Cytokine regulation of angiogenesis in breast cancer: the role of tumor-associated macrophages

Abstract

Studies over the past 20 years have established that the development of new capillaries from an existing vascular network (a process called angiogenesis) is an essential component of tumor growth. Malignant tumors do not grow beyond 2-3 mm3 in size unless they stimulate the formation of new blood vessels and thus provide a route for the increased inflow of nutrients and oxygen and outflow of waste products. Tumor angiogenesis also provides an essential exit route for metastasizing tumor cells from the tumor to the bloodstream. Indeed, extensive neovascularization is a poor prognostic factor in several forms of human cancer. Angiogenesis is a complex, multistep process driven by many local signals within the tumor. This involves the degradation of the extracellular matrix around a local venule after the release of collagenases and proteases, the proliferation and migration of capillary endothelial cells, and their differentiation into functioning capillaries. Cytokines produced by various cell types present within the microenvironment of solid tumors form a complex, dynamic network in which they have multiple effects on tumor progression. Herein we review our work on the presence, and possible regulatory influence on tumor angiogenesis, of a number of these cytokines within invasive breast carcinomas. We have combined immunocytochemistry with a single cell cytokine release assay called the reverse hemolytic plaque assay to investigate the cellular sources of the key angiogenic cytokines, vascular endothelial growth factor, basic fibroblast growth factor, and tumor necrosis factor-alpha. Tumor-associated macrophages in the stromal compartment of these tumors and/or malignant epithelial cells were seen to be a major producer cell for these cytokines, whereas tumor necrosis factor-alpha receptors were expressed by leukocytes, malignant cells, and endothelial cells in tumor blood vessels.

Extracellular Cleavage of the Vascular Endothelial Growth Factor 189-Amino Acid Form by Urokinase Is Required for Its Mitogenic Effect

“…When the cells are stimulated by various stimuli such as hypoxia or growth factors, they respond by increasing VEGF transcription (33,34). In the most ischemic areas of tumors (in breast cancer, for example), VEGF has been described as localized in cell membranes and the matrix of the producing cells (cancer and stromal cells (35)) as well as in tumor-associated macrophages (36), where uPA and its receptor are also localized (37). Thus tumoral up-regulation of VEGF and uPA might lead to the generation of V189 competent to diffuse toward endothelial cells, activate the KDR/Flk-1 receptor pathways, and induce cell proliferation.…”

Distinct Role of Macrophages in Different Tumor Microenvironments

“…Additionally, they express a broad array of angiogenesis-modulating enzymes, including MMP-2, MMP-7, MMP-9, MMP-12, and cyclooxygenase-2 (COX-2; refs. [25][26][27]. TAM production of MMP-9 has been shown to be crucial for angiogenesis in a mouse model of human cervical carcinogenesis (estrogen-treated K14-HPV16 female transgenic mice; ref.…”

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

“…11 It is thought that PBMs are recruited to the tumor micro-environment as a result of the secretion of various chemotactic cytokines, e.g., CSF-1, GM-CSF, VEGF, MCP-1 and TGF-␤1. [12][13][14][15][16][17] However, little is known regarding the mechanisms by which HNSCC induces the migration of PBMs into the tumor micro-environment. To investigate this, CM from HNSCC were evaluated for the ability to attract human PBMs.…”