In thyroid cancer, calcification is mainly present in classical papillary thyroid carcinoma (PTC) and in medullary thyroid carcinoma (MTC), despite being described in benign lesions and in other subtypes of thyroid carcinomas. Thyroid calcifications are classified according to their diameter and location. At ultrasonography, microcalcifications appear as hyperechoic spots ≤ 1 mm in diameter and can be named as stromal calcification, bone formation, or psammoma bodies (PBs), whereas calcifications > 1 mm are macrocalcifications. The mechanism of their formation is still poorly understood. Microcalcifications are generally accepted as a reliable indicator of malignancy as they mostly represent PBs. In order to progress in terms of the understanding of the mechanisms behind calcification occurring in thyroid tumors in general, and in PTC in particular, we decided to use histopathology as the basis of the possible cellular and molecular mechanisms of calcification formation in thyroid cancer. We explored the involvement of molecules such as runt-related transcription factor-2 (Runx-2), osteonectin/secreted protein acidic and rich in cysteine (SPARC), alkaline phosphatase (ALP), bone sialoprotein (BSP), and osteopontin (OPN) in the formation of calcification. The present review offers a novel insight into the mechanisms underlying the development of calcification in thyroid cancer.

Classically, osteopontin (OPN) has been described as a secreted glycophosprotein. Indeed, most data concerning its physiological and pathological roles are mainly related to the secreted OPN (sOPN). However, there are several instances in which intracellular OPN (iOPN) has been described, presenting some specific roles in distinct experimental models, such as in the immune system, cancer cells, and neurological disorders. We herein aimed to highlight and discuss some of these secreted and intracellular roles of OPN and their putative clinical and biological impacts. Moreover, by consolidating data from the OPN protein database, we also analyzed the occurrence of signal peptide (SP) sequences and putative subcellular localization, especially concerning currently known OPN splicing variants (OPN-SV). Comprehending the roles of OPN in its distinct cellular and tissue environments may provide data regarding the additional applications of this protein as biomarkers and targets for therapeutic purposes, besides further describing its pleiotropic roles.

Osteopontin (OPN) is a matricellular phosphoglycoprotein overexpressed in several tumor types and can activate several aspects of cancer progression in solid and non-solid tumors. In the present review, the roles of OPN in mediating resistance to chemotherapy and radiotherapy and their main associated signaling pathways were summarized and discussed. Furthermore, it was detailed how OPN expression may be able to modulate resistance to these therapies by controlling epithelial cell plasticity, stemness potential and cell survival. Based on these data, the use of OPN and associated signaling was then proposed as potential molecular targets in order to sensitize resistant cells to main current therapeutic approaches. Finally, based on experimental evidence obtained by our group, the importance of investigating the specific roles OPN splicing isoforms have and how their properties may specifically control resistance to therapy was highlighted. These data elucidate a better understanding of how total OPN and their splicing isoforms, as well as their associated signaling, may contribute to main aspects of chemoresistance and radioresistance, such as those controlling cell survival, apoptosis, autophagy, stemness, epithelial cell plasticity and associated cell receptors.