The immunological effect of hyaluronan in tumor angiogenesis

Abstract

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.

Figure 1

Immune cells: HA binding and angiogenic signaling. During inflammation immune cells are able to bind HA. Even more, it is well known that these cells are able to modulate angiogenesis by releasing cytokines and angiogenic factors.

Figure 2

HA–CD44 interaction. CD44 has a cytoplasmic domain that can be phosphorylated when HA binds to transduce signaling and so it selects its downstream effectors, it can be cytoskeletal proteins like Ankyrin, different oncogenic signals such as RhoGTPases, PI3K, β-catenin and the release of ECM-degrading enzymes (MMPs). This interactions and modulations generate multiple cellular functions: cytoskeleton activation, tumor cell adhesion, tumor growth and invasion, tumor progression, angiogenesis and metastasis.