Endocrine Abstracts (2009) 20 S17.3

Thyroid: stem cells: normal development and tumorigenesis

Michael Derwahl

Department of Medicine, St Hedwig Kliniken and Charite, University of Berlin, Berlin, Germany.

There is some evidence from different studies that (1) stem cells reside in thyroid tissue (as in all other tissues) for life-time of the organism, (2) stem cells and their progeny are under the control of niches that limit proliferation of these undifferentiated cells, (3) induction of apoptosis and (excessive) growth stimulation can overcome strict niche control, (4) under these conditions actively cycling, more or less differentiated progenitor may grow faster than the surrounding differentiated thyrocytes. Based on this evidence, epidemiological data, and the general concept of stem cells as a source of benign and malignant tumours a role of stem cells and their progeny in the pathogenesis of benign thyroid nodules (A) and thyroid cancer (B) is hypothesised: (A) Population studies have demonstrated that nodular transformation is increasing with age whereas the goitre size is decreasing. Throughout the aging thyroid gland, adult stem cells are detectable that maintain the capacity of proliferation and differentiation. Experimental studies revealed that growth factors, their related receptors and growth-related signalling peptides are highly expressed or even overexpressed in thyroid nodules and nodular goitres. Some of the growth factors are potent stimulators of thyroid stem cell growth. The proliferation of quiescent stem cells is controlled by signals from putative niche cells. In vitro, malnutrition can limit or even overcome the control which results in an outgrowth of stem cells as thyro-spheres. Histological and immunohistochemical studies demonstrated hypofunction, destruction and necrosis of normal thyroid tissue in goitre tissues, conditions that may be equivalent to in vivo focal malnutrition thereby affecting the control of niches on thyroid cell growth in vivo. In addition, there is some experimental evidence that apoptosis of thyrocytes is a main factor of cell loss during goitre formation. Apoptosis of thyrocytes is, however, a prerequisite for thyro-sphere formation and therefore the proliferation of stem and progenitor cells in vitro. Thus, the short but intense stimulation of stem cells by growth factors in vitro may correspond to processes of nodular transformation in vivo that last for months, years or even decades. During this time, some cells may additionally accomplish molecular aberrations that provide a second growth advantage, for example ras mutations in few non-functioning thyroid nodules. (B) Malignant transformation and in turn thyroid carcinogenesis may occur by mutagenesis of more or less differentiated (early) stem/progenitor cells with a high proliferative capacity. Thus, the stem cell hypothesis fits well in with the known genetic aberrations in thyroid cancers but is contradictory to the concept of rarely dividing normal thyrocytes as the origin of thyroid carcinomas.

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