The role of chemokines and their receptors in angiogenesis

Abstract

Chemokines are a vertebrate-specific group of small molecules that regulate cell migration and behaviour in diverse contexts. So far, around 50 chemokines have been identified in humans, which bind to 18 different chemokine receptors. These are members of the seven-transmembrane receptor family. Initially, chemokines were identified as modulators of the immune response. Subsequently, they were also shown to regulate cell migration during embryonic development. Here, we discuss the influence of chemokines and their receptors on angiogenesis, or the formation of new blood vessels. We highlight recent advances in our understanding of how chemokine signalling might directly influence endothelial cell migration. We furthermore examine the contributions of chemokine signalling in immune cells during this process. Finally, we explore possible implications for disease settings, such as chronic inflammation and tumour progression.

Fig. 1

Endothelial autonomous and non-autonomous roles of chemokines during angiogenesis. a Chemokines act directly on endothelial cells expressing chemokine receptors and thereby influence endothelial migration and angiogenesis. b Chemokines indirectly influence endothelial cell behaviours by attracting chemokine receptor-expressing leucocytes. These subsequently secrete proangiogenic factors, such as VEGF, that act on endothelial cells and initiate angiogenesis

Fig. 2

The role of chemokine signalling during tumour formation. a Immune evasion. Chronic local inflammation caused by irritants or pathogens is accompanied by persistent leucocyte infiltration. Activated inflammatory macrophages secrete abundant growth factors and produce reactive oxygen and nitrogen species, which generate a mutagenic environment that ultimately initiates transforming events. b Angiogenesis. The forming hyperplastic tissue is a source of chemoattractants, including CCL2/MCP-1 and CSF-1, which recruit circulating monocytes. As these monocytes colonize the tumour, they are instructed by the tumour environment to differentiate into M2 type TAMs. Tumour cells may also express chemokine receptors and respond to autocrine and paracrine stimulation. c Tissue destruction/remodelling. Tumour growth is associated with accumulation of M2-type TAMs, which not only produce additional chemoattractants, but also actively suppress inflammatory and cytotoxic responses to the tumour. TAMs secrete proangiogenic factors that in addition to proangiogenic chemokines support tumour vascularization. TAMs also provide proteolytic activities that help the tumour to overcome constraining tissue borders and enhance metastasis. Throughout the entire development, new macrophages are recruited and subverted to serve the major objectives of the developing tumour. The major chemoattractant/growth factor producing cell types are highlighted on the right