Albini A, Fontanini G, Masiello L, Tacchetti C, Bigini D, Luzzi P, Noonan D M, Stetler-Stevenson W G
National Institute of Research on Cancer, Genoa, Italy.
AIDS. 1994 Sep;8(9):1237-44. doi: 10.1097/00002030-199409000-00004.
To determine the neoplastic nature of Kaposi's sarcoma (KS). A highly vascularized lesion, KS is frequently associated with AIDS, indicating HIV products may be involved.
We determined the angiogenic properties of KS cell-secreted products and the HIV-1-tat gene product in vivo. Cell-free secreted products (KS-CM) from cultured epidemic and sporadic KS spindle cells or recombinant (r) HIV-1 tat protein were injected into mice with a matrix support (Matrigel).
KS-CM produced lesions carrying all the phenotypic hallmarks of KS, as observed by light and electron microscopy: spindle-shaped cells, haemorrhages and an inflammatory infiltrate, as well as Factor VIII-positive endothelial cells lining new blood vessels. Electron microscopy indicated an initial granulocyte invasion, with spindle-cell migration and neocapillary formation in the centre of the matrix. These lesions required the cofactor heparin; KS-CM or heparin alone were poorly angiogenic. A less intense angiogenesis, with lower cellularity and few granulocytes, was observed in basic fibroblast growth factor (bFGF)/heparin lesions, indicating that factors other than bFGF are present in the KS spindle-cell products. When the collagenase inhibitor tissue inhibitor of metalloproteinases (TIMP)-2 was added to the sponges, KS-CM-induced angiogenesis was reduced by approximately 65% and bFGF-induced angiogenesis inhibited completely. Recombinant HIV-1 tat protein, a growth factor for KS cells, induced vascularization that was also enhanced by heparin, implying that HIV-1 tat could contribute to the aetiology of HIV-associated KS.
KS-like lesions were obtained by injecting cell-free secreted products, suggesting that KS is a 'self-propagating' proliferative lesion caused by a cytokine imbalance and not a true neoplasm. Heparin-binding factors appear to be involved, and HIV-1 tat angiogenic properties implicate this molecule in AIDS-associated KS. Inhibition of KS-CM-induced KS-like lesions by TIMP-2 suggests that metalloproteinase inhibitors could be potential therapeutic agents for KS.
确定卡波西肉瘤（KS）的肿瘤性质。KS是一种血管高度丰富的病变，常与艾滋病相关，提示HIV产物可能参与其中。
我们在体内确定了KS细胞分泌产物和HIV-1-tat基因产物的血管生成特性。将来自培养的流行性和散发性KS梭形细胞的无细胞分泌产物（KS-CM）或重组（r）HIV-1 tat蛋白与基质支持物（基质胶）一起注射到小鼠体内。
通过光镜和电镜观察，KS-CM产生的病变具有KS的所有表型特征：梭形细胞、出血和炎性浸润，以及新血管内衬的VIII因子阳性内皮细胞。电镜显示最初有粒细胞浸润，基质中央有梭形细胞迁移和新毛细血管形成。这些病变需要辅因子肝素；单独的KS-CM或肝素血管生成能力较差。在碱性成纤维细胞生长因子（bFGF）/肝素病变中观察到血管生成较弱，细胞密度较低且粒细胞较少，表明KS梭形细胞产物中存在bFGF以外的因子。当向海绵中添加胶原酶抑制剂金属蛋白酶组织抑制剂（TIMP）-2时，KS-CM诱导的血管生成减少约65%，bFGF诱导的血管生成完全被抑制。重组HIV-1 tat蛋白是KS细胞的生长因子，可诱导血管化，肝素也可增强这种作用，这意味着HIV-1 tat可能与HIV相关KS的病因有关。
通过注射无细胞分泌产物获得了KS样病变，提示KS是由细胞因子失衡引起的“自我增殖”性增殖性病变，而非真正的肿瘤。肝素结合因子似乎参与其中，HIV-1 tat的血管生成特性表明该分子与艾滋病相关KS有关。TIMP-2对KS-CM诱导的KS样病变的抑制作用表明金属蛋白酶抑制剂可能是KS的潜在治疗药物。
