Controlled Extracellular Matrix Degradation in Breast Cancer Tumors Improves Therapy by Trastuzumab
Controlled Extracellular Matrix Degradation in Breast Cancer Tumors Improves Therapy by Trastuzumab
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DOI：
10.1038/mt.2010.256
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发表时间：
2011-03-01
影响因子：
12.4
通讯作者：
Lieber, Andre
中科院分区：
文献类型：
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作者：
Beyer, Ines;Li, Zongyi;Lieber, Andre
实体肿瘤中的细胞外基质（ECM）通过阻断肿瘤内扩散和/或靶受体在恶性细胞上的物理掩蔽来影响治疗的有效性。在乳腺癌患者和异种移植物肿瘤切片的免疫组织化学研究中，我们观察到ECM蛋白和Her2/neu的共定位，Her2/neu是一种肿瘤相关抗原，是广泛使用的单克隆抗体曲妥珠单抗（赫赛汀）的靶标。我们测试了肿瘤内肽激素松弛素（Rlx）的表达是否会导致ECM降解和曲妥珠单抗治疗的改善。由于病毒基因传递到具有广泛肿瘤ECM的上皮肿瘤是低效的，我们使用了一种基于造血干细胞（HSC）的方法将Rlx基因传递到肿瘤。在具有同基因乳腺癌肿瘤的小鼠模型中，hsc介导的瘤内Rlx表达导致ECM蛋白的减少，从而控制肿瘤的生长。此外，在Her2/ new阳性BT474-M1肿瘤和来自HCC1954细胞的更多治疗难治性肿瘤的模型中，我们观察到曲妥珠单抗治疗与Rlx表达联合治疗可显著延缓肿瘤生长。我们的结果对癌症的抗体治疗以及其他基于t细胞或包封化疗药物的抗癌治疗方法具有启示意义。
Extracellular matrix (ECM) in solid tumors affects the effectiveness of therapeutics through blocking of intratumoral diffusion and/or physical masking of target receptors on malignant cells. In immunohistochemical studies of tumor sections from breast cancer patients and xenografts, we observed colocalization of ECM proteins and Her2/neu, a tumor-associated antigen that is the target for the widely used monoclonal antibody trastuzumab (Herceptin). We tested whether intratumoral expression of the peptide hormone relaxin (Rlx) would result in ECM degradation and the improvement of trastuzumab therapy. As viral gene delivery into epithelial tumors with extensive tumor ECM is inefficient, we used a hematopoietic stem cell (HSC)-based approach to deliver the Rlx gene to the tumor. In mouse models with syngeneic breast cancer tumors, HSC-mediated intratumoral Rlx expression resulted in a decrease of ECM proteins and enabled control of tumor growth. Moreover, in a model with Her2/neu-positive BT474-M1 tumors and more treatment-refractory tumors derived from HCC1954 cells, we observed a significant delay of tumor growth when trastuzumab therapy was combined with Rlx expression. Our results have implications for antibody therapy of cancer as well as for other anticancer treatment approaches that are based on T-cells or encapsulated chemotherapy drugs.