The urokinase plasminogen activator (uPA) system (uPAS) consists of the uPA, its cognate receptor (uPAR) and two specific inhibitors, the plasminogen activator inhibitor 1 (PAI-1) and 2 (PAI-2). The uPA converts the proenzyme plasminogen in the serine protease plasmin, involved in a number of physiopathological processes requiring basement membrane (BM) and/or extracellular matrix (ECM) remodelling, including tumor progression and metastasis. Data accumulated over the past years have made increasingly clear that the uPAS has a multifunctional task in the neoplastic evolution, affecting tumor angiogenesis, malignant cell proliferation, adhesion and migration, intravasation and growth at the metastatic site. In agreement with their role in cancer progression and metastasis, an increased expression of uPA, uPAR, and PAI-1 has been documented in several malignant tumors, and a positive correlation between the levels of one or more uPAS members and a poor prognosis has been frequently reported. This is particularly evident in breast cancer, for which uPA has been demonstrated to be the most potent independent prognostic factor described to date. The involvement of the uPAS in cancer progression identifies its components as suitable targets for anti-cancer therapy. Several therapeutical approaches aimed at inhibiting the uPA/uPAR functions have been shown to possess anti-tumor effects in xenograft models, including selective inhibitors of uPA activity, antagonist peptides, monoclonal antibodies able to prevent uPA binding to uPAR and gene therapy techniques silencing uPA/uPAR expression. All these strategies, however, although promising, need definitive confirmation in humans as, up to now, only few uPA inhibitors entered clinical trial.

Implantation and early embryo development are finely regulated processes in which several molecules are involved. Evidence that thyroid hormones (TH: T₄ and T₃) might be part of this machinery is emerging. An increased demand for TH occurs during gestation, and any alteration in maternal thyroid physiology has significant implications for both maternal and fetal health. Not only overt but also subclinical hypothyroidism is associated with infertility as well as with obstetric complications, including disruptions and disorders of pregnancy, labor, delivery, and troubles in early neonatal life. We searched the PubMed and Google Scholar databases for articles related to TH action on ovary, endometrium, trophoblast maturation and embryo implantation. In addition, articles on the regulation of TH activity at cellular level have been reviewed. The findings are hereby summarized and critically discussed. TH have been shown to influence endometrial, ovarian and placental physiology. TH receptors (TR) and thyrotropin (thyroid-stimulating hormone: TSH) receptors (TSHR) are widely expressed in the feto-maternal unit during implantation, and both the endometrium and the trophoblast might be influenced by TH either directly or through TH effects on the synthesis and activity of implantation-mediating molecules. Interestingly, due to the multiplicity of mechanisms involved in TH action (e.g. differential expression of TR isoforms, heterodimeric receptor partners, interacting cellular proteins, and regulating enzymes), the TH concentration in blood is not always predictive of their cellular availability and activity at both genomic and nongenomic level. In addition to the known role of TH on the hormonal milieu of the ovarian follicle cycle, which is essential for a woman's fertility, evidence is emerging on the importance of TH signaling during implantation and early pregnancy. Based on recent observations, a local action of TH on female reproductive organs and the embryo during implantation appears to be crucial for a successful pregnancy. Furthermore, an imbalance in the spatio-temporal expression of factors involved in TH activity might induce early arrest of pregnancy in women considered as euthyroid, based on their hormonal blood concentration. In conclusion, alterations of the highly regulated local activity of TH may play a crucial, previously underestimated, role in early pregnancy and pregnancy loss. Further studies elucidating this topic should be encouraged.

The present review deals with the functional roles of iodine and its metabolism. The main biological function of iodine concerns its role in the biosynthesis of thyroid hormones (THs) by the thyroid gland. In addition, however, further biological roles of iodine have emerged. Precisely, due to its significant action as scavenger of reactive oxygen species (ROS), iodine is thought to represent one of the oldest antioxidants in living organisms. Moreover, iodine oxidation to hypoiodite (IO⁻) has been shown to possess strong bactericidal as well as antiviral and antifungal activity. Finally, and importantly, iodine has been demonstrated to exert antineoplastic effects in human cancer cell lines. Thus, iodine, through the action of different tissue-specific peroxidases, may serve different evolutionarily conserved physiological functions that, beyond TH biosynthesis, encompass antioxidant activity and defense against pathogens and cancer progression.

Over the last few years, a great advance has been made in the comprehension of the molecular pathogenesis underlying thyroid cancer progression, particularly for the papillary thyroid cancer (PTC), which represents the most common thyroid malignancy. Putative cancer driver mutations have been identified in more than 98% of PTC, and a new PTC classification into molecular subtypes has been proposed in order to resolve clinical uncertainties still present in the clinical management of patients. Additionally, the prognostic stratification systems have been profoundly modified over the last decade, with a view to refine patients’ staging and being able to choose a clinical approach tailored on single patient’s needs. Here, we will briefly discuss the recent changes in the clinical management of thyroid nodules, and review the current staging systems of thyroid cancer patients by analyzing promising clinicopathological features (i.e., gender, thyroid auto-immunity, multifocality, PTC histological variants, and vascular invasion) as well as new molecular markers (i.e., BRAF/TERT promoter mutations, miRNAs, and components of the plasminogen activating system) potentially capable of ameliorating the prognosis of PTC patients.