Abstract
Thyroid cancer (TC) is the most common endocrine tumor. Although the majority of TCs show good prognoses, a minor proportion are aggressive and refractory to conventional therapies. So far, the molecular mechanisms underlying TC pathogenesis are incompletely understood. Evidence suggests that TC cells and their precursors are responsive to insulin and insulin-like growth factors (IGFs), and often overexpress receptors for insulin (IR) and IGF-1 (IGF-1R). IR exists in two isoforms, namely IR-A and IR-B. The first binds insulin and IGF-2, unlike IR-B, which only binds insulin. IR-A is preferentially expressed in prenatal life and contributes to development through IGF-2 action. Aggressive TC overexpresses IR-A, IGF-2, and IGF-1R. The over-activation of IR-A/IGF-2 loop in TC is associated with stem-like features and refractoriness to some targeted therapies. Importantly, both IR isoforms crosstalk with IGF-1R, giving rise to the formation of hybrids receptors (HR-A or HR-B). Other interactions have been demonstrated with other molecules such as the non-integrin collagen receptor, discoidin domain receptor 1 (DDR1), and the receptor for the hepatocyte growth factor (HGF), Met. These functional networks provide mechanisms for IR signaling diversification, which may also exert a role in TC stem cell biology, thereby contributing to TC initiation and progression. This review focuses on the molecular mechanisms by which deregulated IR isoforms and their crosstalk with other molecules and signaling pathways in TC cells and their precursors may contribute to thyroid carcinogenesis, progression, and resistance to conventional treatments. We also highlight how targeting these alterations starting from TC progenitors cells may represent new therapeutic strategies to improve the clinical management of advanced TCs.
Highlights
Thyroid cancer (TC) is the tumor with the fastest increasing incidence in the western world [1,2,3]
In vivo experiments in mice harboring BRAF mutation have shown that thyroid-stimulating hormone (TSH) cooperates with oncogenic BRAF to induce thyroid tumorigenesis, partially via cyclic adenosine monophosphate [48]
mitogen-activated protein kinase (MAPK) is activated as a consequence of aberrant expression of proto-oncogenes such as Ret, Neurotrophic tropomyosin receptor kinase (NTRK), Rat sarcoma (RAS) and BRAF
Summary
Thyroid cancer (TC) is the tumor with the fastest increasing incidence in the western world [1,2,3]. Evidence from the literature suggests that TCs resistant to RAI are dependent on the activation of specific signaling pathways for the maintenance of their malignant phenotype [13] These tumors may only be responsive to therapies targeting the molecular signals important for their growth and survival. Besides the formation of IR/IGF-1R hybrid receptors, the functional crosstalk between IR-A and other tyrosine kinase receptors such as the non-integrin collagen receptor, discoidin domain receptor 1 (DDR1), the receptor for the Hepatocyte Growth Factor (HGF) Met, and other still unknown partners might add more complexity to the contribution of IR-A in TC pathogenesis Based on these experimental observations indicating that deregulation of survival pathways and tyrosine kinase receptors-dependent signaling may play an important role in TC development and progression, multikinase inhibitors (MKI) (i.e., sorafenib and lenvatinib) have been approved for use in treatment [11,23]. Targeting the overactivated IR-A/IGF-2 loop could sensitize stem-like cells to classical therapies and reduce relapse rates for the most aggressive TC histotypes
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