Morini M, Benelli R, Giunciuglio D, Carlone S, Arena G, Noonan D M, Albini A
Molecular Biology Laboratory, Tumor Progression Section, Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 10, Genoa, 16132, Italy.
Biochem Biophys Res Commun. 2000 Jun 24;273(1):267-71. doi: 10.1006/bbrc.2000.2941.
Kaposi's sarcoma (KS) is an hyperplastic lesion whose main histological features are typical spindle shaped cells with a mixed endothelial-mesenchymal-macrophage phenotype, an intense vascularization and an inflammatory infiltrate. The etiology of KS appears to be linked to activation of a latent HHV8 infection. Sporadic and iatrogenic KS are slow progressing lesions that can undergo spontaneous regression. In contrast, KS, which is frequently associated with HIV infection, is found in a highly aggressive form in AIDS patients. The HIV-1 Tat has been shown to activate the VEGF receptor KDR in endothelial and KS spindle cells, suggesting this HIV protein could contribute to KS pathogenesis. We used primary 'reactive' KS cell culture from sporadic and epidemic KS, and an immortal KS-line (KS-Imm) isolated in our laboratory from a iatrogenic KS lesion, to verify if Tat-induced cell signaling is able to mediate cellular responses. We demonstrate that KS cells migrated in response to Tat and that VEGF is able to compete with the Tat chemotactic activity towards these cells. A function-blocking anti-KDR antibody was able to abrogate both VEGF and Tat-induced KS chemotactic response, indicating a direct involvement of this receptor. Our data show that HIV-Tat can also activate KS cells derived from sporadic or iatrogenic lesions, suggesting that in AIDS patients Tat could cooperate with VEGF in activation of KDS on KS precursor spindle and endothelial cells, and contribute to the aggressiveness of AIDS-KS lesions.
卡波西肉瘤（KS）是一种增生性病变，其主要组织学特征为具有内皮-间充质-巨噬细胞混合表型的典型梭形细胞、强烈的血管生成和炎症浸润。KS的病因似乎与潜伏性HHV8感染的激活有关。散发性和医源性KS是进展缓慢的病变，可自发消退。相比之下，经常与HIV感染相关的KS在艾滋病患者中以高度侵袭性的形式出现。已证明HIV-1 Tat可激活内皮细胞和KS梭形细胞中的VEGF受体KDR，提示这种HIV蛋白可能参与KS的发病机制。我们使用来自散发性和流行性KS的原发性“反应性”KS细胞培养物，以及我们实验室从医源性KS病变中分离出的永生KS细胞系（KS-Imm），以验证Tat诱导的细胞信号传导是否能够介导细胞反应。我们证明KS细胞对Tat有迁移反应，并且VEGF能够与Tat对这些细胞的趋化活性竞争。一种功能阻断性抗KDR抗体能够消除VEGF和Tat诱导的KS趋化反应，表明该受体直接参与其中。我们的数据表明，HIV-Tat还可以激活源自散发性或医源性病变的KS细胞，提示在艾滋病患者中，Tat可能与VEGF协同激活KS前体梭形细胞和内皮细胞上的KDS，并导致艾滋病相关KS病变的侵袭性。
