Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-γ ligand troglitazone in patients with liposarcoma
Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-γ ligand troglitazone in patients with liposarcoma
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DOI：
10.1073/pnas.96.7.3951
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发表时间：
1999-03-30
影响因子：
11.1
通讯作者：
Singer, S
中科院分区：
文献类型：
--
作者：
Demetri, GD;Fletcher, CDM;Singer, S
核受体过氧化物酶体增殖物激活受体-γ的激动剂配体已显示在体外诱导正常前脂肪细胞和人脂肪肉瘤细胞的终末分化。因为脂肪肉瘤的分化状态是临床结果的预测，所以肿瘤分化状态的调节可能有利地影响临床行为。我们进行了一项使用过氧化物酶体增殖物激活受体-γ配体曲格列酮治疗晚期脂肪肉瘤患者的临床试验，其中进行了广泛的肿瘤分化相关实验室研究。我们在此报告了三例中高度恶性脂肪肉瘤患者的结果，曲格列酮给药在体内诱导了组织学和生化分化。与治疗前活检相比，这些患者在接受曲格列酮治疗期间的肿瘤活检显示肿瘤细胞广泛的脂质蓄积和NMR可检测的肿瘤甘油三酯显著增加的组织学证据。此外，诱导了脂肪细胞谱系中分化特征的几种mRNA转录物的表达。Ki-67（细胞增殖的标志物）的免疫组化表达也明显减少。总之，这些数据表明曲格列酮诱导这些恶性肿瘤中的终末脂肪细胞分化。这些结果表明，在人实体瘤中可以诱导谱系适当的分化。
Agonist ligands for the nuclear receptor peroxisome proliferator-activated receptor-gamma have been shown to induce terminal differentiation of normal preadipocytes and human liposarcoma cells in vitro. Because the differentiation status of liposarcoma is predictive of clinical outcomes, modulation of the differentiation status of a tumor may favorably impact clinical behavior. We have conducted a clinical trial for treatment of patients with advanced liposarcoma by using the peroxisome proliferator-activated receptor-gamma ligand troglitazone, in which extensive correlative laboratory studies of tumor differentiation were performed. We report here the results of three patients with intermediate to high-grade liposarcomas in whom troglitazone administration induced histologic and biochemical differentiation in vivo. Biopsies of tumors from each of these patients while on troglitazone demonstrated histologic evidence of extensive lipid accumulation by tumor cells and substantial increases in NMR-detectable tumor triglycerides compared with pretreatment biopsies. In addition, expression of several mRNA transcripts characteristic of differentiation in the adipocyte lineage was induced. There was also a marked reduction in immunohistochemical expression of Ki-67, a marker of cell proliferation. Together, these data indicate that terminal adipocytic differentiation was induced in these malignant tumors by troglitazone. These results indicate that lineage-appropriate differentiation can be induced pharmacologically in a human solid tumor.