Papel de las proteínas quinasas activadas por mitógenos (MAPK) en el carcinoma de células renales esporádico / Role of Mitogen-Activated Protein Kinase (MAPK) in the Sporadic Renal Cell Carcinoma

Contexto: Últimamente, basándose en la implicación del gen supresor vhl en los casos de carcinoma de células renales (CCR), se ha evaluado la implicación de la ruta de señalización entre pVHL y el factor inducible por hipoxia 1 alfa (HIF-1α), ante la necesidad de encontrar nuevos marcadores diagnósticos, pronósticos y de respuesta a fármacos. Síntesis de evidencia: La sobreexpresión de HIF-1α confiere mejor pronóstico en pacientes afectos de CCR de tipo células claras (ccRCC). Además HIF-1α regula otros genes, concretamente el de la anhidrasa carbónica IX (CA-IX), cuya sobreexpresión es prácticamente exclusiva de los ccRCC y su determinación útil para el diagnóstico de este subtipo. Sin embargo, no se ha demostrado la implicación de CA-IX ni en el pronóstico ni en la respuesta a inmunomoduladores o antiangiogénicos. Ello hace necesario la evaluación global de toda esta ruta: pVHL → HIF-1α → CA-IX, e incluso el análisis de otras proteínas y vías de señalización que también controlan la actividad de HIF-1α. En este último caso, las MAPK, son críticas en la activación de HIF-1α, existiendo evidencias a nivel experimental del control sobre su actividad, aunque no se ha establecido su papel clínico como biomarcador. Si bien está demostrado el papel de las MAPK en los fenómenos de resistencia a quimio y radioterapia convencional, no lo está en la respuesta a sorafenib, dato llamativo si tenemos en cuenta que es inhibidor de varias proteín quinasas. Recientemente se ha observado que las MAPK pueden estar implicadas en la respuesta a distintas terapias, incluidas las basadas en inhibidores de tirosín quinasa. Conclusiones: La confirmación de estos datos supondrá una explicación a la variación observada entre pacientes, que con una misma alteración funcional del gen vhl presentan un distinto comportamiento biológico y clínico, y a una mejor selección de terapias no quirúrgicas (AU)

Context: Only on the basis of the involvement of the vhl suppressor gene in the cases of renal cell carcinomas (RCC), the involvement of the signaling pathway between the pVHL and the Hypoxia inducible factor 1, alpha (HIF-1α) has been evaluated because of the need to find new diagnostic and prognostic and response to drugs markers. Evidence synthesis: The overexpression of HIF-1α confers better prognosis in clear cell type RCC (ccRCC). Furthermore, HIF-1α regulates other genes, specifically that of the carbon anhydrase IX (CA-IX), whose overexpression is practically only of the ccRCC and its determination is useful for this subtype. However, the involvement of the CA-IX has not been demonstrated in the prognosis or in the response to immunomodulators or antiangiogenics. Therefore, it is necessary to make a global evaluation of all this pathway: pVHL → HIF-1α → CA-IX, and even the analysis of other proteins and signaling pathways that also control the HIF-1α activity. In the latter case, the MAPK are critical in the HIF-1α activation, there being evidence on the experimental level of the control on its activity. although its clinical role as a biomarkers has not been established. Although the role of the MAPK in the phenomena of resistance to conventional chemotherapy and radiotherapy has been demonstrated, it has not been demonstrated in response to sorafenib, an important piece of information if we consider that it is an inhibitor of several protein kinases. Recently, it has been observed that the MAPK may be involved in the responses to different therapies, included those based on tyrosine kinase inhibitors. Conclusions: The confirmation of these data would suppose an explanation of the variation observed between patients who, with the same functional alteration of the vhl gene, have a different biological, clinical behavior and better selection of non-surgical therapies (AU)

[Role of mitogen-activated protein kinase (MAPK) in the sporadic renal cell carcinoma]. / Papel de las proteínas quinasas activadas por mitógenos (MAPK) en el carcinoma de células renales esporádico.

CONTEXT: Only on the basis of the involvement of the vhl suppressor gene in the cases of renal cell carcinomas (RCC), the involvement of the signaling pathway between the pVHL and the Hypoxia inducible factor 1, alpha (HIF-1α) has been evaluated because of the need to find new diagnostic and prognostic and response to drugs markers. EVIDENCE SYNTHESIS: The overexpression of HIF-1α confers better prognosis in clear cell type RCC (ccRCC). Furthermore, HIF-1α regulates other genes, specifically that of the carbon anhydrase IX (CA-IX), whose overexpression is practically only of the ccRCC and its determination is useful for this subtype. However, the involvement of the CA-IX has not been demonstrated in the prognosis or in the response to immunomodulators or antiangiogenics. Therefore, it is necessary to make a global evaluation of all this pathway: pVHL → HIF-1α → CA-IX, and even the analysis of other proteins and signaling pathways that also control the HIF-1α activity. In the latter case, the MAPK are critical in the HIF-1α activation, there being evidence on the experimental level of the control on its activity. although its clinical role as a biomarkers has not been established. Although the role of the MAPK in the phenomena of resistance to conventional chemotherapy and radiotherapy has been demonstrated, it has not been demonstrated in response to sorafenib, an important piece of information if we consider that it is an inhibitor of several protein kinases. Recently, it has been observed that the MAPK may be involved in the responses to different therapies, included those based on tyrosine kinase inhibitors. CONCLUSIONS: The confirmation of these data would suppose an explanation of the variation observed between patients who, with the same functional alteration of the vhl gene, have a different biological, clinical behavior and better selection of non-surgical therapies.