Targeting REG3β limits pancreatic ductal adenocarcinoma progression through CTGF downregulation.

Cancer Lett

Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13288, Marseille, France. Electronic address:

Published: August 2021

AI Article Synopsis

  • The interaction between tumor cells and their surrounding microenvironment is crucial for the progression of pancreatic ductal adenocarcinoma (PDAC) and presents potential therapeutic targets.
  • REG3β, a factor produced by the tumor's far microenvironment, promotes PDAC growth, and targeting it with specific antibodies can limit tumor expansion in mice models.
  • The study further reveals that REG3β activates CTGF, and inhibiting REG3β reduces CTGF levels, indicating that REG3β's effect on PDAC progression is mediated by CTGF over-activation, suggesting REG3β as a promising target for PDAC treatment.

Article Abstract

The crosstalk between the transformed tumoral cells and their microenvironment is a key aspect for pancreatic ductal adenocarcinoma (PDAC) progression. This molecular dialog is intensively studied because it may result in an efficient therapeutic target. Contrary to this near microenvironment, the stromal portion in direct contact with the transformed cells, a far microenvironment, placed at the periphery of the tumor mass, produces factors signaling tumors. Among these factors, REG3β, produced by this part of the pancreas, is an important factor in promoting tumor progression. This paper demonstrated that targeting REG3β protein with specific antibodies limits the PDAC tumor growth in an orthotopic, syngeneic mice model induced by injection of Panc02 cells. Then, we showed that CTGF is over-expressed in response to REG3β in PDAC-derived cells. Moreover, inactivation of REG3β by treating tumors with anti-REG3β antibodies results in a strong decrease of CTGF in PDAC tumors. Lastly, we demonstrated that forced expression of CTGF in xenografted Panc02 cells abolishes the therapeutic effect of the anti-REG3β antibody treatment. Altogether, these results indicate that the effect of REG3β in promoting PDAC progression is mediated by CTGF over-activation. Thus, REG3β is a promising therapeutic target to treat PDAC with an original rationale. In conclusion, we demonstrated that the far microenvironment is essential for PDAC progression by producing active secretory factors, and some of them could be used as therapeutic targets.

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Source
http://dx.doi.org/10.1016/j.canlet.2021.08.024DOI Listing

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