Fraunhoffer Nicolás A, Closa Daniel, Folch-Puy Emma, Abuelafia Analía Meilerman, Calvo Ezequiel Luis, Chuluyan Eduardo, Iovanna Juan
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; Laboratory of Immunomodulators, School of Medicine, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), University of Buenos Aires, Buenos Aires, Argentina.
Experimental Pathology Department, Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), 08036, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Spain.
Cancer Lett. 2021 Nov 28;521:64-70. doi: 10.1016/j.canlet.2021.08.024. Epub 2021 Aug 24.
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.
转化的肿瘤细胞与其微环境之间的相互作用是胰腺导管腺癌（PDAC）进展的一个关键方面。这种分子对话受到了深入研究，因为它可能会产生一个有效的治疗靶点。与这种近微环境相反，与转化细胞直接接触的基质部分，即位于肿瘤块外围的远微环境，会产生信号传导至肿瘤的因子。在这些因子中，由胰腺的这一部分产生的REG3β是促进肿瘤进展的一个重要因子。本文证明，在由注射Panc02细胞诱导的同基因原位小鼠模型中，用特异性抗体靶向REG3β蛋白可限制PDAC肿瘤的生长。然后，我们表明CTGF在PDAC来源的细胞中因REG3β而上调表达。此外，用抗REG3β抗体处理肿瘤使REG3β失活会导致PDAC肿瘤中CTGF的强烈减少。最后，我们证明在异种移植的Panc02细胞中强制表达CTGF会消除抗REG3β抗体治疗的疗效。总之，这些结果表明REG3β在促进PDAC进展中的作用是由CTGF的过度激活介导的。因此，REG3β是一个有前景的治疗靶点，可用于以全新的理论基础治疗PDAC。总之，我们证明远微环境通过产生活性分泌因子对PDAC进展至关重要，其中一些因子可作为治疗靶点。
