Publication: Señalización HGF/MET como diana terapéutica en pacientes con mieloma múltiple
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2019-02-18
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Universidad Complutense de Madrid
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Abstract
El Mieloma Múltiple es una neoplasia de linfocitos B que surge a partir de células plasmáticas que proliferan clonalmente en la médula ósea. El mieloma múltiple continúa siendo un cáncer incurable y se hace necesaria la creación de nuevas estrategias terapéuticas para evitar la recaída de la enfermedad, manejar la resistencia y refractariedad a los tratamientos y aumentar el tiempo hasta la recaída. Las células de mieloma se caracterizan por la expresión en su superficie del antígeno CD138. Entre un 20-30% de las células de mieloma producen factor de crecimiento hepático (HGF), y por ello su concentración en suero es especialmente elevada en pacientes con mieloma. CD138 presenta unido en sus extremos cadenas de proteoglicanos heparán sulfato favoreciendo la unión de gran cantidad de HGF. A su vez, HGF es secretado por células del estroma medular. HGF es el ligando del receptor MET. Ambos son esenciales durante el desarrollo embrionario y la vida postnatal. Sin embargo, se ha demostrado que una activación anómala de MET, debida por ejemplo a sobreexpresión, contribuye al desarrollo y progresión de una gran variedad de cánceres humanos. De este modo la unión de HGF a MET juega un papel importante en la regulación autocrina y paracina de las células de Mieloma. Adicionalmente, MET puede presentarse como tránscrito alternativo L1-MET. El efecto que presenta L1-MET no ha sido claramente definido y no existe consenso entre los diferentes tipos de cáncer. En particular, este trabajo se ha centrado en la evaluación de un fármaco inhibidor de la señalización HGF/MET (Crizotinib) como posible nueva diana terapéutica para el tratamiento de pacientes con mieloma, sólo o en combinación con fármacos antimieloma o células estromales sanas...
Multiple Myeloma is a neoplasm of B lymphocytes that arises from clonally proliferation of plasma cells in the bone marrow. Multiple Myeloma continues being an incurable cancer and it is necessary to create new therapeutic strategies to prevent relapse of the disease, manage the resistance and treatments refractoriness and increase the time to relapse. Myeloma cells are characterized by the expression on their surface of CD138 antigen. Between 20-30% of myeloma cells produce liver growth factor (HGF), and therefore their serum concentration is especially high in patients with myeloma. CD138 has at its ends chains of heparan sulfate proteoglycans favoring the binding of a large amount of HGF. In turn, HGF is secreted by bone marrow stromal cells. HGF is the ligand of MET receptor. Both are essential during embryonic development and postnatal life. However, it has been shown that an abnormal activation of MET, for example due to overexpression, contributes to the development and progression of a great variety of human cancers. In this way, binding HGF to MET plays an important role in the autocrine and paracrine regulation of myeloma cells. Additionally, MET can be presented as an alternative transcript L1-MET. The role L1-MET plays, has not been clearly defined and there is no consensus among different types of cancer. Particularly, this work has been focused on the evaluation of a drug inhibitor of HGF/MET signaling (Crizotinib) as a possible new therapeutic target for the treatment of Multiple Myeloma patients, either alone or in combination with anti-myeloma drugs or healthy stromal cells...
Multiple Myeloma is a neoplasm of B lymphocytes that arises from clonally proliferation of plasma cells in the bone marrow. Multiple Myeloma continues being an incurable cancer and it is necessary to create new therapeutic strategies to prevent relapse of the disease, manage the resistance and treatments refractoriness and increase the time to relapse. Myeloma cells are characterized by the expression on their surface of CD138 antigen. Between 20-30% of myeloma cells produce liver growth factor (HGF), and therefore their serum concentration is especially high in patients with myeloma. CD138 has at its ends chains of heparan sulfate proteoglycans favoring the binding of a large amount of HGF. In turn, HGF is secreted by bone marrow stromal cells. HGF is the ligand of MET receptor. Both are essential during embryonic development and postnatal life. However, it has been shown that an abnormal activation of MET, for example due to overexpression, contributes to the development and progression of a great variety of human cancers. In this way, binding HGF to MET plays an important role in the autocrine and paracrine regulation of myeloma cells. Additionally, MET can be presented as an alternative transcript L1-MET. The role L1-MET plays, has not been clearly defined and there is no consensus among different types of cancer. Particularly, this work has been focused on the evaluation of a drug inhibitor of HGF/MET signaling (Crizotinib) as a possible new therapeutic target for the treatment of Multiple Myeloma patients, either alone or in combination with anti-myeloma drugs or healthy stromal cells...
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Tesis de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Medicina, leída el 16/11/2018