The relationship between the immune system and angiogenesis has been described in several contexts, both in physiological and pathological conditions, as pregnancy and cancer. In fact, different types of immune cells, such as myeloid, macrophages and denditric cells, are able to modulate tumor neovascularization. On the other hand, tumor microenvironment also includes extracellular matrix components like hyaluronan, which has a deregulated synthesis in different tumors. Hyaluronan is a glycosaminoglycan, normally present in the extracellular matrix of tissues in continuous remodeling (embryogenesis or wound healing processes) and acts as an important modulator of cell behavior by different mechanisms, including angiogenesis. In this review, we discuss hyaluronan as a modulator of tumor angiogenesis, focusing in intracellular signaling mediated by its receptors expressed on different immune cells. Recent observations suggest that the immune system is an important component in tumoural angiogenesis. Therefore, immune modulation could have an impact in anti-angiogenic therapy as a new therapeutic strategy, which in turn might improve effectiveness of treatment in cancer patients.
Hyaluronan is a glycosaminoglycan normally present in the extracellular matrix in most tissues. Hyaluronan is a crucial player in many processes associated with cancer, such as angiogenesis, invasion, and metastasis. However, little has been reported regarding the action of hyaluronan on monocytes/macrophages (Mo/MØ) in tumor angiogenesis and its consequences on tumor development. In the present study, we investigated the effects of hyaluronan of different sizes on human Mo/MØ angiogenic behavior in colorectal and breast carcinoma. In vitro, the treatment of Mo/MØ with lysates and conditioned media from a breast but not from colorectal carcinoma cell line plus high‐molecular weight hyaluronan induced: (a) an increased expression of angiogenic factors VEGF, IL‐8, FGF‐2, and MMP‐2, (b) an increased endothelial cell migration, and (c) a differential expression of hyaluronan‐binding protein TSG‐6. Similar results were observed in Mo/MØ derived from breast cancer patients treated with tumor lysates. Besides, macrophages primed with high‐molecular weight hyaluronan and inoculated in human breast cancer xenograft tumor increased blood vessel formation and diminished TSG‐6 levels. In contrast, the effects triggered by high‐molecular weight hyaluronan on Mo/MØ in breast cancer context were not observed in the context of colorectal carcinoma. Taken together, these results indicate that the effect of high‐molecular weight hyaluronan as an inductor of the angiogenic behavior of macrophages in breast tumor context is in part consequence of the presence of TSG‐6.
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