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Mechanisms for increased adenylate cyclase responsiveness to TSH in neoplastic human thyroid tissue

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Abstract

We have previously examined TSH receptors and adenylate cyclase (AC) activity in normal and neoplastic human thyroid tissue. We found only minor differences in the affinity and capacity of the TSH receptor between the normal and neoplastic tissue, and yet there was a five-fold greater AC responsiveness in the neoplastic thyroid tissue. To determine why there was a greater AC responsiveness to TSH in most differentiated thyroid neoplasms, we probed the receptor-cyclase unit which consists of at least 3 classes of components: the receptor (R), the guanyl nucleotide regulatory unit (G), and the catalytic unit (C). The G unit binds GTP and forms a link between R and C. We studied the effects of TSH, Gpp(NH)p (a non-hydrolyzable GTP analog) and sodium fluoride (NaF) (which act on G), and forskolin (which acts on C) on the receptor-cyclase unit. The results of these studies demonstrate that: (a) there was a greater AC response to TSH (5/6), Gpp(NH)p (3/5), and NaF (5/6) in T than N; (b) the AC response to forskolin was comparable in T and N in 5/6 patients and higher in T in 1 patient; (c) Gpp(NH)p, NaF, and forskolin all had an additive or synergistic effect when added to TSH in both N and T; (d) NaF and forskolin also had an additive or synergistic effect on AC, whereas Gpp(NH)p and forskolin together in N and Gpp(NH)p and NaF together in T caused a considerably less than additive AC response.

These studies demonstrate that Gpp(NH)p, NaF, and forskolin at optimal concentrations have an additive effect on the AC response to TSH in both normal and neoplastic thyroid tissue and that the altered AC responsiveness to TSH in most, but not all, benign thyroid tumors and differentiated thyroid carcinomas appears to be secondary to an altered guanyl nucleotide regulatory protein.

Résumé

L'auteur a apprécié lors d'études antérieures l'activité des récepteurs T.S.H. et de l'adénylatecyclase (A.C.) au niveau du tissu thyroïdien humain normal et néoplasique. Il a constaté des différences mineures de l'activité des récepteurs T.S.H. entre le tissu thyroïdien normal et le tissu néoplasique mais une activité de l'adénylate-cyclase cinq fois plus grande au niveau du tissu thyroïdien néoplasique. Pour déterminer les causes de ce phénomène particulier, l'unité récepteur-cyclase a été explorée, cette unité comportant 3 éléments constitutifs: l'élément récepteur (R), l'élément régulateur du guanyle-nucléotide (G) et l'élément catalytique (C). L'élément G lie l'élément R et l'élément C.

Les effets sur l'unité récepteur-cyclase de la T.S.H., du Gpp(NH)p (un GTP non hydrolysable), du fluoride de sodium (qui agit sur G) et de la forskoline (qui agit sur C) ont été étudiés. Les résultats de ces études démontrent que:

  1. 1.)

    Il existe une réponse de l'adénylate cyclase plus grande sous l'action de la T.S.H. (5/6), du Gpp (NH) p (3/5) et du NaF (5/6) en présence du parenchyme tumoral.

  2. 2.)

    La réponse à la forskoline a été identique pour le parenchyme normal et le parenchyme tumoral pour 5/6 des patients, sauf dans un cas où elle a été plus élevée.

  3. 3.)

    Les Gpp(NH)p, NaF et forskoline ont tous un effet additif et synergique quand ils sont ajoutés à la T.S.H., qu'il s'agisse de tissu normal ou de tissu tumoral.

  4. 4.)

    Le NaF et la forskoline ont aussi un effet additif ou synergique sur l'adénylate cyclase, alors que le Gpp(NH)p et la forskoline ensemble sur le tissu normal ainsi que le Gpp(NH)p et le NaF ensemble sur le tissu tumoral ont un effet additif considérablement moins marqué que sur l'adénylate cyclase.

Ces études démontrent que le Gpp(NH)p, le NaF et la forskoline à concentration maximum exercent un effet additif sur la réponse de l'adénylate cyclase à la T.S.H. à la fois pour le parenchyme normal et le parenchyme tumoral. La réponse particulière de l'adénylate cyclase à la T.S.H. dans la majorité des cas de tumeurs thyroïdiennes bénignes et de cancers thyroïdiens différenciés apparaît comme secondaire à une modification du processus régulateur guanyle-nucléotide.

