Administration of VEGF receptor tyrosine kinase inhibitor increases VEGF production causing angiogenesis in human small-cell lung cancer xenografts

Abstract

Abstract. Angiogenesis is mediated mainly by vascular endothelial growth factor (VEGF), and VEGF causes rapid growth in cancers, including human small-cell lung cancer (SCLC). The anti-angiogenic strategy of treating cancer using VEGF receptor (VEGFR) inhibition is currently of great interest. We tested the effects of the VEGFR2 tyrosine kinase inhibitor (TKI) vandetanib on the proliferation of two kinds of SCLC cell lines: SBC-1 cells, with detectable VEGFR2 expression and MS-1-L cells, without detectable VEGFR2 expression. To evaluate the anti-tumor and anti-angiogenic effects of vandetanib in vivo, we grafted SBC-1 and MS-1-L cells into mice. After a 3-week treatment, we measured the tumor size and histologically evaluated necrosis and apoptosis using H&E and TUNEL staining, respectively. The microvessels in the xenografts were also quantified by immunostaining of CD31. Vandetanib did not affect the proliferation of SBC-1 cells, but stimulated the growth of MS-1-L cells. In the SCLC xenograft model, vandetanib inhibited growth and tumor angiogenesis in a dose-dependent manner in SBC-1 xenografts. Vandetanib inhibited the growth of MS-1-L xenografts at a low dose (<12.5 mg/kg/day), but it did not affect tumor size or change microvessel counts at a higher dose. Interestingly, secretion of VEGF increased significantly in the MS-1-L cell line in the presence of a high dose of vandetanib in vitro. The effects of vandetanib on tumor angiogenesis were different in SBC-1 and MS-1-L cell lines. Production of angiogenic factors such as VEGF by the tumor potentially stimulates tumor angiogenesis and results in the acquisition of resistance to VEGFR TKI.

Inhibition of tumor growth and angiogenesis by a lysophosphatidic acid antagonist in an engineered three‐dimensional lung cancer xenograft model

“…The critical importance of angiogenesis in growth and metastasis of lung cancers has led to investigation of an increasing number of antiangiogenesis agents for all types of pulmonary malignancies 17. This angiogenesis is mediated by factors such as vascular endothelial growth factor (VEGF) 18. Immobilization of a thiol‐modified heparin derivative in the sECM provided a component that mimicked the heparan sulfate proteoglycans (HSPGs) of native ECMs 19.…”

Evaluating dual activity LPA receptor pan-antagonist/autotaxin inhibitors as anti-cancer agents in vivo using engineered human tumors

“…We explored several customized compositions of sECM for in vivo xenografts of the A-549 cells. Since an intratumoral vascular network is important in pulmonary malignancies (56, 57), we used our angiogenesis plug strategy, selecting Extracel-HP as the sECM for retention of growth factors (18). Extracel-HP, which contains an immobilized form of heparin (43), mimics the heparin sulfate proteoglycans normally present in the ECM to help protect growth factors (GFs) from proteolysis and to slow their release to attached cells.…”

Combination of Vandetanib, Radiotherapy, and Irinotecan in the LoVo Human Colorectal Cancer Xenograft Model

“…36 Mechanisms of resistance include upregulation of alternative proangiogenic signaling pathways as well as recruitment of bone marrow-derived proangiogenic cells. 37,38 In addition, administration of vandetanib itself has been observed to increase VEGF production in certain cancer cell lines as well as in tumor xenografts, 39,40 thereby suggesting an additional contributing mechanism to tumor relapse. More studies will be needed to determine whether additional angiogenic pathways may be induced by triple modality treatment.…”