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.
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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

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Figure 3

BV resistance is associated with increased EGFR activation on VSCs and the tumor vasculature.

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BV resistance is associated with increased EGFR activation on VSCs and t...
(A) Quantification of EGFR+ cells in H1975 xenografts that progressed on vehicle and BV, using LSC. *P < 0.01, t test. (B) Representative IF staining of CD31 (red), p-EGFR (green), and nuclei (blue) using confocal microscopy in vehicle- and BV-treated H1975 and A549 xenografts at progression. At least 5 microphotographs were collected per sample. Original magnification, ×200. Scale bars: 5 μm (H1975 BV); 10 μm (H1975 vehicle); 20 μm (A549). (C) Percent VSCs and ECs (CD31+) expressing p-EGFR in H1975 and A549 vehicle- and BV-treated tumors at progression. p-EGFR+ cells were counted in at least 5 random microscopic fields for each of 4 samples per group (×200). *P < 0.01, **P < 0.05, t test. (D) Representative IF images of p-EGFR, desmin, and nuclei staining in H1975 vehicle- and BV-treated xenografts at progression. At least 5 microphotographs were collected per specimen. White arrow denotes overlapping p-EGFR, desmin, and nuclei staining in BV-resistant H1975 tumors at higher magnification. Original magnification, ×200; ×400 (magnified merge image). (E) Percent desmin+ cells expressing p-EGFR in vehicle- and BV-treated H1975 tumors at progression. At least 5 random microscopic fields (×200) for each sample were analyzed. *P < 0.01, t test. (A–E) n = 4 per group.