Laboratory of Tumor and Development Biology, GIGA-Cancer, Liege University, B23, Avenue Hippocrate 13, Sart-Tilman, 4000, Liege, Belgium.
Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Cell Mol Life Sci. 2022 May 14;79(6):295. doi: 10.1007/s00018-022-04262-w.
Although lymph node (LN) metastasis is an important prognostic parameter in cervical cancer, the tissue remodeling at a pre-metastatic state is poorly documented in LNs. We here identified periostin (POSTN) as a component of non-metastatic LNs by applying proteomic analyses and computerized image quantifications on LNs of patients with cervical cancer. We provide evidence for remarkable modifications of POSTN and lymphatic vessel distributions and densities in non-metastatic sentinel and metastatic human LNs, when compared to distant non-metastatic LNs. POSTN deposition at a pre-metastatic stage was demonstrated in a pre-clinical murine model (the ear sponge assay). Its expression by fibroblastic LN cells was assessed by in situ hybridization and in vitro cultures. In vitro, POSTN promoted lymphatic endothelial cell functions and tumor cell proliferation. Accordingly, the in vivo injection of recombinant POSTN together with VEGF-C boosted the lymphangiogenic response, while the metastatic potential of tumor cells was drastically reduced using a POSTN blocking antibody. This translational study also supports the existence of an unprecedented dialog "in cascade", between the primary tumor and the first pelvic nodal relay in early cervical cancer, and subsequently from pelvic LN to para-aortic LNs in locally advanced cervical cancers. Collectively, this work highlights the association of POSTN deposition with lymphangiogenesis in LNs, and provides evidence for a key contribution of POSTN in promoting VEGF-C driven lymphangiogenesis and the seeding of metastatic cells.
虽然淋巴结（LN）转移是宫颈癌的一个重要预后参数，但 LN 中转移前的组织重构尚未得到充分记录。我们通过对宫颈癌患者 LN 的蛋白质组学分析和计算机图像定量分析，发现骨膜蛋白（POSTN）是无转移 LN 的一个组成部分。与远处无转移 LN 相比，我们提供了无转移前哨和转移性人 LN 中 POSTN 和淋巴管分布及密度显著改变的证据。在临床前鼠模型（耳部海绵检测）中，我们在转移前阶段证明了 POSTN 的沉积。通过原位杂交和体外培养评估了成纤维细胞 LN 细胞中 POSTN 的表达。在体外，POSTN 促进了淋巴管内皮细胞的功能和肿瘤细胞的增殖。因此，使用 POSTN 阻断抗体，与 VEGF-C 一起体内注射重组 POSTN 可增强淋巴管生成反应，同时大大降低肿瘤细胞的转移潜能。这项转化研究还支持在早期宫颈癌中，原发肿瘤与第一个盆腔淋巴结之间存在一种前所未有的级联对话，随后在局部晚期宫颈癌中，从盆腔 LN 到腹主动脉旁 LN 也存在这种对话。总之，这项工作强调了 POSTN 沉积与 LN 中的淋巴管生成之间的关联，并为 POSTN 在促进 VEGF-C 驱动的淋巴管生成和转移细胞定植中的关键作用提供了证据。
