Iovanna Juan L, Closa Daniel
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, Marseille, France.
Department of Experimental Pathology, Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Oncoimmunology. 2017 Aug 8;6(11):e1358840. doi: 10.1080/2162402X.2017.1358840. eCollection 2017.
The REG3β protein was identified more than 2 decades ago, but its role in PDAC development was only recently reported. In Pancreatic Ductal Adenocarcinoma (PDAC), REG3β protein is expressed and released by the far microenvironment, which is situated out of the tumor, at the periphery of the tumor mass, and is part of the healthy peri-tumoral region. This compartment is completely unrelated to the classical microenvironment that corresponds to the intra-tumoral stoma. Clinically relevant, the far microenvironment, and the factors released by it, could be novel and original therapeutic targets for treating patients with a PDAC. In this way we recently demonstrated that REG3β is an essential soluble factor necessary for PDAC development which is able to stimulate several simultaneous pro-tumoral mechanisms. We also find that secreted REG3β boosts interactions between epithelial cells and immune cells by activating the CXCL12/CXCR4 signaling cascade, which facilitates tumor escape through evasion of immune surveillance, and promotes metastasis. In addition, REG3β interfere the intercellular communication inside the tumor mediated by extracellular vesicles, resulting in relevant changes in macrophage phenotype or tumor cell migration. Therefore, we are proposing to call as near microenvironment to the classical microenvironment that is constituted by fibroblasts, inflammatory cells and fibers and located into the tumor, and as far microenvironment, which is constituted by the parenchymal non transformed cells located at the periphery of the tumor mass.
REG3β蛋白在20多年前就已被发现，但其在胰腺癌发生发展中的作用直到最近才被报道。在胰腺导管腺癌（PDAC）中，REG3β蛋白由远微环境表达并释放，该远微环境位于肿瘤外部、肿瘤块周边，是健康的肿瘤周围区域的一部分。这个区域与对应肿瘤内基质的经典微环境完全无关。具有临床相关性的是，远微环境及其释放的因子可能是治疗PDAC患者的新的和原始的治疗靶点。通过这种方式，我们最近证明REG3β是PDAC发生发展所必需的一种可溶性因子，它能够刺激多种同时发生的促肿瘤机制。我们还发现，分泌的REG3β通过激活CXCL12/CXCR4信号级联反应增强上皮细胞与免疫细胞之间的相互作用，这有助于肿瘤通过逃避免疫监视而逃逸，并促进转移。此外，REG3β干扰由细胞外囊泡介导的肿瘤内细胞间通讯，导致巨噬细胞表型或肿瘤细胞迁移发生相关变化。因此，我们建议将由成纤维细胞、炎性细胞和纤维组成且位于肿瘤内部的经典微环境称为近微环境，而将由位于肿瘤块周边的实质未转化细胞组成的微环境称为远微环境。
