Expression and function of angiopoietin-1 in breast cancer

Abstract

Angiopoietin-1 (Ang1) has been shown to act as an angiogenic promoter in embryonic angiogenesis by promoting vascular branching, pericyte recruitment and endothelial survival. We have investigated the role of Ang1 in tumour neovascularization under clinical conditions and in animal models. The expression of Ang1 in clinical breast cancer specimens was analysed by using laser-capture microdissection and reverse transcriptase-linked polymerase chain reaction (RT-PCR) on RNA isolated from the samples. Despite the expression of Ang1 in many human breast cancer cell lines, the gene was expressed in only three of 21 breast cancer clinical specimens, even though its receptor, Tie2, is abundant in the vasculature of all of these tumours. Ang1 was then overexpressed in a human breast cancer cell line (MCF-7) on its own and in conjunction with FGF1, an angiogenic factor shown to be able to increase the tumorigenicity of MCF-7 cells. High concentrations of Ang1 were produced in the conditioned media of the transfected cells (range 156–820 ng ml–1). However, in contrast to its physiological role as promoter of angiogenesis, overexpression of Ang1 did not enhance tumour growth, but instead caused up to a 3-fold retardation of tumour growth (P = 0.003). © 2000 Cancer Research Campaign

Stabilization of breast cancer xenograft tumour neovasculature by angiopoietin-1

“…Human breast cancer cell line MCF-7 was stably transfected with full length Ang1 gene, and the secretion of Ang1 into the conditioned media was determined as described (Hayes et al, 2000). In vitro culture, harvest and inoculation of 5610 6 cells in the region of the mammary fat pads of the mice was performed as described (Hayes et al, 2000).…”

“…We recently reported (Hayes et al, 2000) that overexpression of Ang1 in an MCF-7 xenograft model of tumour angiogenesis resulted in a retardation of tumour growth and the extent of inhibition correlated to the extent of Ang1 overexpression. Others also reported a similar inhibition of colon cancer xenograft tumour growth (Ahmad et al, 2001).…”

“…It has also been reported that Ang1 as well as Ang2 were direct substrates in endothelial cell adhesion mediated by integrins (Carlson et al, 2001). Many studies have investigated the expression patterns of Ang1, other angiopoietins, and Tie2 in a variety of tumours, including cancers of the breast (Hayes et al, 2000;Currie et al, 2001), brain (Stratmann et al, 1998;Zagzag et al, 1999;Eggert et al, 2000), liver (Tanaka et al, 1999), ovary (Martoglio et al, 2000), lung (Takahama et al, 1999;Wong et al, 2000), Kaposi's sarcoma and cutaneous angiosarcoma , thyroid gland (Bunone et al, 1999), and leukaemia (Kukk et al, 1997). These studies revealed a complex pattern of expression of the angiopoietins and Tie2 that is consistent with an important role for Ang2 and VEGF in the destabilization of vasculature and initiation of tumour angiogenesis.…”

The enigmatic role of angiopoietin-1 in tumor angiogenesis

“…In sharp contrast to the findings from the transgenic studies showing that Ang1 is a promoter of vasculogenesis and angiogenesis during embryonic development, studies using xenograft models demonstrate that ectopic expression of Ang1 in breast [82] and colon [69] cancer cells results in decreased tumor proliferation and angiogenesis. In addition, Ang1 inhibits colon cancer peritoneal [87] and hepatic metastases [88].…”

“…Increasing evidence, however, is suggesting a lack of a role for Ang1 in several cancers in a clinical setting. Recently, we reported that breast cancer epithelial cells do not express Ang1 [82]; others have confirmed decreased Ang1 expression in breast tumors compared to normal breast tissue [83]. Similarly, immunohistochemistry studies demonstrated that Ang1 is expressed in normal colonic epithelium, whereas colon tumors lack appreciable Ang1 staining [84].…”