Li Shaowei, Takeuchi Fumiko, Wang Ji-an, Fuller Christopher, Pacheco-Rodriguez Gustavo, Moss Joel, Darling Thomas N
Department of Dermatology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
J Exp Med. 2005 Sep 5;202(5):617-24. doi: 10.1084/jem.20042469. Epub 2005 Aug 29.
Patients with tuberous sclerosis complex (TSC) develop hamartomatous tumors showing loss of function of the tumor suppressor TSC1 (hamartin) or TSC2 (tuberin) and increased angiogenesis, fibrosis, and abundant mononuclear phagocytes. To identify soluble factors with potential roles in TSC tumorigenesis, we screened TSC skin tumor-derived cells for altered gene and protein expression. Fibroblast-like cells from 10 angiofibromas and five periungual fibromas produced higher levels of monocyte chemoattractant protein-1 (MCP-1) mRNA and protein than did fibroblasts from the same patient's normal skin. Conditioned medium from angiofibroma cells stimulated chemotaxis of a human monocytic cell line to a greater extent than conditioned medium from TSC fibroblasts, an effect blocked by neutralizing MCP-1-specific antibody. Overexpression of MCP-1 seems to be caused by loss of tuberin function because Eker rat embryonic fibroblasts null for Tsc2 (EEF Tsc2(-/-)) produced 28 times as much MCP-1 protein as did EEF Tsc2(+/+) cells; transient expression of WT but not mutant human TSC2 by EEF Tsc2(-/-) cells inhibited MCP-1 production; and pharmacological inhibition of the Rheb-mTOR pathway, which is hyperactivated after loss of TSC2, decreased MCP-1 production by EEF Tsc2(-/-) cells. Together these findings suggest that MCP-1 is an important paracrine factor for TSC tumorigenesis and may be a new therapeutic target.
结节性硬化症（TSC）患者会发生错构瘤性肿瘤，这些肿瘤表现出肿瘤抑制因子TSC1（错构瘤蛋白）或TSC2（结节蛋白）功能丧失，以及血管生成增加、纤维化和大量单核吞噬细胞。为了鉴定在TSC肿瘤发生中具有潜在作用的可溶性因子，我们筛选了TSC皮肤肿瘤来源的细胞，以寻找基因和蛋白质表达的改变。来自10个血管纤维瘤和5个甲周纤维瘤的成纤维细胞样细胞产生的单核细胞趋化蛋白-1（MCP-1）mRNA和蛋白质水平高于同一患者正常皮肤的成纤维细胞。血管纤维瘤细胞的条件培养基比TSC成纤维细胞的条件培养基更能刺激人单核细胞系的趋化作用，这种作用被中和MCP-1特异性抗体所阻断。MCP-1的过表达似乎是由结节蛋白功能丧失引起的，因为Tsc2基因缺失的Eker大鼠胚胎成纤维细胞（EEF Tsc2(-/-)）产生的MCP-1蛋白是EEF Tsc2(+/+)细胞的28倍；EEF Tsc2(-/-)细胞瞬时表达野生型而非突变型人TSC2可抑制MCP-1的产生；TSC2缺失后过度激活的Rheb-mTOR途径的药理学抑制降低了EEF Tsc2(-/-)细胞的MCP-1产生。这些发现共同表明，MCP-1是TSC肿瘤发生的重要旁分泌因子，可能是一个新的治疗靶点。
