Neutralizing murine TGFβR2 promotes a differentiated tumor cell phenotype and inhibits pancreatic cancer metastasis.
Neutralizing murine TGFβR2 promotes a differentiated tumor cell phenotype and inhibits pancreatic cancer metastasis.
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DOI：
10.1158/0008-5472.can-13-1807
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发表时间：
2014-09-15
期刊：
影响因子：
11.2
通讯作者：
Brekken RA
中科院分区：
文献类型：
--
作者：
Ostapoff KT;Cenik BK;Wang M;Ye R;Xu X;Nugent D;Hagopian MM;Topalovski M;Rivera LB;Carroll KD;Brekken RA
TGF-β 水平升高是胰腺癌患者的负面预后指标；因此，TGF-β 途径是一个有吸引力的治疗靶点。然而，TGF-β药物抑制的临床应用仍然具有挑战性，因为TGF-β在包括胰腺癌在内的许多上皮恶性肿瘤中具有肿瘤抑制功能。事实上，TGF-β 的直接中和可促进胰腺癌遗传小鼠模型的肿瘤进展。在这里，我们报告使用单克隆抗体 (2G8) 中和鼠 TGF-β 受体 2 的活性，在原位人类肿瘤异种移植物、同基因肿瘤和胰腺癌遗传模型中具有有效的抗转移活性。 2G8 减少活化的成纤维细胞、胶原蛋白沉积、微血管密度和血管功能。这些基质特异性变化导致肿瘤细胞上皮分化并有效减少转移。我们得出的结论是，基质细胞内的 TGF-β 信号传导直接参与肿瘤细胞表型和胰腺癌的进展。因此，抑制基质细胞的TGF-β依赖性效应器功能的策略可能对胰腺肿瘤的治疗有效。
Elevated levels of TGF-β are a negative prognostic indicator for patients diagnosed with pancreatic cancer; as a result the TGF-β pathway is an attractive target for therapy. However, clinical application of pharmacologic inhibition of TGF-β remains challenging because TGF-β has tumor suppressor functions in many epithelial malignancies including pancreatic cancer. In fact, direct neutralization of TGF-β promotes tumor progression of genetic murine models of pancreatic cancer. Here we report that neutralizing the activity of murine TGF-β receptor 2 using a monoclonal antibody (2G8) has potent anti-metastatic activity in orthotopic human tumor xenografts, syngenic tumors and a genetic model of pancreatic cancer. 2G8 reduced activated fibroblasts, collagen deposition, microvessel density and vascular function. These stromal specific changes resulted in tumor cell epithelial differentiation and a potent reduction in metastases. We conclude that TGF-β signaling within stromal cells participates directly in tumor cell phenotype and pancreatic cancer progression. Thus, strategies that inhibit TGF-β dependent effector functions of stromal cells could be efficacious for the therapy of pancreatic tumors.