Paracrine angiogenic loop between head-and-neck squamous-cell carcinomas and macrophages

Abstract

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...

Monocyte chemoattractant protein‐1 expression correlates with macrophage infiltration and tumor vascularity in human esophageal squamous cell carcinomas

“…Nesbit et al 38 showed that macrophages activated by MCP-1 release TNF-␣, which may induce angiogenesis in melanoma. Liss et al 39 reported that monocytes/macrophages are recruited and activated by tumor derived MCP-1 and TGF-␤1 and that activated macrophages produce TNF-␣ and IL-1␣, which in turn stimulate tumor cells to produce VEGF and IL-8. MCP-1 also influences angiogenesis directly.…”

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

“…Vol. 63,2006 Review Article 459 plastic cells, tumoral fibroblasts and smooth muscle cells produce distinct monocyte-attracting factors, including monocyte chemoattractant protein-1 (MCP-1), colonystimulating factor-1 (CSF-1), granulocyte-colony stimulating factor (G-CSF), VEGF-A, PlGF and VEGF-C [198][199][200]. Upon invasion into the tumor tissue, monocytes differentiate into macrophages and are specifically activated or de-activated, depending on the cytokine milieu encountered.…”

Tumour-derived TGF-β1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells

“…In addition, paracrine interactions have been demonstrated between squamous carcinoma cells and other cell types found in stroma. Liss et al (2001) found tumour-derived TGF-b1 and monocyte chemotactic protein-1 attracted and activated monocytes. They suggested that macrophages secreted TNF-alpha and IL-1, which in turn stimulated tumour cells to produce IL-8 and VEGF, the latter cytokine then inducing angiogenesis.…”