肿瘤中的血管通常功能失调。这损害了治疗剂向癌细胞的递送和在癌细胞之间的分布。随后，治疗效果会降低，剂量增加会增加对非恶性组织的不利影响。功能障碍的血管表型归因于异常的促血管生成信号传导，抗血管生成剂可以改善血管功能障碍的特征。然而，它们同时降低了血管密度，从而阻碍了药物输送和分布。为了探索在不影响肿瘤微环境中血管密度的情况下改善血管功能的可能性，我们评估了参与上皮间质转化（EMT）的转录因子（TF）作为潜在靶点。基于 EMT 和内皮细胞血管生成激活之间的相似性，我们假设这些 TF，特别是 Snai1，可能作为血管功能障碍的关键调节因子。体外实验表明，Snai1（类似 Slug 和 Twist1）可调节内皮细胞通透性、肿瘤细胞迁移的允许性以及尖端/茎细胞的形成。小鼠内皮特异性、杂合性敲除 Snai1 可改善植入肿瘤的血管质量。这导致更好的氧合和减少转移。值得注意的是，Snai1KD 小鼠的肿瘤对化疗的反应明显更好，因为药物以显着增加的速率转运到肿瘤中并且分布更均匀。因此，我们证明在恶性肿瘤中恢复血管稳态而不影响血管密度是可行的。将此类血管再造与抗癌药物相结合，可实现减少非恶性组织治疗毒性的战略治疗方法。© 2024。作者。

Blood vessels in tumors are often dysfunctional. This impairs the delivery of therapeutic agents to and distribution among the cancer cells. Subsequently, treatment efficacy is reduced, and dose escalation can increase adverse effects on non-malignant tissues. The dysfunctional vessel phenotypes are attributed to aberrant pro-angiogenic signaling, and anti-angiogenic agents can ameliorate traits of vessel dysfunctionality. However, they simultaneously reduce vessel density and thereby impede drug delivery and distribution. Exploring possibilities to improve vessel functionality without compromising vessel density in the tumor microenvironment, we evaluated transcription factors (TFs) involved in epithelial-mesenchymal transition (EMT) as potential targets. Based on similarities between EMT and angiogenic activation of endothelial cells, we hypothesized that these TFs, Snai1 in particular, might serve as key regulators of vessel dysfunctionality. In vitro, experiments demonstrated that Snai1 (similarly Slug and Twist1) regulates endothelial permeability, permissiveness for tumor cell transmigration, and tip/stalk cell formation. Endothelial-specific, heterozygous knock-down of Snai1 in mice improved vascular quality in implanted tumors. This resulted in better oxygenation and reduced metastasis. Notably, the tumors in Snai1KD mice responded significantly better to chemotherapeutics as drugs were transported into the tumors at strongly increased rates and more homogeneously distributed. Thus, we demonstrate that restoring vessel homeostasis without affecting vessel density is feasible in malignant tumors. Combining such vessel re-engineering with anti-cancer drugs allows for strategic treatment approaches that reduce treatment toxicity on non-malignant tissues.© 2024. The Author(s).