Desensitization in Normal and Neoplastic Human Thyroid Cell Lines

Abstract

Abstract. Because some papillary thyroid cancers continue to grow when thyroid-stimulating hormone (TSH) levels are suppressed, we questioned whether desensitization (i.e., a decreased cAMP response to repeat stimulation with TSH) occurs in normal and neoplastic thyroid tissue. If desensitization does occur, is it similar or different in these human thyroid cells? Normal and papillary thyroid cancer cells from the same patient were cultured as we have previously described. Normal and neoplastic thyroid tissues responded to TSH (0.01-10.0 mU/ml) by increasing cAMP production and growth in a dose-dependent manner. In normal cells there was an 11-fold mean increase in cAMP production at 4 hours, and all thyroid cultures responded. In neoplastic cells cAMP production increased from 1.5-fold to 3.0-fold with a mean 2.0-fold increase at 4 hours. In normal thyroid cells the cAMP response to a second TSH stimulus (desensitization) decreased up to 75% (range 25-75%), and desensitization occurred in all normal thyroid cell cultures. In neoplastic thyroid cells, however, the cAMP response to a second TSH stimulus decreased up to 17% (range 0 -17%); and desensitization occurred in only two of the five neoplastic thyroid cell cultures. Thus when normal thyroid and neoplastic cells from the same patients were studied, greater desensitization occurred in the normal cells (75% vs. 17%). These studies document that there is greater desensitization in normal tissue than in neoplastic thyroid tissue, which may account for the increased growth of thyroid neoplasms in the presence of ever-changing low levels of TSH.

Growth Regulation of Thyroid and Thyroid Tumors in Humans

“…Our investigations using normal human thyrocytes in culture with steady TSH stimulation using 0.1 IE/ml medium for 3 days demonstrated an increase in basal cAMP production in normal human thyrocytes, from 0.52 to 1.55 pmol cAMP/2 ϫ 10 5 cells/2 hr, and a decrease in maximal TSH stimulatable cAMP production in these cells, from 26.0 to 6.2 pmol cAMP/2 ϫ 10 5 cells/2 hr. This desensitization of normal human thyrocytes after incubation in TSH-enriched medium with unphysiologically high TSH concentrations was also demonstrated by Al-Sobhi et al [41] with a The increased response to TSH and G-protein-dependent AC stimulation [by Gpp(NH)p] was present in most benign adenomas independent of enhanced or decreased iodine uptake ("hot nodule" and "cold nodule"), which may be interpreted as increased TSH sensitivity in respect to functional and growth activation. The higher basal AC activity in tissues from differentiated carcinomas was interpreted as resulting from increased basal cell growth activity (which is controversial).…”

“…Finally, the question arose whether serum TSH levels continuously elevated above normal may induce downregulation of the TSH receptor or its second messenger system, resulting in timelimited TSH effectiveness [41]. The latter phenomen of TSH receptor downregulation or second messenger downregulation, however, questions, the need for TSH suppressive therapy in patients after operation for differentiated thyroid tumors.…”

Establishment and characterization of OCUT‐1, an undifferentiated thyroid cancer cell line expressing high level of telomerase

“…Several differences between DTC and UTC have also been demonstrated using molecular biologic methods. Recently, detailed cellular studies using cultured cell lines have revealed several abnormal characteristics that may be responsible for the aggressive growth of UTC, such as the acquisition of independence from thyroid-stimulating hormone (TSH) regulation [4], production of cytokines or growth factors [5], loss of intercellular communication [6], and gene alteration [7][8][9]. Still the mechanism of cellular aggressiveness in UTC is not fully understood.…”