Thursday, 23rd January 2020

Role of the epithelial to mesenchymal transition (EMT) of mesothelial cells in peritoneal fibrosis and metastasis






Manuel López Cabrera







Research summary:

We have demonstrated that peritoneal mesothelial cells undergo an epithelial-to-mesenchymal transition (EMT) in response to dialysis. Transdifferentiated mesothelial cells acquire myofibroblastic characteristics and are capable of invading the submesothelialstroma, where they produce large amounts of extracellular matrix, as well as angiogenic and inflammatory factors, thus favouring the processes that lead to membrane failure. Our data suggest that the EMT of mesothelial cells is a good marker of membrane failure and could be a therapeutic target to prevent PD-induced fibrosis and/or angiogenesis.




  fig01-300   ---- fig02-300  ----

In the peritoneum new fibroblast-like cells arise from local conversion of mesothelial cells (MCs) by epithelial to mesenchymal transition (EMT) during peritoneal dialysis. Trans-differentiated MCs invade the submesothelialstroma, where they participate in the fibrotic and angiogenic processes, which ultimately lead to peritoneal ultrafiltration failure.













Peritoneal dissemination is a frequent metastatic route for cancers of the ovary and gastrointestinal tract.We have shown that in peritoneal metastatic implants a sub-population of carcinoma-associated fibroblasts (CAFs) derives from mesothelial cells through mesothelial to mesenchymal transition (MMT). Moreover, MMT promotes the adhesion and invasion of tumor cells.







Furthermore, characterization of the EMT process of mesothelial cells has opened a new line of research for our group, which consists of analyzing the role of transdifferentiation of mesothelial cells in the intraperitoneal implantation and growth of metastatic tumors. Cancer-associated fibroblasts (CAFs) participate in all stages of tumor progression. However, the origin of CAFs has not been clearly established. Our group is trying to demonstrate that in the case of peritoneal metastasis, CAFs may also derive from mesothelial cells via EMT. The fact that mesothelial cells that have undergone EMT produce large amounts of the pro-angiogenic factor VEGF suggests that these cells may play an important role in tumour vascularisation and growth.

The aim of this our work is to expand the knowledge of the pathological implications of the EMT of mesothelial cells and the molecular mechanisms that regulate this process, and to identify molecular targets for the design of therapeutic strategies, with possible applications in diseases associated with peritoneal fibrosis/angiogenesis, and in peritoneal metastasis.


Relevant publications:

1.-Blocking TGF-β1 protects the peritoneal membrane from dialysate-induced damage.
Loureiro J, Aguilera A, Selgas R, Sandoval P, Albar-Vizcaíno P, Pérez-Lozano ML, Ruiz-Carpio V, Majano PL, Lamas S, Rodríguez-Pascual F, Borras-Cuesta F, Dotor J, López-Cabrera M.
J Am Soc Nephrol. 2011 Sep;22(9):1682-95

2.- Expression of pituitary tumor-transforming gene 1 (PTTG1)/securin in hepatitis B virus (HBV)-associated liver diseases: evidence for an HBV X protein-mediated inhibition of PTTG1 ubiquitination and degradation.
Molina-Jiménez F, Benedicto I, Murata M, Martín-Vílchez S, Seki T, Antonio Pintor-Toro J, Tortolero M, Moreno-Otero R, Okazaki K, Koike K, Barbero JL, Matsuzaki K, Majano PL, López-Cabrera M.
Hepatology. 2010 Mar;51(3):777-87.

3.- Cyclooxygenase-2 mediates dialysate-induced alterations of the peritoneal membrane.
Aroeira LS, Lara-Pezzi E, Loureiro J, Aguilera A, Ramírez-Huesca M, González-Mateo G, Pérez-Lozano ML, Albar-Vizcaíno P, Bajo MA, del Peso G, Sánchez-Tomero JA, Jiménez-Heffernan JA, Selgas R, López-Cabrera M.
J Am Soc Nephrol. 2009 Mar;20(3):582-92.

4.- Epithelial to mesenchymal transition and peritoneal membrane failure in peritoneal dialysis patients: pathologic significance and potential therapeutic interventions.
Aroeira LS, Aguilera A, Sánchez-Tomero JA, Bajo MA, del Peso G, Jiménez-Heffernan JA, Selgas R, López-Cabrera M.
J Am Soc Nephrol. 2007 Jul;18(7):2004-13.

5.- Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells.
Yáñez-Mó M, Lara-Pezzi E, Selgas R, Ramírez-Huesca M, Domínguez-Jiménez C, Jiménez-Heffernan JA, Aguilera A, Sánchez-Tomero JA, Bajo MA, Alvarez V, Castro MA, del Peso G, Cirujeda A, Gamallo C, Sánchez-Madrid F, López-Cabrera M.
N Engl J Med. 2003 Jan 30;348(5):403-13.


Doctoral theses:

Guadalupe Tirma González Mateo (2011). Caracterización y modulación de la inflamación peritoneal para limitar la fibrosis causada por el líquido de diálisis: modelo de ratón. Universidad Complutense de Madrid. Director: Manuel López Cabrera y Rafael Selgas Gutiérrez.

Ignacio Benedicto Español (2011). Interrelación entre proteínas asociadas a uniones intercelulares estrechas, polaridad de los hepatocitos y el virus de la hepatitis C. Universidad Autónoma de Madrid. Directores: Manuel López Cabrera y Pedro Lorenzo Majano Rodríguez.

Jesús Loureiro Álvarez (2011). Transición epitelio-mesenquimal como diana terapéutica en modelos experimentales de diálisis peritoneal. Universidad Autónoma de Madrid. Director: Manuel López Cabrera.


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