Tumorigenic and Metastatic Activity of Human Thyroid Cancer Stem Cells

The recent discovery of CSCs as responsible for tumor development and progression has considerable therapeutic implications, since current cytotoxic drugs have a limited efficacy on CSCs and need to be replaced by target therapies. For this reason, much research effort has been addressed to identify and isolate CSCs as well as to improve understanding of the molecular mechanisms that control oncogenic process and chemotherapy resistance. Thyroid carcinomas are the most frequently diagnosed endocrine malignancy with a global increasing incidence. Data obtained during PhD course in Immunopharmacology showed that thyroid cancer tissues derived from follicular, papillary or anaplastic subtypes contain a small population of ALDHhigh cells that can undergo self-renewal and be expanded indefinitely in vitro as thyrospheres. When orthotopically injected into the thyroid gland of immunocompromised mice, these ALDHhigh cells are tumorigenic and reproduce the phenotypic characteristics of the original tumors, including the aggressive features of undifferentiated thyroid carcinoma (UTC). The metastatic behavior of UTC is sustained by constitutive activation of Met and Akt. Consistently, the functional blockade of these molecules determined a complete abrogation of UTC spheres metastatic potential both in vitro and in vivo, indicating a promising effect for the treatment of aggressive thyroid cancer. In this context, a better knowledge of the genetic alterations involved in thyroid cancer pathogenesis may provide new insights for development and preclinical 2 validation of novel targeted therapies. Although RET/PTC1, BRAF(V600E) and mutant p53 affect thyroid cancers, the role of these genetic alterations in tumor initiation and progression is not well known. The aim of this study was to understand whether RET/PTC1, BRAF(V600E) and mutant p53 may be responsible for cancer initiation. For this reason, thyroid SCs (TSCs) have been isolated from goiters in order to transform them with lentiviral vectors coding for RET/PTC1, BRAF(V600E) or p53 mutant. It was noticed that normal cells, after exogenous expression of these oncogenes, showed an high degree of self-renewal and migration capacity. Moreover, in vivo results demonstrated that the same cells acquire the ability to initiate tumor in NOD/SCID mice and that the resultant xenografts possess the pattern of CK19 and Tg expression of PTC and UTC xenogratfs. Overall, these findings define a good model to identify the specific genetic alterations involved into thyroid carcinogenesis.