Modulation of bcl-xL in Tumor Cells Regulates Angiogenesis through CXCL8 Expression

Abstract

In this paper, we investigated whether bcl-xL can be involved in the modulation of the angiogenic phenotype of human tumor cells. Using the ADF human glioblastoma and the M14 melanoma lines, and their derivative bcl-xL -overexpressing clones, we showed that the conditioned medium of bcl-xL transfectants increased in vitro endothelial cell functions, such as proliferation and morphogenesis, and in vivo vessel formation in Matrigel plugs, compared with the conditioned medium of control cells. Moreover, the overexpression of bcl-xL induced an increased expression of the proangiogenic interleukin-8 (CXCL8), both at the protein and mRNA levels, and an enhanced CXCL8 promoter activity. The role of CXCL8 on bcl-xL -induced angiogenesis was validated using CXCL8-neutralizing antibodies, whereas down-regulation of bcl-xL through antisense oligonucleotide or RNA interference strategies confirmed the involvement of bcl-xL on CXCL8 expression. Transient overexpression of bcl-xL led to extend this observation to other tumor cell lines with different origin, such as colon and prostate carcinoma. In conclusion, our results showed that CXCL8 modulation by bcl-xL regulates tumor angiogenesis, and they point to elucidate an additional function of bcl-xL protein. (Mol Cancer Res 2007;5(8):761 -71)

Human and Mouse Osteoprogenitor Cells Exhibit Distinct Patterns of Osteogenesis in Three-Dimensional Tissue Engineering Scaffolds

“…48 -50 IL-8 stimulates endothelial cell growth via increased secretion of vascular growth factors such as VEGF and basic fibroblast growth factor. 48,50 Expression of IL-8/keratinocyte chemoattractant and VEGF can hence be used to monitor angiogenic activity during osteogenic differentiation. Interesting, we did not note any interspecies differences in expression of angiogenic markers IL-8/keratinocyte chemoattractant and VEGF.…”

Microarray Comparative Genomic Hybridization Detection of Copy Number Changes in Desmoplastic Melanoma and Malignant Peripheral Nerve Sheath Tumor

“…9 Also amplified was ARTN on chromosome 1p, which encodes the protein artemin, which is reported to promote invasion of pancreatic carcinoma, influence perineural invasion, and increase the oncogenicity and invasiveness of endometrial carcinoma. 10 Interestingly, the gene AMPK on chromosome 1p was also amplified; although adenosine monophosphate-activated protein kinase (AMPK) has proapoptotic properties, it is well known to be involved in UV-induced skin cell damage and also plays a major role in the regulation of vascular endothelial growth factor expression and has a potential role in tumor angiogenesis. [11][12][13][14] Also amplified on chromosome 1p was the oncogene NRAS, a member of the RAS family, which encodes a membrane protein involved in the cellular signal transduction.…”

Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF expression in hypoxic tumor cells

“…7 In addition to protecting from apoptosis and increasing survival, bcl-2 and bcl-xL are involved in several other important functions, including angiogenesis. [8][9][10][11][12][13][14][15][16] In this context, we have previously reported that bcl-2 expression in tumor cells exposed to hypoxia increases the expression of vascular endothelial growth factor (VEGF) through the hypoxia-inducible factor-1 (HIF-1). 9,11 In vitro and in vivo inhibition of bcl-2 functions has a strong effect on HIF-1 target genes that, in some cases, is functionally unrelated to the prosurvival effect of bcl-2.…”