Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitor–resistant human lung adenocarcinoma
Tina Cascone, … , Robert R. Langley, John V. Heymach
Tina Cascone, … , Robert R. Langley, John V. Heymach
Published March 23, 2011
Citation Information: J Clin Invest. 2011;121(4):1313-1328. https://doi.org/10.1172/JCI42405.
View: Text | PDF
Research Article

Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitor–resistant human lung adenocarcinoma

Abstract

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.

Authors

Tina Cascone, Matthew H. Herynk, Li Xu, Zhiqiang Du, Humam Kadara, Monique B. Nilsson, Carol J. Oborn, Yun-Yong Park, Baruch Erez, Jörg J. Jacoby, Ju-Seog Lee, Heather Y. Lin, Fortunato Ciardiello, Roy S. Herbst, Robert R. Langley, John V. Heymach

×

Figure 2

BV resistance is associated with increased expression of stromal genes involved in angiogenesis.

Options: View larger image (or click on image) Download as PowerPoint
BV resistance is associated with increased expression of stromal genes i...
(A) Stromal and human angiogenic genes were differentially regulated in H1975 BV-resistant xenografts compared with vehicle controls (n = 3 per group). P < 0.005, 2-sample t test with random variance model. Exact permutation P values for significant genes were computed based on 10 available permutations. Data represent differences in fold change of genes in BV-resistant tumors versus controls. The dashed red line indicates fold change 1 (i.e., no change versus controls). Red and blue arrows indicate Egfr and Fgfr family member genes, respectively. (B) Functional pathway analysis of selected genes and their interaction nodes in a gene network significantly modulated between the BV-resistant and control xenograft mouse stroma. Network score was calculated by the inverse log of the P value and indicates the likelihood of focus genes in a network being found together not by chance. The selected genes (Egfr, Bax, and Dnajb1) and their interaction segments are highlighted by a blue border. Gene expression variation by at least 1.5-fold is indicated by color (red, upregulated; green, downregulated; gray, NS). (C and D) qRT-PCR showing human EGFR and mouse Egfr (C) and human FGFR2 and mouse Fgfr2 (D) mRNA expression in H1975 xenografts that progressed on vehicle and BV treatments (n = 4 per group). Data are normalized relative to vehicle progression samples and shown as relative fold change. *P < 0.05, t test.