In a new article published in Cancer Cell, a subset of cancer-associated fibroblasts (CAFs) was shown to have a crucial role in promoting lymphovascular invasion (LVI) in early-stage bladder cancer.

In this study, LVI analysis in tissue samples from patients with bladder cancer showed that LVI in patients with early-stage disease was associated with increased rates of lymph node (LN) metastases and poor prognosis. Single-cell RNA sequencing analyses showed an enrichment of PDGFRα⁺ITGA11⁺ CAFs specifically in patients with LVI-positive early-stage bladder cancer. The presence of this CAF subpopulation was associated with poor prognosis and LVI. Conditional knockout of PDGFRα⁺ITGA11⁺ CAFs in a mouse model of bladder cancer substantially reduced LVI and LN metastases, suggesting that this CAF population has a crucial role in LVI. Mechanistically, PDGFRα⁺ITGA11⁺ CAFs were shown to attach to human lymphatic endothelial cells (HLECs) in vitro in an ITGA11-dependent manner, as this attachment was impaired in the absence of ITGA11. The surface receptor SELE was identified as the strongest ITGA11 binding partner on HLECs, and an increased ITGA11–SELE interaction was observed in tissue samples from patients with LVI-positive versus LVI-negative early-stage bladder cancer. SELE was required for PDGFRα⁺ITGA11⁺ CAF migration and attachment to HLECs. Moreover, transendothelial migration of bladder cancer cells in vitro decreased upon genetic knockdown of SELE or ITGA11. Mechanistically, the ITGA11–SELE interaction was shown to promote VEGFR3 phosphorylation and subsequent MAPK pathway activation in HLECs, which in turn promoted transendothelial migration of bladder cancer cells. The evidence that the activation of VEGFR–MAPK per se was not sufficient to promote bladder cancer LVI and LN metastasis prompted the authors to investigate the existence of additional mechanisms mediated by other factors on PDGFRα⁺ITGA11⁺ CAFs. An upregulation of extracellular matrix (ECM) remodelling genes was observed in PDGFRα⁺ITGA11⁺ CAFs, and this ECM remodelling was shown to increase bladder cancer cell spheroid migration through overexpression of the ECM remodelling cytokine CHI3L1.

在《Cancer Cell》上发表的一篇新文章中，癌症相关成纤维细胞 (CAF) 的一个子集被证明在促进早期膀胱癌的淋巴血管侵袭 (LVI) 方面发挥着至关重要的作用。

在这项研究中，对膀胱癌患者组织样本的 LVI 分析表明，早期疾病患者的 LVI 与淋巴结 (LN) 转移率增加和预后不良相关。单细胞 RNA 测序分析显示 PDGFRα ⁺ ITGA11 ⁺ CAF 在 LVI 阳性早期膀胱癌患者中富集。该 CAF 亚群的存在与不良预后和 LVI 相关。在膀胱癌小鼠模型中条件性敲除 PDGFRα ⁺ ITGA11 ⁺ CAF 显着减少了 LVI 和 LN 转移，表明该 CAF 群体在 LVI 中具有至关重要的作用。从机制上讲，PDGFRα ⁺ ITGA11 ⁺ CAF 在体外以 ITGA11 依赖性方式附着在人淋巴内皮细胞 (HLEC) 上，因为这种附着在缺乏 ITGA11 的情况下受损。表面受体 SELE 被确定为 HLEC 上最强的 ITGA11 结合配偶体，并且在 LVI 阳性早期膀胱癌患者和 LVI 阴性早期膀胱癌患者的组织样本中观察到 ITGA11-SELE 相互作用增加。 PDGFRα ⁺ ITGA11 ⁺ CAF 迁移和附着到 HLEC 需要 SELE。此外，当 SELE 或 ITGA11 基因敲低时，膀胱癌细胞的体外跨内皮迁移减少。从机制上讲，ITGA11-SELE 相互作用被证明可以促进 HLEC 中 VEGFR3 磷酸化和随后的 MAPK 通路激活，进而促进膀胱癌细胞的跨内皮迁移。 VEGFR-MAPK 的激活本身不足以促进膀胱癌 LVI 和 LN 转移的证据促使作者研究 PDGFRα ⁺ ITGA11 ⁺ CAF 上其他因素介导的其他机制的存在。在 PDGFRα ⁺ ITGA11 ⁺ CAF 中观察到细胞外基质 (ECM) 重塑基因的上调，并且这种 ECM 重塑被证明通过 ECM 重塑细胞因子 CHI3L1 的过度表达来增加膀胱癌细胞球体迁移。