Double Stem cell Despite the overall low mortality rate of thyroid cancer, poorly differentiated thyroid carcinoma and ATC rank among the most deadly of all human cancers. This high mortality rate is partially due to the high rate of resistance to conventional cancer therapies.
According to the classic multi step carcinogenics model, poorly differentiated thyroid carcinomas derive from well-differentiated ones through the sequential accumulation of genetic alterations.
Indeed, occurrence of novel mutations into well-differentiated thyroid carcinomas results in a deregulation of several signaling pathways and, as a consequence, a differentiation process and a marked epithelial-to-hymeneal transition.
This hypothesis is supported by the common observation that in many poorly differentiated and ATC specimens, well-differentiated thyroid cancer of funicular origin may also be present.
Moreover, further evidence does not support a multi-step model of thyroid cancer: first, mature thyroid funicular cells undergo a limited number of replications (eight to ten during the lifespan), thereby reducing the possibility of accumulating mutations for transformation; second, some genetic alterations that are present in well-differentiated thyroid carcinomas, such as RET/PTC and the PAX8/PPAR-γ rearrangements, are not found in poorly differentiated thyroid carcinomas.
However, novel evidence is emerging that cancer cells within a given tumor are not homogeneous and support a stem cell model for thyroid carcinogens and cancer progression.
The cancer stem cell model implies a hierarchical organization of cancer cells and that only a subset of cancer cells can self-renew, giving rise to progenitor cells that may drive tumor growth.
These cells are also believed to give rise to poorly differentiated thyroid carcinomas. Cancer stem cells are believed to be the driving force of tumors as they posses the ability both to undergo self-renewal and to differentiate into various cancer cell types.
In this view, they may also play a major role in metastasis and resistance to chemo- and radio-therapy.
Cancer stem cells have been found in several solid tumors including thyroid cancer and it is reasonable to suppose that current therapeutics may not effectively target thyroid cancer stem cells in poorly differentiated thyroid carcinomas.