期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 121, 期 4, 页码 1313-1328出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI42405
关键词
-
资金
- AstraZeneca
- Department of Defense [W81XWH-06-1-0303, W81XWH-07-1-03060]
- University of Texas Southwestern Medical Center
- University of Texas M.D. Anderson Cancer Center Lung SPORE NIH [P50 CA070907]
- NCI [P30CA016672]
- Damon Runyon Cancer Research Foundation [CI 24-04]
- M.D. Anderson Cancer Center
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
Angiogenesis is critical for tumor growth and metastasis, and several inhibitors of angiogenesis are currently in clinical use for the treatment of cancer. However, not all patients benefit from antiangiogenic therapy, and those tumors that initially respond to treatment ultimately become resistant. The mechanisms underlying this, and the relative contributions of tumor cells and stroma to resistance, are not completely understood. Here, using species-specific profiling of mouse xenograft models of human lung adenocarcinoma, we have shown that gene expression changes associated with acquired resistance to the VEGF inhibitor bevacizumab occurred predominantly in stromal and not tumor cells. In particular, components of the EGFR and FGFR pathways were upregulated in stroma, but not in tumor cells. Increased activated EGFR was detected on pericytes of xenografts that acquired resistance and on endothelium of tumors with relative primary resistance. Acquired resistance was associated with a pattern of pericyte-covered, normalized revascularization, whereas tortuous, uncovered vessels were observed in relative primary resistance. Importantly, dual targeting of the VEGF and EGFR pathways reduced pericyte coverage and increased progression-free survival. These findings demonstrated that alterations in tumor stromal pathways, including the EGFR and FGFR pathways, are associated with, and may contribute to, resistance to VEGF inhibitors and that targeting these pathways may improve therapeutic efficacy. Understanding stromal signaling may be critical for developing biomarkers for angiogenesis inhibitors and improving combination regimens.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据