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

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Figure 5

Altered patterns of tumor vascular density, tortuosity, and pericyte coverage in BV-resistant xenograft tumors.

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Altered patterns of tumor vascular density, tortuosity, and pericyte cov...
(A) Microphotographs of CD31+ tumor vessels (red) in H1975 and A549 xenografts treated with vehicle and BV after 2 weeks and at progression. 5–10 microscopic fields were collected from each of 4 specimens per group. Arrows indicate the different vessel morphology in H1975 (top panel) and A549 (lower panel) BV-resistant tumors. Original magnification, ×100. (B and C) Quantification of MVD (B) and vessel tortuosity (C) based on CD31-stained tumor sections in H1975 and A549 xenografts treated with vehicle and BV after 2 weeks and at progression. 5 hotspot microscopic fields (×200) per tumor section were analyzed to quantify MVD; 5 random microscopic fields (×100) were quantified for vessel tortuosity analysis. n = 4 per group. Units of the y axis for MVD (B) represent CD31 + vessels per HPF (high power field). The y axis for vessel tortuosity (C) represents the ratio T = (L/S) – 1. (D) Pericyte coverage of H1975 xenografts was quantified as percent CD31+ vessels with at least 50% coverage of associated desmin+ cells in at least 5 microscopic fields (×200) in tumors receiving long-term treatment. n = 2 (vandetanib); 3 (erlotinib); 4 (vehicle, BV, and erlotinib+BV). (B–D) *P < 0.01, **P < 0.05, t test.