Montaldo F, Maffé A, Morini M, Noonan D, Giordano S, Albini A, Prat M
Department of Medical Sciences, University of Piemonte Orientale, School of Medicine, Novara, Italy.
J Cell Physiol. 2000 Aug;184(2):246-54. doi: 10.1002/1097-4652(200008)184:2<246::AID-JCP13>3.0.CO;2-O.
Kaposi's sarcoma (KS) is the most frequent malignant lesion in patients with AIDS and is characterized by spindle cell proliferation, inflammatory cell infiltration, angiogenesis, edema, and invasiveness. KS origin is still debated. The complex aspect of this disease is probably supported by multiple concomitant pathogenetic factors, among which growth factors and their cognate tyrosine kinase receptors are deeply involved. Here we have investigated the expression status and functional integrity of KDR and Met receptors, as well as of their ligands, in an immortalized KS cell line (KS-IMM). The MET and KDR genes encode the tyrosine kinase receptors for Hepatocyte Growth Factor (HGF) and Vascular Endothelial Growth Factor (VEGF) respectively. Both factors are pleiotropic cytokines controlling growth, survival, motility, invasive migration and differentiation of endothelial cells. We have found that KS-IMM cells, which retain most of the features of the parental tumor and can induce KS-like sarcomas when injected subcutaneously in nude mice, express the Met receptor, but not its ligand. The receptor, which is basally inactive, is functional, being tyrosine phosphorylated in response to ligand stimulation and mediating the expected HGF-dependent biological responses of motility, invasion and proliferation. Moreover, we report that KS-IMM cells coexpress VEGF and KDR and that KDR is constitutively tyrosine phosphorylated, possibly as a consequence of the establishment of an autocrine loop. The receptor, however, maintains responsiveness to exogenously added ligand, by increasing the level of tyrosine phosphorylation and by responding in biological assays of motility, invasion and proliferation. Finally, we have found that the two growth factors synergize in a motility assay. These data show that HGF and VEGF are growth factors active on KS-IMM cells.
卡波西肉瘤（KS）是艾滋病患者中最常见的恶性病变，其特征为梭形细胞增殖、炎症细胞浸润、血管生成、水肿和侵袭性。KS的起源仍存在争议。这种疾病的复杂性可能由多种并存的致病因素共同支撑，其中生长因子及其相关的酪氨酸激酶受体深度参与其中。在此，我们研究了永生化KS细胞系（KS-IMM）中KDR和Met受体及其配体的表达状态和功能完整性。MET和KDR基因分别编码肝细胞生长因子（HGF）和血管内皮生长因子（VEGF）的酪氨酸激酶受体。这两种因子都是多效性细胞因子，可控制内皮细胞的生长、存活、运动、侵袭性迁移和分化。我们发现，KS-IMM细胞保留了亲代肿瘤的大部分特征，皮下注射到裸鼠中时可诱导出KS样肉瘤，该细胞系表达Met受体，但不表达其配体。该受体基础状态下无活性，但具有功能，在配体刺激下会发生酪氨酸磷酸化，并介导预期的HGF依赖性运动、侵袭和增殖的生物学反应。此外，我们报告KS-IMM细胞共表达VEGF和KDR，且KDR持续发生酪氨酸磷酸化，这可能是自分泌环形成的结果。然而，该受体对外源性添加的配体仍保持反应性，通过增加酪氨酸磷酸化水平以及在运动、侵袭和增殖的生物学检测中做出反应。最后，我们发现在运动检测中这两种生长因子具有协同作用。这些数据表明HGF和VEGF是对KS-IMM细胞有活性的生长因子。
