AXL Is a Novel Predictive Factor and Therapeutic Target for Radioactive Iodine Refractory Thyroid Cancer.

Francesca Collina,Gabriella Aquino,Renato Franco,Luciano Pezzullo,Monica Cantile,Maria Grazia Chiofalo,Giuseppina Liguori,Elvira La Mantia,Lucia La Sala,Laura Arenare,Giancarlo Vecchio,Nunzia Simona Losito,Federica Liotti,Rosa Marina Melillo,Nella Prevete,Francesca Di Gennaro,Gerardo Botti

doi:10.3390/cancers11060785

Abstract

Papillary thyroid carcinomas (PTCs) have an excellent prognosis, but a fraction of them show aggressive behavior, becoming radioiodine (RAI)-resistant and/or metastatic. AXL (Anexelekto) is a tyrosine kinase receptor regulating viability, invasiveness and chemoresistance in various human cancers, including PTCs. Here, we analyze the role of AXL in PTC prognosis and as a marker of RAI refractoriness. Immunohistochemistry was used to assess AXL positivity in a cohort of human PTC samples. Normal and cancerous thyroid cell lines were used in vitro for signaling, survival and RAI uptake evaluations. 38.2% of human PTCs displayed high expression of AXL that positively correlated with RAI-refractoriness and disease persistence or recurrence, especially when combined with v-raf murine sarcoma viral oncogene homolog B(BRAF) V600E mutation. In human PTC samples, AXL expression correlated with V-akt murine thymoma viral oncogene homolog 1 (AKT1) and p65 nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation levels. Consistently, AXL stimulation with its ligand growth arrest-specific gene 6 (GAS6) increased AKT1- and p65 NF-kB-phosphorylation and promoted survival of thyroid cancer cell lines in culture. Enforced expression or activation of AXL in normal rat thyroid cells significantly reduced the expression of the sodium/iodide symporter (NIS) and the radioiodine uptake. These data indicate that AXL expression levels could be used as predictor of RAI refractoriness and as a possible novel therapeutic target of RAI resistant PTCs.

Highlights

Thyroid carcinoma (TC) that derives from epithelial follicular cells represents the most common endocrine malignancy, with an increasing incidence all over the world [1]
To evaluate the distribution of AXL in human Papillary thyroid carcinomas (PTCs) and in normal thyroid tissues, we analyzed its expression in a panel of 110 PTC samples and in 5 normal thyroids by immunohistochemistry (IHC)
AXL expression was considered evaluable in 102/110 PTCs Tissue MicroArray (TMA) cores

Summary

Introduction

Thyroid carcinoma (TC) that derives from epithelial follicular cells represents the most common endocrine malignancy, with an increasing incidence all over the world [1]. Surgery followed by thyroid hormone therapy and selective use of radioactive iodine (RAI) remains the most effective therapeutic option for PTCs. 20–30% of PTC patients experience recurrence/persistence and/or metastasis with subsequent increased mortality [1]. 5% of metastatic PTCs lose thyroid-differentiating features, the most important of which is the expression of the sodium/iodide symporter (NIS), responsible for iodine uptake. This event allows PTCs to become radioactive iodine-refractory (RAI-R) and significantly reduces the survival rate for these tumors [1].

Methods

Results

Conclusion