Antitumor/Antiestrogenic Effect of the Chemokine Interferon Inducible Protein 10 (IP-10) Involves Suppression of VEGF Expression in Mammary Tissue

Abstract

Vascular endothelial growth factor (VEGF) promotes angiogenesis in a number of tumor model systems. We reported previously that estrogen supports the growth of CCL-51 cell-based mammary tumors in mice, which could be blocked with specific chemokines. We investigated whether promotion of tumor growth by estrogen, and suppression of tumor growth by chemokines, was associated with VEGF protein expression. Female C3H mice were treated with vehicle, estradiol, or with one of several chemokines for 72 h. The presence of VEGF in mammary tissue samples was detected and quantified by sodium dodecyl sulfate polyacrylamide gel electrophoresis and immunoblotting using antimurine VEGF antibodies. Estrogen significantly increased mammary VEGF expression. Cotreatment with tamoxifen or the chemokine interferon-inducible protein-10 (IP-10) suppressed the action estrogen on VEGF expression. CCL-51 tumor cells were placed into mammary tissue of C3H mice. Mice were treated every 72-h with either vehicle or estradiol, in the presence or absence of IP-10 for 21 days. Estrogen supported CCL-51 tumor growth, with an average of 2.3 tumors present/animal. Cotreatment of mice with estrogen and IP-10 resulted in significantly lower numbers of tumors in mammary tissue in comparison to animals treated with estrogen alone. VEGF levels in mammary tissue and tumors of IP-10 and estrogen cotreated mice were 40-50% less than those detected in mammary tissue of estrogen-treated mice. Our results suggest that estrogenic support of CCL-51 mammary tumor growth is related to increased VEGF expression, and that the inhibitory action of IP-10 may be related to suppressing VEGF levels in mammary tissue.

The emerging role of CXCL10 in cancer (Review)

“…CXCL10 inhibits the growth of cervical carcinoma by down-regulating the formation of microvessels, the expression of proliferating cell nuclear antigens and the expression of human papillomavirus oncoproteins E6 and E7 through an increase in the apoptotic rate (41). In estrogen receptorpositive (ER + ) mammary tumors, CXCL10 inhibits vascular endothelial growth factor levels to reduce tumor burden (50).…”

Absence of CXCL10 Aggravates Herpes Stromal Keratitis with Reduced Primary Neutrophil Influx in Mice

“…HSV-1 infection of the mouse cornea is shown to increase the expression of potent angiogenic factors, VEGF-A and FGF-2, to enhance HSK severity (1,10). CXCL10 is a known angiostatic factor capable of suppressing the expression of VEGF-A and the angiogenic responses induced by both VEGF-A and FGF-2 (26)(27)(28)(29). As absence of CXCL10 enhances the angiogenesis of HSK, we examined the influence of CXCL10 deficiency on the expression of the angiogenic factors VEGF-A and FGF-2.…”

“…However, CXCL10 has been implicated in aggravating virus-induced diseases, such as demyelination in the mouse brain induced by mouse hepatitis virus, meningoencephalitis in mice induced by lymphocytic choriomeningitis virus, liver damage in humans induced by chronic hepatitis C virus infection, and neurological disorders induced by human immunodeficiency virus (19,(23)(24)(25). Additionally, CXCL10 serves as an angiostatic factor to inhibit the expression of VEGF-A or the angiogenic response induced by FGF-2 or VEGF-A (26)(27)(28)(29).…”

Chemokine Receptors as Targets for Cancer Therapy

“…The regression of murine renal cell cancers by IL-12, for instance, has been demonstrated to be mediated through either CXCL9 or CXCL10 [97]. Interestingly, the anti-tumor/angiogenic effects of CXCL10 were associated with decreased expression of VEGF within mammary tumors [98].…”