interleukin-8 and vatalanib

Glioblastoma (GBM) was shown to relapse faster and displayed therapeutic resistance to antiangiogenic therapies (AATs) through an alternative tumor cell-driven mechanism of neovascularization called vascular mimicry (VM). We identified highly upregulated interleukin 8 (IL-8)-CXCR2 axis in tumor cells in high-grade human glioma and AAT-treated orthotopic GBM tumors.. Human GBM tissue sections and tissue array were used to ascertain the clinical relevance of CXCR2-positive tumor cells in the formation of VM. We utilized U251 and U87 human tumor cells to understand VM in an orthotopic GBM model and AAT-mediated enhancement in VM was modeled using vatalanib (anti-VEGFR2) and avastin (anti-VEGF). Later, VM was inhibited by SB225002 (CXCR2 inhibitor) in a preclinical study.. Overexpression of IL8 and CXCR2 in human datasets and histological analysis was identified as a bonafide candidate to validate VM through in vitro and animal model studies. AAT-treated tumors displayed a higher number of CXCR2-positive GBM-stem cells with endothelial-like phenotypes. Stable knockdown of CXCR2 expression in tumor cells led to decreased tumor growth as well as incomplete VM structures in the animal models. Similar data were obtained following SB225002 treatment.. The present study suggests that tumor cell autonomous IL-8-CXCR2 pathway is instrumental in AAT-mediated resistance and VM formation in GBM. Therefore, CXCR2 can be targeted through SB225002 and can be combined with standard therapies to improve the therapeutic outcomes in clinical trials.

Topics: Angiogenesis Inhibitors; Animals; Bevacizumab; Brain Neoplasms; Glioblastoma; Humans; Interleukin-8; Molecular Targeted Therapy; Neovascularization, Pathologic; Phenylurea Compounds; Phthalazines; Pyridines; Rats, Nude; Receptors, Interleukin-8B; Tissue Array Analysis; Tumor Burden; Xenograft Model Antitumor Assays

Transformation of small avascular masses of tumor cells into rapidly progressive cancers is triggered by the angiogenic switch, a process that involves vascular endothelial growth factor (VEGF) signaling. We have shown that VEGF enhances the survival and angiogenic potential of endothelial cells by activating the Bcl-2-CXCL8 signaling axis. The purpose of this study was to evaluate the effect of a small-molecule inhibitor of VEGF receptors (PTK/ZK) on the initial stages of head and neck tumor angiogenesis. In vitro, PTK/ZK blocked head and neck tumor cell (OSCC3 or UM-SCC-17B)-induced Bcl-2 and CXCL8 expression in endothelial cells. Oral administration of PTK/ZK decreased xenograft head and neck tumor microvessel density, and inhibited Bcl-2 and CXCL8 expression in tumor-associated endothelial cells. Analysis of these data demonstrates that PTK/ZK blocks downstream targets of VEGF signaling in endothelial cells, and suggests that PTK/ZK may inhibit the angiogenic switch in head and neck tumors.

Topics: Angiogenesis Inhibitors; Animals; Carcinoma, Squamous Cell; Cell Line, Tumor; Coculture Techniques; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelial Cells; Endothelium, Vascular; Head and Neck Neoplasms; Humans; Interleukin-8; Mice; Mice, SCID; Microvessels; Neoplasm Transplantation; Neovascularization, Pathologic; Phthalazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Pyridines; Receptors, Vascular Endothelial Growth Factor; Transplantation, Heterologous; Tumor Cells, Cultured

Patients with breast cancer brain metastases cannot be cured and have a poor prognosis, with a median survival time of six months after diagnosis, despite developments in diagnostic and therapeutic modalities. In large part the progress in understanding the biology of breast cancer brain metastasis has been limited by the lack of suitable cell lines and experimental models. The objective of this study was to develop a reliable experimental model to study the pathogenesis of breast cancer brain metastases, using intra-internal carotid artery injection of breast cancer cells into nude mice. Brain metastasis-selected variant cells were recovered after three cycles of injection into the internal carotid artery of nude mice and harvest of brain metastases, resulting in variants termed MDA-231 BR1, -BR2 and -BR3. The metastasis-selected cells had increased potential for experimental brain metastasis and mice injected with these cells had significantly shorter mean survival than mice injected with the original cell line. Brain metastatic lesions of the selected variants contained significantly more CD31-positive blood vessels than metastases of the non-selected cell line. The variants selected from brain metastases released significantly more VEGF-A and IL-8 into culture supernatants than the original cell line, and more VEGF-A RNA when cultured in normoxic conditions. Mice injected with MDA-231 BR3 into the carotid artery were treated with the VEGF-receptor tyrosine kinase inhibitor PTK787/Z 222584. Oral administration of the inhibitor resulted in a significant decrease in brain tumor burden, reduced CD31-positive vessels in the brain lesions and incidence of PCNA positive tumor cells, and increased apoptosis in the tumor, as measured by TUNEL labeling. We conclude that elevated VEGF expression contributes to the ability of breast cancer cells to form brain metastases. Targeting endothelial cells with a VEGF-receptor specific tyrosine kinase inhibitor reduced angiogenesis and restricted the growth of the brain metastases.

Topics: Animals; Brain Neoplasms; Breast Neoplasms; Carcinoma, Ductal; Carotid Artery, Internal; Cell Hypoxia; Cell Line, Tumor; Enzyme Inhibitors; Female; Humans; Injections, Intra-Arterial; Interleukin-8; Mice; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Phthalazines; Pyridines; Receptors, Vascular Endothelial Growth Factor; RNA, Messenger; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays