During hematogenous metastasis, cancer cells escape from primary lesions and enter into the circulatory system, and only a few can colonize distant organs. However, the mechanism of cell survival and metastasis in the hematopoietic environment remains unclear. Angiorrhea is the character of pathological neovascularization in malignant tumors and commonly detected in osteosarcoma (OS), a bone tumor that prefers circulatory metastasis. In the present study, we focused on the notable role of serum albumin, the highest content in blood plasma, on OS progression. Our results indicated that serum albumin might act as a barrier against exogenous cancer cells during hematogenous metastasis. OS cells with high metastatic potential could gradually obtain strong viability through dedifferentiation under the effect of serum albumin in the angiorrhea region. Further exploration showed that serum albumin could increase the intracellular calcium concentration by activating the voltage-dependent calcium channel Cav2.1 in OS cells to affect the cytoskeleton, sequentially leading to dedifferentiation. Dedifferentiated OS cells with increased FAS apoptosis inhibitory molecule 2 (FAIM2) expression would gradually acquire survival ability, whereas knockdown of FAIM2 caused apoptosis in serum albumin. Moreover, FAIM2 overexpression rescued the viability of OS cells with low metastatic potential in serum albumin. In clinical specimens, OS cells showed markedly stronger positive staining of FAIM2 in the angiorrhea area. Taken together, our findings indicate that serum albumin in the angiorrhea region is a critical substance during pulmonary metastasis of OS cells. Angiorrhea is a nonnegligible prognostic element and FAIM2 might serve as a promising therapeutic target.

中文翻译：

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间质性血清白蛋白通过FAIM2转录使骨肉瘤细胞通过去分化获得生存力。

在血源性转移过程中，癌细胞从原发灶中逸出并进入循环系统，只有少数能在远处器官定居。然而，在造血环境中细胞存活和转移的机制仍不清楚。血管紧张是恶性肿瘤中病理性新血管形成的特征，通常在骨肉瘤（OS）中发现，骨肉瘤是一种优先循环转移的骨肿瘤。在本研究中，我们集中研究血清白蛋白（血浆中最高含量）对OS进展的显著作用。我们的结果表明，血清白蛋白可能在血源性转移过程中作为针对外源性癌细胞的屏障。具有高转移潜能的OS细胞可在血管紧张素区域的血清白蛋白作用下通过去分化逐渐获得强大的活力。进一步的研究表明，血清白蛋白可以通过激活OS细胞中的电压依赖性钙通道Cav2.1来影响细胞骨架，从而增加细胞内钙的浓度，从而导致去分化。具有增加的FAS凋亡抑制分子2（FAIM2）表达的去分化OS细胞将逐渐获得生存能力，而敲低FAIM2则导致血清白蛋白凋亡。此外，FAIM2的过表达拯救了血清白蛋白中具有低转移潜能的OS细胞的活力。在临床标本中，OS细胞在血管炎区域显示出明显更强的FAIM2阳性染色。综上所述，我们的发现表明，在OS细胞的肺转移过程中，血管紧张区域的血清白蛋白是关键物质。