Mast cells: the JEKYLL and HYDE of tumor growth

doi:10.1016/j.it.2004.02.013

Trends in Immunology

Volume 25, Issue 5, 1 May 2004, Pages 235-241

https://doi.org/10.1016/j.it.2004.02.013 Get rights and content

Abstract

Mast cells accumulate in the stroma surrounding certain tumors, especially mammary adenocarcinoma, and molecules they secrete could benefit the tumor. These include heparin, interleukin-8 (IL-8) and vascular endothelial cell growth factor (VEGF), which induce neovascularization, histamine, which is an immunosuppressant, mitogenic factors, such as platelet-derived growth factor (PDGF), nerve GF (NGF), stem-cell factor (SCF), and proteases, which disrupt the surrounding matrix and facilitate metastases. By contrast, mast-cell mediators detrimental to the tumor include cytokines, such as IL-1, IL-4, IL-6 and tumor necrosis factor-α (TNF-α), which can induce apoptosis of tumor cells, tryptase, which stimulates protease-activated receptors and induces inflammation, and chondroitin sulfate, which could act as a decoy and inhibit metastases. We propose that beneficial and destructive mediators are either released from separate granules or much smaller vesicles regulated by selectively distinct signals, such as tumor-derived oxidized polyamines or nitric oxide from new endothelial cells. This dual role of mast cells could be additive to that of tumor infiltrating macrophages, the ’polarization’ of which to M2 type appears to be conducive to tumor growth.

Section snippets

Mast-cell biology

Mast cells derive from a specific bone marrow progenitor cell and migrate into tissues where they mature depending on microenvironmental conditions. Mast cells are located perivascularly in close proximity to neurons and have recently been shown to have a crucial role in neuroinflammatory diseases [21]. Mast cells vary considerably in their cytokine and proteolytic enzyme content. At least two easily identifiable types of human mast cells have been reported: connective tissue mast cells that

Mast cells: beneficial to the tumor?

Mast cells appear to be able to promote tumor development through many different ways (Figure 1a): they could facilitate tumor angiogenesis through heparin-like molecules, and heparin could further permit neovascularization and metastases through its anti-clotting effects. Moreover, vascular endothelial cell growth factor [VEGF; vascular permeability factor (VPF)] is secreted in response to FcϵRI crosslinking from mouse bone marrow-derived and human cultured mast cells [29], as well as from

Mast cells: detrimental to the tumor?

Mast cells could increase at sites of breast cancer and associated lymph nodes in reaction to the tumor and might participate in tumor rejection (Figure 1b). Certain findings suggest that where tumor burden is high, mast cells might be inhibited from degranulation by tumor-derived blockers, such as oxidized polyamines [28].

Perivascular tumor-associated mast cells in mammary adenocarcinoma could secrete several cytokines and proteolytic enzymes that could be detrimental to the tumor cells (

Breast cancer

An increased number of mast cells has been noted in rat mammary tumors when the carcinogen, cis-hydroxyproline, is used in Buffalo rats [54]. Interestingly, rat mammary adenocarcinoma induced by 7,12-dimethylbenz(α)anthracene (DMBA) is also associated with a high number of mast cells, however, these are resistant to degranulation [55]. Similar findings were obtained from human mammary adenocarcinoma biopsies, in which accumulated mast cells in an area of intense tumor infiltration appeared to

Basal-cell carcinoma and melanoma

Mast cells have been repeatedly noted to accumulate around basal-cell carcinoma lesions and are thought to contribute to cancer growth by inducing immunosuppression [63]. In addition, mast cells in basal-cell carcinoma express VEGF, IL-8 and RANTES.

Mast-cell accumulation has also been noted repeatedly around melanomas, especially invasive melanoma 64, 65. In fact, mast-cell accumulation was correlated with increased neovascularization, mast-cell overexpression of VEGF, tumor aggressiveness and

Neurofibromatosis

Mast cells have been noted around peripheral nerves and nerve tumors. An increased number of mast cells has been reported around neurofibromatosis type 1 (NF1) lesions, in which c-kit and SCF have been implicated in mast-cell proliferation [66]. It is interesting to note that the NF1 tumor suppressor gene product modulates both melanocyte and mast-cell growth [67]. The histamine-1 receptor antagonist ketotifen reduces NF1 growth [68]. A recent publication reports that in NF1 patients and NF1^+/-

Concluding remarks

Mounting evidence indicates that mast cells accumulate around tumors and could either promote or inhibit tumor growth depending on the local stromal conditions. Mast cells might, therefore, act as a new target for the adjuvant treatment of solid tumors, such as mammary adenocarcinoma or melanoma, through the selective inhibition of tumor-promoting molecules but permitting secretion of cytotoxic cytokines. Certain natural substances could fulfill these inhibitory requirements 70, 71.

Acknowledgments

Work discussed was supported in part by a ’Concept Award’ No. BC024430 from the United States Department of Defense (TCT) and funds from Theta Biomedical Consulting and Development Co., Inc. (Brookline, MA, USA). The possible therapeutic role of inhibiting mast cell-derived molecules beneficial to tumor growth, as well as mast cell and macrophage-secreted IL-6, is covered by US patent 6 689 748 and US patent applications 10/439 301, US 09/771 669, US 09/773 576, US 10/166 088 and assigned to

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Trends in Immunology

Mast cells: the JEKYLL and HYDE of tumor growth

Abstract

Section snippets

Mast-cell biology

Mast cells: beneficial to the tumor?

Mast cells: detrimental to the tumor?

Breast cancer

Basal-cell carcinoma and melanoma

Neurofibromatosis

Concluding remarks

Acknowledgments

Trends Immunol.

Trends Immunol.

Trends Immunol.

J. Lab. Clin. Med.

Blood

J. Neuroimmunol.

Blood

J. Urol.

Biochem. Pharmacol.

Blood

Am. J. Pathol.

Cancer Lett.

Cell

J. Invest. Dermatol.

J. Invest. Dermatol.

Mast cells in innate immunity

Immunol. Rev.

Stromal cell involvement in cancer

Cancer Res.

Chemokines and the molecular basis of cancer metastasis

N. Engl. J. Med.

Host microenvironment in breast cancer development: inflammatory and immune cells in tumour angiogenesis and arteriogenesis

Breast Cancer Res.

Vascular endothelial growth factor secretion by tumor-infiltrating macrophages essentially supports tumor angiogenesis, and IgG immune complexes potentiate the process

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Eur. J. Immunol.

Nitric oxide: a regulator of mast cell activation and mast cell-mediated inflammation

Clin. Exp. Immunol.

Mast cells can secrete vascular permeability factor/vascular endothelial cell growth factor and exhibit enhanced release after immunoglobulin E-dependent upregulation of Fcε reptor I expression

J. Exp. Med.