Resumen

Numerosos estudios clínicos han demostrado que el tratamiento de pacientes con tumores benignos de tiroides con hormona tiroidea resulta en disminución significativa del tamaño del tumor en alrededor de dos tercios de los pacientes. Otros estudios han demostrado que algunos cánceres diferenciados de la tiroides responden al tratamiento con hormona tiroidea, y que la recurrencia del cáncer se hace menos frecuente y la supervivencia mejor. Soporte adicional que sugiere una relatión importante entre niveles aumentados de TSH y crecimiento del cáncer tiroideo es la elevada tasa de mortalidad por cáncer de tiroides observada en regiones de bocio endémico. Estudios de receptor de TSH y de adenilato ciclasa (AC), y estudios metabolicos, también sustenta el papel importante de TSH en relación al crecimiento y función de las neoplasias tiroideas. Los tumores benignos y los cánceres diferenciados de tiroides poseen receptores de TSH, y estos tumores exhiben incrementada actividad de AC en respuesta a TSH.

Nuestro grupo ha examinado previamente los receptores de TSH y la actividad de la adenilato ciclasa (AC) en tejido tiroideo humano normal y neoplásico. Encontramos apenas pequeñas diferencias en la afinidad y capacidad del receptor de TSH entre el tejido normal y el tejido neoplásico, y sin embargo se presentó un grado de respuesta de la AC cinco veces mayor en el tejido neoplásico tiroideo. Con el objeto de determinar por qué habría mayor grado de respuesta de la AC a TSH en la mayoría de los neoplasmas diferenciados de la tiroides, exploramos la unidad receptor-ciclasa, la cual consiste de por lo menos tres clases de componentes: el receptor (R), la unidad regulatoria guanil nucleótido (G) y la unidad catalítica (C). La unidad G liga GTP y forma una unión entre R y C. Estudiamos los efectos de TSH, Gpp(NH)p (un análogo no hidrolizable de GTP), fluoruro sódico (NaF), el cual actúa sobre G, y forskolina, la cual actúa sobre C, en la unidad receptor-ciclasa. Los resultados de estos estudios demuestran que: (1) hubo una mayor respuesta de la AC a TSH (5/6), Gpp(NH)p (3/5) y NaF (5/6) en T que en N; (2) la respuesta de la AC a la forskalina fue comparable en T y N en 5/6 pacientes y más alta en T en 1 paciente; (3) Gpp(NH)p, NaF y forskolina presentaron un efecto aditivo o sinergístico cuando fueron añadidos a TSH tanto en N como T; (4) NaF y forskolina también presentaron un efecto aditivo o sinergístico sobre AC, en tanto que Gpp(NH)p y forskolina juntas en N, y Gpp(NH)p y NaF juntas en T causaron un efecto considerablemente menor que la respuesta aditiva de AC.

Estos estudios demuestran que Gpp(NH)p, NaF y forskolina a concentraciones óptimas poseen un efecto aditivo sobre la respuesta de AC a TSH tanto en el tejido tiroideo normal como en el neoplásico, y que la alteración en el grado de respuesta de AC a TSH en la mayoría, pero no en la totalidad, de los tumores tiroideos benignos y de los carcinomas diferenciados de tiroides parece ser secundario a una proteína regulatoria guanil nucleótico alterada.

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Authors and Affiliations

  1. Medical (Endocrinology) Services, Veterans Administration Medical Center, USA

    Orlo H. Clark M.D., Patricia L. Gerend M.A. & Robert A. Nissenson Ph.D.

  2. Departments of Surgery and Medicine, University of California, San Francisco, California, USA

    Orlo H. Clark M.D., Patricia L. Gerend M.A. & Robert A. Nissenson Ph.D.

  3. Surgical Service, VA Medical Center, 4150 Clement Street, 94121, San Francisco, California, USA

    Orlo H. Clark M.D., Patricia L. Gerend M.A. & Robert A. Nissenson Ph.D.

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  1. Orlo H. Clark M.D.
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  2. Patricia L. Gerend M.A.
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  3. Robert A. Nissenson Ph.D.
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Supported in part by the Medical Research Service of the Veterans Administration and by a grant from the University of California Academic Senate.

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Clark, O.H., Gerend, P.L. & Nissenson, R.A. Mechanisms for increased adenylate cyclase responsiveness to TSH in neoplastic human thyroid tissue. World J. Surg. 8, 466–473 (1984). https://doi.org/10.1007/BF01654915

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