Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-γ ligand troglitazone in patients with liposarcoma

Agonist ligands for the nuclear receptor peroxisome proliferator-activated receptor-γ 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-γ 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.

过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor-γ）的激动剂配体，已被证实可在体外诱导正常前脂肪细胞与人脂肪肉瘤细胞发生终末分化。鉴于脂肪肉瘤的分化状态可预测临床结局，对肿瘤分化状态进行调控或可改善其临床行为。我们开展了一项采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，并针对肿瘤分化开展了大量相关实验室研究。本文报告3例中高级别脂肪肉瘤患者的治疗结果：曲格列酮给药可在体内诱导肿瘤发生组织学与生物化学分化。相较于治疗前活检样本，这3例患者在接受曲格列酮治疗期间的肿瘤活检均显示，肿瘤细胞存在广泛脂质蓄积的组织学证据，且核磁共振（Nuclear Magnetic Resonance，NMR）可检测到的肿瘤甘油三酯水平显著升高。此外，脂肪细胞谱系分化相关的多种特征性mRNA转录本的表达也被诱导激活。同时，细胞增殖标志物Ki-67的免疫组化表达水平显著降低。综上，上述数据表明曲格列酮可在这些恶性肿瘤中诱导终末脂肪细胞分化。本研究结果证实，可通过药理学手段在人类实体瘤中诱导与细胞谱系匹配的分化过程。