Editorial: anaplastic carcinoma of the thyroid--will aurora B light a path for treatment?

Anaplastic (undifferentiated) thyroid carcinoma is one of the most aggressive malignancies known to humans. It carries an almost uniformly fatal prognosis and, despite accounting for only 1.6% of thyroid malignancies in the United States, is responsible for more than half of all deaths attributed to thyroid cancer (1–3). Worldwide, anaplastic carcinoma constitutes 1–7% of all thyroid cancer cases (4). This disease typically affects older adults, with some female predominance. Most patients present with a rapidly growing neck mass often associated with dysphagia, dyspnea, and vocal cord paralysis caused by widespread local invasion. Almost half of the patients have distant metastasis at presentation, and in most of the remaining cases complete surgical resection is not possible because of advanced local disease. A combination of local radiation and aggressive systemic chemotherapy is the currently recommended treatment modality; unfortunately, it has only modest response rates resulting in a median survival of 3–9 months in most series (5). In the face of this dismal prognosis, novel therapeutic approaches are essential. Their development, however, is dependent to a large extent on the better understanding of the pathogenesis and molecular basis for the initiation and progression of this cancer. Anaplastic carcinoma arises from thyroid follicular cells and shows morphological features of a highly malignant, undifferentiated neoplasm. The tumor is characterized by sheets of markedly atypical cells with frequent multinucleation; large, bizarre nuclei; and multiple atypical mitotic figures; it reveals no follicular structures, colloid formation, or other features of thyroid differentiation. Although the pathogenesis is not entirely understood, several lines of evidence suggest that anaplastic carcinomas develop from preexisting, well-differentiated thyroid carcinomas of papillary or follicular type (6). The clinical evidence supporting this progression is that many patients with anaplastic carcinoma have a long-standing history of thyroid cancer or history of a previous incompletely resected thyroid tumor. Pathological evidence is based on the presence of coexisting foci of well-differentiated thyroid cancer in up to 90% of anaplastic carcinomas. Finally, molecular evidence has recently emerged demonstrating that identical mutations or similar patterns of chromosomal gains and losses are detected in well-differentiated and anaplastic tumor components, implying a common origin (7–9). Anaplastic carcinomas are characterized by complex chromosomal alterations, a high rate of aneuploidy, and profound chromosome instability as evidenced by numerous chromosomal imbalances resulting from gains and losses of entire chromosomes or discrete chromosomal loci (10, 11). Two general groups of specific genetic mutations have been identified in these tumors. One group represents genetic alterations that are found in both anaplastic and welldifferentiated carcinomas, such as BRAF and RAS point mutations (7, 12). The fact that these mutations have been documented in well-differentiated and anaplastic cancers suggests that they are early events in thyroid tumorigenesis and are insufficient alone to lead to tumor dedifferentiation. The second group includes p53 and possibly CTNNB1 ( catenin) mutations, which are frequently found in anaplastic carcinomas but not in well-differentiated cancers (13, 14), suggesting that these mutations may be directly involved in tumor dedifferentiation. The p53 tumor suppressor gene, which is inactivated in more than half of all anaplastic carcinomas, has been considered as a candidate for therapeutic intervention. Indeed, the reintroduction of wild-type p53 into anaplastic carcinoma cell lines reduces cell proliferation, restores some of the differentiation qualities, and increases tumor sensitivity to certain chemotherapeutic agents (15–17). The experimental attempts for adenovirus-mediated p53 gene therapy showed some promise in controlling anaplastic carcinoma cell growth (18), although this therapeutic modality has not been further tested in the clinical setting. In this issue of the JCEM, the paper by Sorrentino et al. (19) identifies Aurora B as an important protein in the progression of anaplastic thyroid carcinomas and as an excellent candidate for target treatment. The Aurora kinases are key regulators of mitotic cell division (20, 21). In mammalian cells, this subfamily of serine/threonine kinases consists of three members: Aurora A, B, and C. They share a highly homologous kinase domain but differ in their N-terminal regions. The Aurora kinases exhibit unique tissue expression patterns and show distinct localization and expression profiles during the cell cycle. Aurora B regulates several crucial mitotic activities including chromosome alignment, segregation, and cytokinesis (cytoplasmic division after nuclear division) (22). To fulfill these functions, the protein undergoes localization changes as mitosis progresses. Specifically, Aurora B becomes associated with centromeres/kinetochores (the sites of chromosome attachment to microtubules) during prometaphase, redistributes to the spindle midzone during anaphase, and eventually localizes to the midbody between dividing cells. Deregulation of Aurora B kinase activity is associated with multiple defects in the mitotic machinery. Aurora B inactivation in vitro results in disruption of proper chromosome attachment to microtubules that affects the accuracy of chromosomal segregation into daughter cells. In mammalian cells, overexpression of the protein leads to chromosome instability and cell aneuploidy primarily through an increase in phosphorylation of histone H3 and subsequent disruption of chromosome segregation and chroJCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community. 0021-972X/05/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 90(2):1243–1245 Printed in U.S.A. Copyright © 2005 by The Endocrine Society doi: 10.1210/jc.2004-2478