolism", "oxidative phosphorylation", "glycolysis", "oxidative stress", "reactive oxygen species", and "oncogenes". HTC is characterized by frequent complex I mitochondrial DNA mutations as early clonal events. This genetic signature is associated with the abundance of malfunctioning mitochondria in cancer cells. HTC relies predominantly on aerobic glycolysis as a source of energy production, as oxidative phosphorylation-related genes are downregulated. The enhanced glucose utilization by HTC is used for diagnostic purposes in the clinical setting for the detection of metastases by fluorodeoxyglucose positron emission tomography (FGD-PET/CT) imaging. A comprehensive metabolomic profiling of HTC in association with its molecular landscape might be necessary for the implementation of tumor-specific therapeutic approaches.

Keywords: Hürthle cell; metabolism; mitochondria; oncogenes; oxidative phosphorylation; thyroid cancer.

Figure 1

Diagram representing the role of mitochondrial mutations, near haploid genome and somatic mutations in Hürthle cell thyroid cancer development. Mitochondrial mutations, leading to the inactivation of complex I of the respiratory chain, are associated with the decreased OXPHOS and increased glycolysis. Near haploid genome, associated with the inactivation of several tumor suppressors, leads to the overactivation of PI3K/AKT/mTOR signaling pathway, enhancing cell proliferation and glycolysis. Somatic mutations in nuclear DNA are associated with abnormal protein translation, overactivation of PI3K/AKT/mTOR and RAS/RAF/MEK/ERK signaling pathways and altered cytoskeleton, leading to enhanced proliferation, resistance to apoptosis, and metastatic potential.

Figure 2

Model depicting the drug targets in Hürthle cell thyroid cancer that are being exploited in the ongoing clinical trials. (A) The inhibitory molecules acting upon various oncogenic pathways are shown in the green box. (B) Diagrammatic representation of the mechanism of action of various immunotherapy agents currently employed in clinical trials for Hürthle cell thyroid cancer.