EDITORIAL

Interferon-{alpha} Is Implicated in the Transcriptional Regulation of Vascular Endothelial Growth Factor

Giovanna Tosato

Correspondence to: Giovanna Tosato, M.D., Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Dr., Bethesda, MD 20892 (e-mail: tosatog{at}mail.nih.gov).

A number of seminal observations over the last century have linked tumor growth with increased vascularization. In 1945, Algire et al. (1) noted that transplanted tumor cells could induce vessel sprouting before substantial tumor growth occurred and suggested that tumor explants require the development of a new vascular supply to grow. He further proposed that ". . . it is entirely possible that the change in the tumor cell that enables it to evoke capillary proliferation is the only change necessary to give the tumor cell its increased autonomy of growth relative to the normal cell from which it arose." In the 1960s, Ian Tannock (2) observed that the mitotic index of tumor cells was lowest in cells most distant from the blood supply, suggesting that tumor expansion requires oxygen and nutrients derived from vessels. There is now compelling evidence that tumor growth is dependent on angiogenesis, the process of new vessel formation and that cancer cells can promote vascular growth very early in the tumorigenic process (3,4). The acquisition of an angiogenic phenotype called "the angiogenic switch" is a marker of malignant transformation because it is linked to oncogene mutations or amplifications (59). In adults, angiogenesis is limited mostly to the ovaries (in conjunction with corpus luteum formation), the uterus (in conjunction with the estrous cycle), and to sites of tissue regeneration and inflammation (10). Thus, the selective dependency of tumors on angiogenesis has provided great impetus to the idea that targeting angiogenesis or destroying newly formed tumor vessels could be an effective strategy in treating cancer (1113).

Among the most characterized proangiogenic factors, vascular endothelial growth factor (VEGF) has emerged as being particularly important both in physiologic and in tumor-associated angiogenesis (4). A large number of different tumor types produce VEGF (14), and VEGF expression in nontumorigenic Chinese hamster ovary (CHO) cells renders them tumorigenic in mice, without changing their growth characteristics in vitro (15). Anti-VEGF neutralizing antibodies have been found to substantially reduce the growth of experimental tumors in mice and to halt tumor neovascularization (16,17). Drugs that can block VEGF signaling inhibit tumor growth in a variety of experimental systems (18,19), and expression of a dominant negative mutant Flk1/VEGF-R2 in endothelial cells reduces tumor growth in mice (20). In addition, VEGF inactivation in mature animals through Cre-lox technology can prevent tumor growth (21).

On the basis of this compelling evidence linking VEGF with tumor growth, much effort has been placed into developing anticancer drugs designed to reduce availability of biologically active VEGF. At present, a recombinant humanized monoclonal antibody directed at VEGF and a number of small molecules that inhibit VEGF receptor signaling are in various stages of clinical development (4,13). Furthermore, a number of anticancer drugs originally designed to target tumor cells in various ways indirectly inhibit VEGF expression (13).

In this issue of the Journal, von Marschall and colleagues (22) provide evidence linking the antitumor activity of interferon alpha (IFN-{alpha}) to inhibition of VEGF transcription. The authors focused on neuroendocrine tumors that are highly vascular and are sensitive to treatment with IFN-{alpha}. They show that IFN-{alpha} treatment is associated with reduced microvessel density and VEGF mRNA content in liver metastasis and with decreased levels of VEGF in plasma. In vitro, IFN-{alpha} inhibited transcription of the VEGF gene in tumor cell lines that constitutively express VEGF. Using promoter–reporter gene constructs, the authors mapped the IFN-{alpha} responsiveness to a region within VEGF promoter GC box I and found that this region can specifically bind the transcription factors Sp1 and Sp3. Thus, they concluded that IFN-{alpha} likely inhibits VEGF promoter activity by inhibiting Sp1 and/or Sp3 transactivating activity.

It was not previously known that IFN-{alpha} can directly regulate VEGF expression, but it was known that IFN-{alpha} displays antiangiogenic activities. In 1980, IFN-{alpha} was reported to inhibit endothelial cell motility in vitro (23). Subsequently, IFN-{alpha} was found to inhibit angiogenesis in mice (24,25). On the basis of these preclinical observations, beginning in the 1980s, a number of patients with hemangiomas were treated successfully with IFN-{alpha} (26,27). Studies on the mechanisms underlying these activities revealed that IFN-{alpha} decreases expression of basic fibroblast growth factor (bFGF) and other proangiogenic molecules, including matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) and interleukin 8 (IL-8) (28,29). The current article adds VEGF as a target for IFN-{alpha} effects and provides insight regarding its mechanism.

Since its initial discovery as an antiviral agent in the 1950s, IFN-{alpha} has emerged as a multifunctional regulator of cell growth and differentiation (30). Because of its antiproliferative and antitumor activities, IFN-{alpha} is a U.S. Food and Drug Administration (FDA)-approved drug for use in the treatment of a variety of malignancies, including hairy-cell leukemia, follicular lymphoma, chronic lymphocytic leukemia, melanoma, condylomata acuminata, and acquired immunodeficiency syndrome (AIDS)-associated Kaposi’s sarcoma. In general, response rates to IFN-{alpha} have been low in cancer patients (31). Pharmacokinetic studies and experiments in mice have suggested that current regimens based on intermittent treatment with IFN-{alpha} at maximal tolerated doses may not be as effective as daily low doses. In a preclinical mouse model of metastatic colon cancer in which the tumor cells were resistant to the antiproliferative effects of IFN-{alpha}, daily administration of IFN-{alpha} at low doses was effective at reducing tumor burden, whereas intermittent administration at higher doses was ineffective (29). Because effective IFN-{alpha} treatment was associated with lower vessel density in the tumor tissue and decreased expression of bFGF, MMP-9, and IL-8 by the tumor cells, it was concluded that the antitumor activity of IFN-{alpha} was related to its antiangiogenic activities rather than to direct antitumor effects (29).

Angiogenesis inhibitors are a new class of anticancer agents that target the tumor vasculature rather than the tumor cells (13). The principles that have been developed from the use of chemotherapeutic agents, which are toxic and target the genetically unstable tumor cells, are unlikely to apply to angiogenesis inhibitors, which tend to be nontoxic and target genetically stable cells. Based on earlier results and those of von Marschall and colleagues (22), IFN-{alpha} could be considered a broad-spectrum indirect angiogenesis inhibitor. As our understanding of the regulation of angiogenesis continues to improve, perhaps we will learn how best to use IFN-{alpha} as an anticancer agent that targets tumor angiogenesis.

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