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Angiogenesis, an essential step in the development of neoplasia, is a complex process that involves the interaction of tumor cells with stromal cells. Tumor-associated macrophages (TAMs) can participate in the induction of tumor angiogenesis and are thought to be of prognostic value in some neoplasms. We have investigated how macrophages contribute to angiogenesis in head-and-neck squamous-cell carcinoma (HNSCC) and have found that tumor cells attract monocytes and activate them to secrete angiogenic factors. The attraction of macrophages was due to the secretion of monocyte chemotactic protein-1 and TGF-␤1 by tumor cells, while tumor production of TGF-␤1 was responsible for activating macrophages. In addition, activated macrophages produced cytokines that acted in a paracrine fashion by secreting both TNF-␣ and IL-1, which in turn stimulated tumor cells to secrete increased levels of IL-8 and VEGF. These data demonstrate that TAMs play an important role in the in vivo induction of angiogenesis in HNSCC and suggest that antiangiogenic therapies for HNSCC and perhaps other neoplasms must include strategies that will block the ability of tumor cells to recruit macrophages into the tumor microenvironment.Key words : squamous-cell carcinoma; angiogenesis; macrophages; angiogenic loop; head-and-neck cancer Angiogenesis, the growth of new blood vessels from pre-existing ones, is an essential phenotype for tumor formation. 1 Expression of the angiogenic phenotype in the tumor micro-environment is a complex process involving the interaction of many different cell types. The interplay between tumor cells and the various constituents of the surrounding stroma is thought to be critically important in various aspects of tumor biology, including angiogenesis. 2 Macrophages, part of the tumor stroma, are members of the mononuclear phagocyte system of inflammatory cells. A very heterogeneous group, they perform a wide variety of functions depending on the physiologic or pathophysiologic condition to which they are recruited. Given the remarkable versatility of macrophages, it is not surprising that they participate in the induction of tumor angiogenesis. 3 There is a great deal of interest in developing chemotherapeutic clinical trials that are based on anti-angiogenic therapies. 4 However, one of the major challenges for designing such therapies is that there are numerous direct and indirect mechanisms by which tumors can induce new blood vessel growth, including eliciting the help of various stromal cells. Therefore, it is reasonable to assume that successful anti-angiogenic protocols must address each of the possible mechanisms by which tumors can induce new blood vessel growth. Our aim was to identify additional potential mechanisms by which human head-and-neck squamous-cell carcinoma (HNSCC) may induce neovascularization in vivo. Specifically, we investigated how macrophages contribute to angiogenesis in HNSCC and show that HNSCC tumor cells attract monocytes and activate them to secrete angiogenic factors. In additio...

Cervical cancer is associated with human papilloma virus infection. However, this infection is insufficient to induce transformation and progression. Loss of heterozygosity analyses suggest the presence of a tumor suppressor gene (TSG) on chromosome 6p21.3-p25. Here we report the cloning NOL7, its mapping to chromosome band 6p23, and localization of the protein to the nucleolus. Fluorescence in situ hybridization analysis demonstrated an allelic loss of an NOL7 in cultured tumor cells and human tumor samples. Transfection of NOL7 into cervical carcinoma cells inhibited their growth in mouse xenografts, confirming its in vivo tumor suppressor activity. The induction of tumor dormancy correlated with an angiogenic switch caused by a decreased production of vascular endothelial growth factor and an increase in the production of the angiogenesis inhibitor thrombospondin-1. These data suggest that NOL7 may function as a TSG in part by modulating the expression of the angiogenic phenotype.

Angiogenesis, an essential step in the development of neoplasia, is a complex process that involves the interaction of tumor cells with stromal cells. Tumor-associated macrophages (TAMs) can participate in the induction of angiogenesis and are of prognostic value in some neoplasms. Specimens from head and neck squamous cell carcinomas (HNSCC) often contain large numbers of TAMs. In addition, experimental evidence has demonstrated that HNSCC tumor cells can attract and activate macrophages to participate in the expression of the angiogenic phenotype. These findings suggest that antiangiogenic therapies for HNSCC must include strategies that will block the recruitment of macrophages into the tumor microenvironment. We investigated the ability of retinoic acid (RA) to modulate the ability of tumor cells to recruit and activate monocytes for participation in tumor angiogenesis. Owing to a decrease in the secretion of MCP-1 and transforming growth factor-␤1 (TGF-␤1), tumor cells treated with RA were unable to induce peripheral blood monocyte (PBM) chemotaxis. Also, as a result of the decrease in TGF-␤1 secretion, RA-treated tumor cells were unable to activate macrophages for secretion of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). In addition to its affects on tumor cells, RA also directly altered the ability of monocytes to participate in the tumor angiogenesis process. PBM exposed to RA were unable to migrate toward inducers of PBM such as MCP-1 and TGF-␤1. Finally, RA decreased the ability of tumor-activated macrophages to secrete IL-8 and VEGF. These data demonstrate alternative mechanisms by which RA may modulate angiogenesis in the tumor microenvironment. In addition, it underscores the necessity to develop antiangiogenic treatment protocols that can block each of the ways in which new blood vessel growth is induced in tumor microenvironments.

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