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Blood, 15 October 2004, Vol. 104, No. 8, pp. 2224-2234. Prepublished online as a Blood First Edition Paper on July 1, 2004; DOI 10.1182/blood-2004-03-1109. This Article Full Text (PDF) All Versions of this Article: 2004-03-1109v1 104/8/2224    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Murdoch, C. Articles by Lewis, C. E Search for Related Content PubMed PubMed Citation Articles by Murdoch, C. Articles by Lewis, C. E Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 24, 2004 Accepted May 28, 2004 Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues Craig Murdoch, Athina Giannoudis, and Claire E Lewis* Tumor Targeting Group, Academic Unit of Pathology, Division of Genomic Medicine, University of Sheffield Medical School, Sheffield, United Kingdom * Corresponding author; email: claire.lewis{at}sheffield.ac.uk. The mechanisms responsible for recruiting monocytes from the bloodstream into solid tumors are now well characterized. However, recent evidence has shown that these cells then differentiate into macrophages and accumulate in large numbers in avascular and necrotic areas where they are exposed to hypoxia. This parallels their tendency to congregate in ischemic areas of other diseased tissues such as atherosclerotic plaques and arthritic joints. In tumors, macrophages appear to undergo marked phenotypic changes when exposed to hypoxia and to switch on their expression of a number of mitogenic and pro-angiogenic cytokines and enzymes. This then promotes tumor growth, angiogenesis and metastasis. Here, we compare the various mechanisms responsible for monocyte recruitment into tumors with those regulating the accumulation of macrophages in hypoxic/necrotic areas. As the latter are best characterized in human tumors, we focus mainly on these but also discuss their relevance to macrophage migration in ischemic areas of other diseased tissues. Finally, we discuss the relevance of these mechanisms to the development of novel cancer therapies, both in providing targets to reduce the pro-angiogenic contribution made by hypoxic macrophages in tumors, and in developing the use of macrophages to deliver therapeutic gene constructs to hypoxic areas of diseased tissues. 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