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Interleukin-8 and human cancer biology

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Abstract

The aggressive nature of metastatic human cancer has been shown to be related to numerous abnormalities in growth factors and their receptors. These perturbations confer a tremendous growth advantage to the malignant cells. Interleukin-8 (IL-8), originally discovered as a chemotactic factor for leukocytes, has recently been shown to contribute to human cancer progression through its potential functions as a mitogenic, angiogenic, and motogenic factor. While it is constitutively detected in human cancer tissues and established cell lines, IL-8 expression is regulated by various tumor microenvironment factors, such as hypoxia, acidosis, nitric oxide, and cell density. Understanding the mechanisms of both inducible and constitutive IL-8 expression will be helpful in designing potential therapeutic strategies of targeting IL-8 to control tumor growth and metastasis. In this review, the role and regulation of IL-8 expression in the growth and metastasis of human cancer with a focus on human pancreatic adenocarcinoma will be discussed.

Section snippets

IL-8 expression

IL-8 was originally identified as a neutrophil chemotactic factor in the supernatants of activated human monocytes. As a member of the CXC chemokine family, IL-8 plays an important role as an activator and chemoattractant for neutrophils. The initial observation of IL-8 expression was done in human melanocytes and malignant melanoma cell lines stimulated with either TNF-α or IL-1α, the IL-8 mRNA signal corresponded well with the amount of secreted IL-8 protein [20]. It was predicted that IL-8

Regulation of IL-8 expression

It is now known that IL-8 is produced by various normal and tumorigenic human cells. While the production of IL-8 can be induced by various stimuli, such as lipopolysaccharide, phorbol 12-myristate 13-acetate (PMA), IL-1, and TNF (Fig. 1) [77], [78], [79], [80], [81], many tumor cells apparently express IL-8 constitutively. Furthermore, we have found that several stress factors, such as hypoxia, acidosis, nitric oxide (NO), and cell density, significantly influence the expression of IL-8 in

IL-8 expression and cancer progression

As a potential prognostic factor, IL-8 expression has been investigated in clinical studies using patient tumor tissue specimens and preclinical animal models using established cell lines. In human pancreatic cancer, IL-8 is overexpressed in tumor tissue as compared with normal tissue. To determine the role of IL-8 expression in tumor growth and metastasis, we used an orthotopic xenograft model to evaluate the tumorigenic and metastatic potential of COLO357, FG, SG, and L3.3 cells, which were

IL-8 and mitogenic effect

Since the discovery of IL-8 production by tumor cells, it has been predicted that IL-8 may stimulate tumor growth [20]. Schadendorf et al. [48] first demonstrated that endogenously produced human IL-8 can act as an important growth factor for human melanoma cells. They found that human melanoma cell lines secrete significant amounts of bioactive IL-8 protein into the culture supernatant and that this secretion was inducible by IL-1 and PMA. Exposure of some human melanoma cell lines in vitro to

IL-8 and angiogenic effect

The angiogenic activity of IL-8 produced by monocytes and macrophages was first demonstrated by Koch et al., [142] in 1992. They found that human recombinant IL-8 was potently angiogenic when implanted in a rat cornea and induced proliferation and chemotaxis of human umbilical vein endothelial cells. The angiogenic activity present in the conditioned medium of inflamed human rheumatoid synovial tissue macrophages and lipopolysaccharide-stimulated blood monocytes was equally blocked by

IL-8 and motogenic effect

IL-8 is a physiological initiator of the chemotactic migration of leukocytes, e.g. neutrophils and macrophages. Overexpression of IL-8 by tumor cells may lead to elevated infiltration of leukocytes, which have been shown to potentially produce various growth factors and angiogenic factors in large quantities and rapid expansion of tumor mass. The tumor cell-initiated and tumor infiltration cell-mediated tumor angiogenesis may produce strong indirect tumor-stimulating effects and underscore the

Targeting IL-8 expression for cancer treatment

The role of IL-8 in the growth and metastasis of some types of cancer, including human pancreatic adenocarcinoma, makes IL-8 an attractive target for treatment of cancer. A direct strategy may be to use an IL-8-neutralizing antibody to interfere with the functions of IL-8. Alternatively, blocking the IL-8 receptors will also block the signal transduction pathway initiated by IL-8. Additionally, there are two receptors for IL-8: IL-8Rα, which is specific for IL-8, and IL-8Rβ, which also binds to

Conclusion and future directions

The development of multiple autocrine growth-signaling pathways renders tumor cells a tremendous growth advantage and imposes significant difficulties in designing effective cancer therapy. Adding to the long list of growth factors and cytokines, IL-8 may also play a role in human cancer progression. The inference of the impact of IL-8 expression on tumor growth requires combined consideration of data obtained from cell cultures, animal models, and clinical studies. Nevertheless, multiple

Acknowledgements

I thank Don Norwood for editorial comments and Judy King for assistance in the preparation of this manuscript. This work was supported by the Research Project Grant #RPG-00-054-01-CMS from the American Cancer Society, the Lustgarten Pancreatic Cancer Research Foundation, the Multidisciplinary Pancreatic Program Research Grant, and Cancer Center Support Core grant CA 16672-23 form the National Institutes of Health (to Keping Xie).

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