Epithelial thyroid cancer (TC) is the most common endocrine malignancy, accounting for about 1% of all human tumors and representing the fifth most expected cancer in women. The majority of TC (90-95%) are well differentiated carcinomas (WDTC), mainly occurring as papillary or follicular histotypes, the incidence of which has been increasing over recent years. The prognosis of WDTC is largely favourable, but in some cases they can evolve and give rise to highly aggressive forms that do not respond to the currently available therapies, often with a fatal outcome.
Malignant cells rely on multiple nutrients to meet cellular bioenergetics and macromolecular synthesis demands of rapidly dividing cells. Although the role of glucose and glutamine in cancer metabolism is well understood, less is known about the relative contribution of acetate. A number of clinical studies of PET imaging documented an avid [11C]-acetate uptake in several cancer types. Moreover, recent high-profile reports evidenced that the cell capability of using acetate as alternative metabolic substrate plays a major part in the earlier stages of tumor development as well as in metastatization. Some proteins involved in acetate metabolism have been proven to exert oncogenic actions in different cancer types, and now are regarded as new potential therapeutic targets. Based on these lines of evidence, the present research proposal is aimed at investigating the role of acetate as nutritional source in thyroid carcinomas.
The information that might be acquired in this research would fill a major gap of knowledge concerning the acetate fates in thyroid carcinomas, whose importance shall be presumed by the well documented evidence that acetate metabolism plays a foremost part in many different types of cancer. Malignant cells living in the adverse microenvironment of tumor masses, characterized by hypoxia and low nutrient availability, are prompted to develop many adaptive features, such as genomic instability, altered cellular bioenergetics, resistance to apoptosis and increased motility. These changes contribute to tumor survival and progression but, at the same time, they may introduce drawbacks that can be exploited to create new approaches for cancer treatment. Highly stressed regions of tumors have been shown to select cells for apoptotic resistance, invasive behaviour, insensitivity to treatments and relapse. The growing evidence that these cells often become addicted to certain metabolic pathways has strongly prompted the evaluation of metabolic drivers as new potential therapeutic targets. The use of therapies specifically targeting the adaptive metabolism of TC cells inside central areas of the tumor masses could prove to be an effective regimen against hard-to-treat cancers, such as PDTC and ATC.