PDGFR Signaling Blockade in Marrow Stroma Impairs Lung Cancer Bone Metastasis
PDGFR Signaling Blockade in Marrow Stroma Impairs Lung Cancer Bone Metastasis
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DOI：
10.1158/0008-5472.can-10-1708
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发表时间：
2011-01-01
期刊：
影响因子：
11.2
通讯作者：
Lecanda, Fernando
中科院分区：
文献类型：
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作者：
Catena, Raul;Luis-Ravelo, Diego;Lecanda, Fernando
骨微环境和细胞-细胞相互作用对于转移的启动和发展至关重要。通过药理学方法，使用多靶点酪氨酸激酶抑制剂舒尼替尼，我们测试了骨髓（BM）基质室中血小板衍生生长因子受体（PDGFR）轴与肺癌骨转移的启动和发展的相关性。发现PDGFR β是舒尼替尼在BM基质ST-2和MC 3 T3-E1前成骨细胞中表达的主要酪氨酸激酶靶点。相反，在A549 M1中未发现舒尼替尼靶向受体的表达，而在H460 M5肺癌转移细胞中发现低水平的舒尼替尼靶向受体。ST-2和人BM内皮细胞与舒尼替尼的孵育导致有效的细胞生长抑制和以剂量依赖性方式诱导细胞凋亡。类似地，舒尼替尼在体内诱导了对BM基质PDGFR β（+）细胞的强促凋亡作用，并在BM腔中产生了组织结构和血管渗漏的广泛破坏。用舒尼替尼预处理ST-2细胞也阻碍了对肺癌细胞系的异型粘附。这些效应与基质细胞和肿瘤细胞中细胞-细胞和细胞-基质分子的变化相关。在心内接种A549 M1或H460 M5细胞之前用舒尼替尼预处理小鼠引起肿瘤细胞归巢到骨的显著抑制，而当肿瘤细胞在接种前预处理时没有发现效果。舒尼替尼治疗显著增加了总生存率，并防止了肿瘤定植，但不能防止骨病变，而与唑来膦酸联合治疗则导致溶骨性病变和骨肿瘤负荷显著减少。因此，BM基质中PDGFR轴的破坏改变了异型肿瘤-基质和肿瘤-基质的相互作用，从而阻止了骨归巢和骨定植所需的有效接合。这些结果支持了这样的观点，即同时靶向肿瘤和间质隔室是阻断骨转移的更有效的方法。Cancer Res; 71（1）; 164-74. (C)2010年AACR。
Bone microenvironment and cell-cell interactions are crucial for the initiation and development of metastasis. By means of a pharmacologic approach, using the multitargeted tyrosine kinase inhibitor sunitinib, we tested the relevance of the platelet-derived growth factor receptor (PDGFR) axis in the bone marrow (BM) stromal compartment for the initiation and development of lung cancer metastasis to bone. PDGFR beta was found to be the main tyrosine kinase target of sunitinib expressed in BM stromal ST-2 and MC3T3-E1 preosteoblastic cells. In contrast, no expression of sunitinib-targeted receptors was found in A549M1 and low levels in H460M5 lung cancer metastatic cells. Incubation of ST-2 and human BM endothelial cells with sunitinib led to potent cell growth inhibition and induction of apoptosis in a dose-dependent manner. Similarly, sunitinib induced a robust proapoptotic effect in vivo on BM stromal PDGFR beta(+) cells and produced extensive disruption of tissue architecture and vessel leakage in the BM cavity. Pretreatment of ST-2 cells with sunitinib also hindered heterotypic adhesion to lung cancer cell lines. These effects were correlated with changes in cell-cell and cell-matrix molecules in both stromal and tumor cells. Pretreatment of mice with sunitinib before intracardiac inoculation of A549M1 or H460M5 cells caused marked inhibition of tumor cells homing to bone, whereas no effect was found when tumor cells were pretreated before inoculation. Treatment with sunitinib dramatically increased overall survival and prevented tumor colonization but not bone lesions, whereas combination with zoledronic acid resulted in marked reduction of osteolytic lesions and osseous tumor burden. Thus, disruption of the PDGFR axis in the BM stroma alters heterotypic tumor-stromal and tumor-matrix interactions, thereby preventing efficient engagement required for bone homing and osseous colonization. These results support the notion that concomitant targeting of the tumor and stromal compartment is a more effective approach for blocking bone metastasis. Cancer Res; 71(1); 164-74. (C) 2010 AACR.