Human Medullary Thyroid Carcinoma: Initial Characterization and In Vitro Differentiation of Two New Cell Lines

Abstract

of the thyroid (MCT), a tumor of calcitonin (CT)\p=m-\secret-ing C cells, can display a variable malignant potential with poor prognosis linked to decreased cell differentiation. In vitro study of MCT has been hampered by the fact that few cell lines derived from this neoplasm have been available for study. Herein are reported the characteristics of two new lines derived from human MCT that are tumorigenic in athymic mice and do not secrete CT. After treatment with various concentrations of retinoic acid (a vitamin A derivative) and cyclic adenosine monophosphate, both lines exhibit the traits of more differentiated cells with a decrease in cellular proliferation and an increase in cytoplasmic CT content as shown by in situ immunoperoxidase staining. These cell lines should prove of great value in the study of the biology of MCT and the mechanisms underlying induced differentiation in this type of tumor.In 1959, Hazard et al1 proposed the designation of medullary carcino¬ ma of the thyroid (MCT) for a solid, nonfollicular tumor characterized by high amounts of stromal amyloid and a proclivity for lymph node métasta¬ ses. This neoplasm accounts for approximately 5% to 12% of all thy¬ roid tumors and is one component of the multiple endocrine neoplasia type 2 syndrome, which consists of tumors of the thyroid, adrenal medulla, and parathyroid. Two forms of this syn¬ drome are recognized, a sporadic, nonheritable type as well as a familial form that is inherited as an autosomal dominant trait. The natural history of treated MCT reveals it to be potential¬ ly aggressive, with a ten-year survival rate of 50% to 67%. The tumor's ulti¬ mate behavior is influenced by the type of initial treatment, anatomic location, and chronologic age at recur¬ rence.23Williams4 in 1966 suggested that MCT arose from the neural crestderived C cells of the thyroid, which synthesize and secrete the hypocalcé¬ mie substance calcitonin (CT). With the advent of radioimmunoassay, it became feasible to examine blood CT levels and utilize these as unique markers for detecting and monitoring disease activity. Following treatment, elevation in CT levels may signify disease recurrence, whereas a drop in CT levels may signal cure or a loss of the tumor's ability to secrete the hor¬ mone; this in turn is associated with a poorer prognosis.3·5 Once MCT metastasizes, it can exhibit aggressive behavior with a poor response to radi¬ ation therapy or chemotherapy. Since conventional therapies appear to have limited efficacy, alternative ap¬ proaches to treating disseminated MCT are needed.As a first approach to studying the biologic behavior of this neoplasm, accessible in vitro models are required. To date, only a limited num¬ ber of short-term cultured cell lines derived from human MCT have been reported.68 Moreover, long-term studies of cells derived from human MCT surgical specimens are ham¬ pered by instability in cell population as judged by time-dependent de¬ creases in medium CT concentra¬ tions.9 The most widely used MCT culture is the TT line fir...

Modified binding of proteins from calcitonin-negative tumor cells to the neuroendocrine-specific CANNTG motif of the calcitonin gene

“…Identification of the cell-specific component in the CT basal enhancer Once the elements of the cell-specific enhancer were mapped and autonomous motifs were identified, it was possible to determine which was inactivated in CT-negative cells. Starting with a fragment containing both E2 and Ets (nucleotides -965 to -920), I examined enhancer activity in the following cell lines: TT, a slowly-dividing (doubling time of 83 hours [14]) CTpositive MTC cell line; RO-D81, a rapidly-dividing (doubling time of 24 hours [15]) CT-negative MTC cell line; and HeLa, a CT-negative, non-neuroendocrine line. Fragment -965 to -920 (containing Ets and E2) enhanced transcription by 6 fold in UT cells, 5 fold in RO-D81 and 1.5 fold in HeLa (Figure 3).…”

Chronic Administration of Cyclosporine A Changes Expression of BDNF and TrkB in Rat Hippocampus and Midbrain

“…Treatment with RA induced neuronal differentiation of SH-SY5Y cells and enabled those to obtain a phenotype that is functionally and electrically similar to neurons [20]. To determine whether CsA treatment alters the cell viability in cultured RA-treated SH-SY5Y cells, morphological observations and LDH assays were performed after cells were treated with CsA for 24 h. No significant morphological alteration was observed in CsA-treated cells with 0-15 lg/ml compared with the control (Fig.…”

Prognostic Factors in Well-Differentiated Follicular-Derived Carcinoma and Medullary Thyroid Carcinoma

“…The tumor occurs in sporadic and familial forms, either alone or as a part of multiple endocrine neoplasia syndromes (MEN type IIA or type IIB). Up to 25% of medullary carcinoma cases are familial and detection of ret oncogene mutations are used for screening of these familial cases (1,3,5,101,102). The prognosis of medullary carcinoma is usually considered as intermediate between WDTC and anaplastic carcinoma.…”

“…From the clinical point of view, a majority of these tumors classified as welldifferentiated follicular-derived thyroid carcinomas (WDTC) are slow growing and show indolent biological behavior, whereas, a small proportion of tumors classified as anaplastic carcinoma are highly aggressive tumors and can lead to demise within matter of months after diagnosis (1,2). Medullary carcinoma of the thyroid is a totally separate entity of parafollicular-cell origin and is intriguing due to its association with multiple endocrine neoplasia syndrome (MEN); genetic testing is very important in early diagnosis (3)(4)(5). From the pathologist's perspective, the thyroid tumors can exhibit variable morphological patterns, which on few occasions can pose problems in diagnostic interpretation (1,6,7).…”