Latent transforming growth factor β (TGFβ)-binding proteins (LTBPs) are important for the secretion, activation, and function of mature TGFβ, especially so in cancer cell physiology. However, specific roles of the LTBPs remain understudied in the context of the primary tumor microenvironment. Herein, we investigated the role of LTBP3 in the distinct processes involved in cancer metastasis. By using three human tumor cell lines of different tissue origin (epidermoid HEp-3 and prostate PC-3 carcinomas and HT-1080 fibrosarcoma) and several metastasis models conducted in both mammalian and avian settings, we show that LTBP3 is involved in the early dissemination of primary cancer cells, namely in the intravasation step of the metastatic cascade. Knockdown of LTBP3 in all tested cell lines led to significant inhibition of tumor cell intravasation, but did not affect primary tumor growth. LTBP3 was dispensable in the late steps of carcinoma cell metastasis that follow tumor cell intravasation, including vascular arrest, extravasation, and tissue colonization. However, LTBP3 depletion diminished the angiogenesis-inducing potential of HEp-3 cells in vivo, which was restorable by exogenous delivery of LTBP3 protein. A similar compensatory approach rescued the dampened intravasation of LTBP3-deficient HEp-3 cells, suggesting that LTBP3 regulates the induction of the intravasation-supporting angiogenic vasculature within developing primary tumors. Using our recently developed microtumor model, we confirmed that LTBP3 loss resulted in the development of intratumoral vessels with an abnormal microarchitecture incompatible with efficient intravasation of HEp-3 carcinoma cells. Collectively, these findings demonstrate that LTBP3 represents a novel oncotarget that has distinctive functions in the regulation of angiogenesis-dependent tumor cell intravasation, a critical process during early cancer dissemination. Our experimental data are also consistent with the survival prognostic value of LTBP3 expression in early-stage head and neck squamous cell carcinomas, further indicating a specific role for LTBP3 in cancer progression toward metastatic disease.

中文翻译：

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LTBP3促进癌细胞扩散期间的早期转移事件。

潜在的转化生长因子β（TGFβ）结合蛋白（LTBPs）对于成熟的TGFβ的分泌，激活和功能很重要，尤其是在癌细胞生理学中。然而，在原发性肿瘤微环境的背景下，LTBPs的具体作用仍未被研究。本文中，我们研究了LTBP3在涉及癌症转移的不同过程中的作用。通过使用三种不同组织起源的人类肿瘤细胞系（表皮样HEp-3和前列腺PC-3癌以及HT-1080纤维肉瘤）和在哺乳动物和禽类环境中进行的几种转移模型，我们表明LTBP3参与了早期传播原发性癌细胞的转移，即在转移级联的浸润步骤中。在所有测试的细胞系中敲低LTBP3可以显着抑制肿瘤细胞的浸润，但不影响原发肿瘤的生长。LTBP3在肿瘤细胞浸润后癌细胞转移的晚期步骤（包括血管停滞，浸润和组织定植）中是必不可少的。但是，LTBP3的消耗减少了体内HEp-3细胞的血管生成诱导潜力，这可以通过外源传递LTBP3蛋白来恢复。一种类似的补偿方法挽救了LTBP3缺失的HEp-3细胞的浸润性血管内浸润，提示LTBP3调节了正在发展的原发性肿瘤内支持血管内渗入的血管生成血管的诱导。使用我们最近开发的微肿瘤模型，我们证实了LTBP3的缺失导致了具有异常微结构的肿瘤内血管的发展，而这些血管与HEp-3癌细胞的有效浸润不相容。总的来说，这些发现表明，LTBP3代表一种新型的癌靶标，在调节血管生成依赖性肿瘤细胞的浸润过程中具有独特的功能，这是早期癌症传播过程中的关键过程。我们的实验数据也与LTBP3表达在早期头颈部鳞状细胞癌中的生存预后价值一致，进一步表明LTBP3在癌症向转移性疾病进展中具有特定作用。