Review
Mast cells as therapeutic target in cancer

https://doi.org/10.1016/j.ejphar.2015.02.056Get rights and content

Abstract

Mast cells promote tumorigenesis and tumor progression, and have functions that favor the host. Increased mast cell number correlates with a poor prognosis in several human tumors. In different vascular tumors, as well as a number of hematological and solid tumors, mast cell accumulation correlate with increased neovascularization, tumor aggressiveness, and metastatic spread. Mast cells might act as a new target for the adjuvant treatment of tumors through the selective inhibition of angiogenesis, tissue remodeling and tumor-promoting molecules, permitting the secretion of cytotoxic cytokines and preventing mast cell-mediated immune suppression.

Section snippets

The role of mast cells in tumor growth and angiogenesis

Although some evidence suggest that mast cells can promote tumorigenesis and tumor progression, there are some clinical data and experimental tumor models in which mast cells seem to have functions that favor the host (Ribatti and Crivellato, 2009).

Mast cells are attracted in the tumor microenvironment by stem cell factor (SCF) secreted by tumor cells and secrete several angiogenic factors (Table 1) as well as matrix metalloproteinases (MMPs), which promote tumor vascularization and

Mast cells as therapeutic target in cancer

Many pharmacological agents have been developed that modulates mast cell functions. They block mediator receptors on target cells, including H1 receptor antagonists, CysLT1 receptor antagonists PGD2 receptors antagonists; inhibit mast cell mediator synthesis, including omalizumab, disodium cromoglycate and imatinib; block mast cell activation or mediator release, including steroids and non steroidal anti-inflammatory drugs (NSAID). Actually, there are no pharmacologic agents that can solely and

Inhibition of the SCF/kit axis

The tyrosine kinase receptor Kit (CD117) is upregulated in tumor cells and mutations in c-kit are associated to the development of gastrointestinal stromal tumor (GIST), in various forms of mastocytosis and mast cell leukemia (Pittoni et al., 2011a). Mast cells express high levels of c-kit and SCF, the ligand for kit, is produced by mast cells and is involved in their development, survival, migration, and function (Ribatti and Crivellato, 2014). SCF enhances tumor growth through increased

Tyrosine-kinase inhibitors

Neoplastic mast cells are resistant against conventional cytostatic drugs (Arock and Valent, 2010). Systemic mastocytosis is a myeloid disorder characterized by abnormal growth and accumulation of neoplastic mast cells in internal organs (Metcalfe, 2008). The first tyrosine kinase inhibitor introduced into the clinic STI571 (Imatinib mesylate, Gleevec) has been used for some varieties of mastocytosis, although some kit activating mutations involved in mastocytosis are resistant to it inhibitory

Other molecules

Obatoclax (GX015-070), a novel BH3 mimetic, small molecule-type-targeted drug that binds and blocks the antiapoptotic activity of several members of the Bcl-2 family, induces growth arrest in primary human and canine neoplastic mast cells, as well as in different mast cell lines (Peter et al., 2014). Obatoclax exerts synergistic antineoplastic effects on mast cells when combined with dasatinib (Peter et al., 2014). Administration in mouse models of anti-TNF-α antibodies (Gounaris et al., 2007),

Concluding remarks

Some of the new targeted anti-cancer therapies may exert effects on mast cells (Table 2). Chemoprevention with an anti-inflammatory approach has the potential to inhibit neovascularization before the onset of the angiogenic switch, resulting in a significant delay in tumor growth. Moreover, the development of novel therapies to alter mast cell function in the tumor microenvironment could inhibit tissue remodeling and tumor growth and activate the immune system.

In the light of the present

Acknowledgments

This study was supported in part by a Grant from Associazione Italiana Mastocitosi.

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