ReviewMast cells as therapeutic target in cancer
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.
References (81)
- et al.
MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis
Cell
(2000) - et al.
Melanoma. An ultrastructural study of the host inflammatory and vascular responses
J. Investig. Dermatol.
(1980) KIT mutations in mastocytosis and their potential as therapeutic targets
Immunol. Allergy Clin. N. Am.
(2006)- et al.
Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation
Blood
(2005) - et al.
SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment
Blood
(2008) - et al.
Phase II study of oral masitinib mesilate in imatinib-naive patients with locally advanced or metastatic gastro-intestinal stromal tumour (GIST)
Eur. J. Cancer
(2010) Mast cells and mastocytosis
Blood
(2008)- et al.
The effect of histamine, antihistamines, and a mast cell stabilizer on the growth of cloudman melanoma cells in DBA/2 mice
J. Investig. Dermatol.
(1983) - et al.
New models for analyzing mast cell functions in vivo
Trends Immunol.
(2012) - et al.
Mast cells, angiogenesis, and tumour growth
Biochim. Biophys. Acta
(2012)
Mast cell ontogeny: an historical overview
Immunol. Lett.
Neovascularization and mast cells with tryptase activity increase simultaneously with pathologic progression in human endometrial cancer
Am. J. Obstet. Gynecol.
Neovascularisation, expression of fibroblast growth factor-2, and mast cells with tryptase activity increase simultaneously with pathological progression in human malignant melanoma
Eur. J. Cancer
CD52 is expressed on human mast cells and is a potential therapeutic target in Waldenstrom׳s Macroglobulinemia and mast cell disorders
Clin. Lymphoma Myeloma
Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis
Blood
Effect of mast cells on tumor angiogenesis in lung cancer
Ann. Thorac. Surg.
Tyrosine kinase inhibitors in the treatment of systemic mastocytosis
Leukoc. Res.
The biology of Kit in disease and the application of pharmacogenetics
J. Allergy Clin. Immunol.
Pathogenesis, classification and treatment of mastocytosis: state of the art in 2010 and future perspectives
Expert Rev. Hematol.
The role of mast cell tryptase in neoangiogenesis of premalignant and malignant lesions of the uterine cervix
J. Histochem. Cytochem.
Human mast cells stimulate vascular tube formation. Tryptase is a novel, potent angiogenic factor
J. Clin. Investig.
Histamine, mast cells and tumour cell proliferation in breast cancer: does preoperative cimetidine administration have an effect?
Br. J. Cancer
Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis
Genes Dev.
Expression of mast cell proteases correlates with mast cell maturation and angiogenesis during tumor progression
PLoS One
Vascular endothelial growth factors synthesized by human lung mast cells exert angiogenic effects
J. Allergy Clin. Immunol.
Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT
PLoS One
The prognostic relevance of angiogenesis and mast cells in squamous cell carcinoma of the oesophagus
J. Clin. Pathol.
Atypical association of H1 and H2 histamine receptors with signal transduction pathways during multistage mouse skin carcinogenesis
Inflamm. Res.
Angiogenesis and mast cells in non-Hodgkin׳s lymphoma: a strong correlation in angioimmunoblastic T-cell lymphoma
Leuk. Lymphoma
Synergistic growth-inhibitory effects of two tyrosine kinase inhibitors, dasatinib and PKC412, on neoplastic mast cells expressing the D816V-mutated oncogenic variant of KIT
Haematologica
Mast cells in hemangiomas and vascular malformations
Pediatrics
Mast cells are an essential hematopoietic component for polyp development
Proc. Natl. Acad. Sci USA
Mast cells and cancer of the cervix
Surg. Gynecol. Obstet.
Mast cell-derived interleukin 10 limits skin pathology in contact dermatitis and chronic irradiation with ultraviolet B
Nat. Immunol.
Immunoglobulin free light chains are biomarkers of poor prognosis in basal-like breast cancer and are potential targets in tumor-associated inflammation
Oncotarget
Mast cells and metachromasia in human breast cancer: their occurrence, significance and consequence: a preliminary report
J. Pathol.
Increase of mast cells and tumor angiogenesis in oral squamous cell carcinoma
J. Oral Pathol. Med.
Mast cells correlate with angiogenesis and poor outcome in stage I lung adenocarcinoma
Eur. Respir. J.
The critical role of mast cell-derived hypoxia-inducible factor-1α in human and mice melanoma growth
Int. J. Cancer
Tissue inhibitor of metalloproteinases 4 (TIMP4) is involved in inflammatory processes of human cardiovascular pathology
Histochem. Cell Biol.
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2023, European Journal of PharmacologyVisualizing mast cell migration to tumor sites using sodium iodide symporter of nuclear medicine reporter gene
2023, Neoplasia (United States)Human C1q Tumor Necrosis Factor 8 (CTRP8) defines a novel tryptase+ mast cell subpopulation in the prostate cancer microenvironment
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2022, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :By comparing immunocyte infiltration between high and low IL-1α groups, we found that tumors with high IL-1α expression have low mast cells [37]. Mounting evidence supports that mast cells play major and complicated roles in cancer [38,39]. Several studies have reported a correlation between mast cells and angiogenesis in renal cancer [40,41].
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2021, CellCitation Excerpt :Moreover, we observed an increase of TNF+ mast cells in lung cancer (LUNG) patients at the residual disease (RD) state, compared to patients before tyrosine kinase inhibitors therapy (TN) or at the progressive disease (PD) state (Figure S3G; Maynard et al., 2020), which further supports the importance of TNF+ mast cells in anti-tumor immunity. Mast cells in tumors are thought to play a dual role in influencing the fate of tumor cells (Ribatti, 2016). Apart from TNF, mast-derived VEGFA is a key gene associated with tumor angiogenesis (Marone et al., 2016), which informed us to evaluate the complexity of mast cells.