Responses of vascular endothelial cells to angiogenic signaling are important for tumor cell survival

Abstract

Neoplastic cells overexpress several angiogenic cytokines, which stimulate neovascularization. Whether the responses of the host endothelial cells to these signaling molecules affect tumor cells during early tumorigenesis has not been investigated. We investigated pre-angiogenic tumor cell survival and angiogenesis initiation by two murine tumor lines (4T1 mammary carcinoma and B16 melanoma), which constitutively expressed GFP, in dorsal skin-fold window chambers of mice treated with extracellular domain of Tie-2 (ExTek) or bFGF. ExTek reduced tumor cell survival, retarded tumor growth, and inhibited angiogenesis onset compared with controls. bFGF increased tumor cell survival and promoted earlier angiogenesis and tumor growth. Neither bFGF nor ExTek affected cell proliferation in vitro. RT-PCR showed mRNA expression of bFGF receptor 2 (FGFR2) IIIb, which does not bind bFGF efficiently, by 4T1 cells and B16 cells express FGFR1 but not FGFR2. B16 cells expressed angiopoietin (Ang) 2, but neither cell line expresses Ang1. Both tumor lines express VEGF. These findings suggested that effects of bFGF and ExTek on tumor cell survival and angiogenesis were not due to direct action but were instead a result of paracrine factors secreted by endothelial cells. These subsequent signals from endothelial cells promote early survival and proliferation of disseminated tumor cells before onset of angiogenesis.

Graft-versus-tumor effects on murine mammary carcinoma in a model of nonmyeloablative haploidentical stem cell transplantation

“…The fact that FGFR2IIIb, the receptor that specifically binds KGF, 39,40 is present on breast cancer cell lines 41 and that there are reports of increased proliferation and migration in various tumor cells in response to KGF, [42][43][44][45] stresses the necessity to rule out any negative effect this growth factor might have in breast cancer patients. In view of a recent publication, revealing that 4T1 cells express mRNA of FGFR2IIIb, 46 prompted us to study the effect of KGF treatment in mice bearing this tumor. Our results demonstrate that neither tumor development nor survival are influenced by a 9-day KGF treatment in mice receiving a syngeneic transplant and that haploidentical transplantation in combination with KGF can prevent breast cancerinduced death.…”

Targeting Matrix Metalloproteinases and Endothelial Cells with a Fusion Peptide against Tumor

“…3, 4), angiostatin, endostatin, and pigment epitheliumderived factor (5,6), basic fibroblast growth factor (bFGF; ref. 7), platelet-derived endothelial cell growth factor (8) and the tie and tek receptors (9,10). The others are involved in the breakdown of basement membranes and extracellular matrix, and include proteases and their receptors such as the members of matrix metalloproteinases (MMP; ref.…”

3-D photoacoustic and pulse echo imaging of prostate tumor progression in the mouse window chamber

“…Hemorrhaging has previously been associated with prostate cancer. 32,35 It is possible that the rigid coverslip and rapid growth of the prostate tumor-induced excessive stress at the skin surface, causing blood vessels to rupture. Alternatively, the hemorrhage may have also been caused by rapid angiogenesis and resulting collapse of the hemorrhage-prone blood vessels near the tumor.…”