TFPI2 Promotes Perivascular Migration in an Angiotropism Model of Melanoma.
TFPI2 Promotes Perivascular Migration in an Angiotropism Model of Melanoma.
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DOI：
10.3389/fonc.2021.662434
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发表时间：
2021
影响因子：
4.7
通讯作者：
Sun B
中科院分区：
文献类型：
--
作者：
Mo J;Zhao X;Wang W;Zhao N;Dong X;Zhang Y;Cheng R;Sun B
向血管性是癌细胞附着于血管并沿着血管迁移以获得脉管系统、扩散和转移的过程。然而，这种血管与肿瘤相互作用的分子基础尚未完全阐明，部分原因是实验模型有限。本研究旨在观察和探讨黑色素瘤血管生成的分子机制。为了监测人黑素瘤细胞与体内脉管系统的相互作用，通过皮下共注射高度和低度侵袭性黑素瘤细胞来采用鼠共异种移植模型。为了鉴定参与黑色素瘤血管生成表型的关键途径和基因，进行差异表达基因（DEG）分析和基因集富集分析（GSEA）。组织因子途径抑制物2（TFPI 2）在血管生成中的作用通过免疫染色、粘附试验、shRNA和体内致瘤性进行评价。采用免疫组化染色法检测恶性黑色素瘤手术标本中的血管生成和TFPI 2表达。分析来自癌症基因组图谱（TCGA）的数据，以探讨TFPI 2在葡萄膜和皮肤黑色素瘤中的表达和预后意义。在异种移植模型中，高度侵袭性的黑色素瘤细胞沿着瘤内血管的分支扩散到侵袭的前沿，类似于向血管的迁移。促血管生成的机制主要与分子功能调节剂、细胞群体增殖调节、发育过程、细胞分化、对细胞因子的反应和细胞运动/运动有关。TFPI 2下调减弱了高度侵袭性黑色素瘤细胞的血管周围迁移。高水平的TFPI 2分别与葡萄膜和皮肤黑色素瘤的较差和较好的生存率相关。这些结果提供了一个直接的体内模型，观察血管生成，并表明TFPI 2可以抑制黑色素瘤的血管生成表型。
Angiotropism is the process by which cancer cells attach to and migrate along blood vessels to acquire vasculature, disseminate, and metastasize. However, the molecular basis for such vessel–tumor interactions has not been fully elucidated, partly due to limited experimental models. In this study, we aimed to observe and explore the molecular mechanism underlying angiotropism in melanoma. To monitor the interactions of human melanoma cells with the vasculature in vivo, a murine coxenograft model was employed by co-injecting highly and poorly invasive melanoma cells subcutaneously. To identify key pathways and genes involved in the angiotropic phenotype of melanoma, analysis of differentially expressed genes (DEGs) and gene set enrichment analysis (GSEA) were performed. The role of tissue factor pathway inhibitor 2 (TFPI2) in angiotropism was evaluated by immunostaining, adhesion assay, shRNA, and in vivo tumorigenicity. Angiotropism and TFPI2 expression were examined in surgical specimens of melanoma by immunohistochemical staining. Data from The Cancer Genome Atlas (TCGA) were analyzed to explore the expression and prognostic implications of TFPI2 in uveal and cutaneous melanoma. Highly invasive melanoma cells spread along the branches of intratumor blood vessels to the leading edge of invasion in the coxenograft model, resembling angiotropic migration. Mechanisms underlying angiotropism were primarily associated with molecular function regulators, regulation of cell population proliferation, developmental processes, cell differentiation, responses to cytokines and cell motility/locomotion. TFPI2 downregulation weakened the perivascular migration of highly invasive melanoma cells. High levels of TFPI2 were correlated with worse and better survival in uveal and cutaneous melanoma, respectively. These results provide a straightforward in vivo model for the observation of angiotropism and suggest that TFPI2 could inhibit the angiotropic phenotype of melanoma.
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影响因子：
4.6
作者：
Andresen, Marianne S.;Stavik, Benedicte;Skretting, Grethe
通讯作者：
Skretting, Grethe
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
1.1
作者：
Hung, Tawny;Morin, Jason;Barnhill, Raymond L.
通讯作者：
Barnhill, Raymond L.
影响因子：
3.5
作者：
Izumi, H;Takahashi, C;Noda, M
通讯作者：
Noda, M
影响因子：
5
作者：
Barnhill, Raymond L.;Ye, Mengliang;Lugassy, Claire
通讯作者：
Lugassy, Claire