Solid tumors are composed of tumor cells and stromal cells including lymphatic endothelial cells (LEC), which are mainly viewed as cells forming lymphatic vessels involved in the transport of metastatic and immune cells. We here reveal a new mechanism by which tumor exposed-LEC (teLEC) exert mitogenic effects on tumor cells. Our conclusions are supported by morphological and molecular changes induced in teLEC that in turn enhance cancer cell invasion in 3D cultures and tumor cell proliferation in vivo. The characterization of teLEC secretome by RNA-Sequencing and cytokine array revealed that interleukine-6 (IL6) is one of the most modulated molecules in teLEC, whose production was negligible in unexposed LEC. Notably, neutralizing anti-human IL6 antibody abrogated teLEC-mediated mitogenic effects in vivo, when LEC were mixed with tumor cells in the ear sponge assay. We here assign a novel function to teLEC that is beyond their role of lymphatic vessel formation. This work highlights a new paradigm, in which teLEC exert “fibroblast-like properties”, contribute in a paracrine manner to the control of tumor cell properties and are worth considering as key stromal determinant in future studies.

实体瘤由肿瘤细胞和基质细胞（包括淋巴管内皮细胞（LEC））组成，后者主要被视为形成参与转移和免疫细胞运输的淋巴管的细胞。我们在这里揭示了肿瘤暴露的LEC（teLEC）对肿瘤细胞产生促有丝分裂作用的新机制。我们的结论得到teLEC诱导的形态学和分子变化的支持，进而增强癌细胞在3D培养中的侵袭和体内肿瘤细胞的增殖。通过RNA测序和细胞因子阵列对teLEC分泌基因组进行表征，结果表明interleukine-6（IL6）是teLEC中调节最多的分子之一，在未暴露的LEC中其产量可忽略不计。值得注意的是，中和抗人IL6抗体消除了teLEC介导的促有丝分裂作用在体内，在耳海绵测定中将LEC与肿瘤细胞混合时。我们在这里为teLEC赋予了一种新的功能，这超出了它们形成淋巴管的作用。这项工作突出了一种新的范例，其中teLEC发挥“成纤维样性质”，以旁分泌方式有助于控制肿瘤细胞的性质，值得在以后的研究中作为关键的基质决定因素。