Herrera Alberto, Herrera Mercedes, Guerra-Perez Natalia, Galindo-Pumariño Cristina, Larriba María Jesús, García-Barberán Vanesa, Gil Beatriz, Giménez-Moyano Sara, Ferreiro-Monteagudo Reyes, Veguillas Pilar, Candia Antonio, Peña Raúl, Pinto Jesús, García-Bermejo Mª Laura, Muñoz Alberto, García de Herreros Antonio, Bonilla Félix, Carrato Alfredo, Peña Cristina
Department of Medical Oncology, Hospital Universitario Puerta de Hierro de Majadahonda, Majadahonda, Madrid, Spain.
Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
Oncogenesis. 2018 Sep 24;7(9):76. doi: 10.1038/s41389-018-0085-z.
Carcinomas, such as colon cancer, initiate their invasion by rescuing the innate plasticity of both epithelial cells and stromal cells. Although Snail is a transcriptional factor involved in the Epithelial-Mesenchymal Transition, in recent years, many studies have also identified the major role of Snail in the activation of Cancer-Associated Fibroblast (CAF) cells and the remodeling of the extracellular matrix. In CAFs, Platelet-derived growth factor (PDGF) receptor signaling is a major functional determinant. High expression of both SNAI1 and PDGF receptors is associated with poor prognosis in cancer patients, but the mechanism(s) that underlie these connections are not understood. In this study, we demonstrate that PDGF-activated fibroblasts stimulate extracellular matrix (ECM) fiber remodeling and deposition. Furthermore, we describe how SNAI1, through the FAK pathway, is a necessary factor for ECM fiber organization. The parallel-oriented fibers are used by endothelial cells as "tracks", facilitating their activation and the creation of tubular structures mimicking in vivo capillary formation. Accordingly, Snail1 expression in fibroblasts was required for the co-adjuvant effect of these cells on matrix remodeling and neoangiogenesis when co-xenografted in nude mice. Finally, in tumor samples from colorectal cancer patients a direct association between stromal SNAI1 expression and the endothelial marker CD34 was observed. In summary, our results advance the understanding of PDGF/SNAI1-activated CAFs in matrix remodeling and angiogenesis stimulation.
诸如结肠癌之类的癌症，通过恢复上皮细胞和基质细胞的固有可塑性来启动侵袭过程。尽管Snail是一种参与上皮-间质转化的转录因子，但近年来，许多研究也已确定Snail在癌症相关成纤维细胞（CAF）的激活以及细胞外基质重塑中发挥主要作用。在CAF中，血小板衍生生长因子（PDGF）受体信号传导是主要的功能决定因素。SNAI1和PDGF受体的高表达均与癌症患者的不良预后相关，但尚不清楚这些关联背后的机制。在本研究中，我们证明PDGF激活的成纤维细胞会刺激细胞外基质（ECM）纤维的重塑和沉积。此外，我们描述了SNAI1如何通过FAK途径成为ECM纤维组织形成的必要因素。平行排列的纤维被内皮细胞用作“轨道”，促进其激活并形成模仿体内毛细血管形成的管状结构。因此，当在裸鼠中共移植时，成纤维细胞中Snail1的表达对于这些细胞对基质重塑和新血管生成的协同辅助作用是必需的。最后，在来自结直肠癌患者的肿瘤样本中，观察到基质SNAI1表达与内皮标志物CD34之间存在直接关联。总之，我们的结果推动了对PDGF/SNAI1激活的CAF在基质重塑和血管生成刺激方面的理解。
