Blackwell Publishing Ltd

Letter to the Editor

Might mast cells have a role in neoplastic angiogenesis

of canine melanomas?

Letters
I read the article by Mukaratirwa et al., describing Mast cells
and angiogenesis in canine melanomas: malignancy and
clinicopathological factors, with an interest.1 My concern
in this study is that we have recently demonstrated in vitro
antitumour effect of human mast cells (MC) against different
human tumours, contrasting with their study conclusion.2,3
Although current evidence controversially supports an
accessory role for MCs in the development and progression of cutaneous malignancies, mounting emerging
data also suggest that MCs might, in fact, have opposing
roles in tumours, depending on the microenvironment.4 Here,
I also make comments about MCs alleged role in tumourassociated angiogenesis in the light of recent literature.
I agree that MCs are prominent in the tumour microenvironment and are thought to provide a host response of the
innate immunity to neoplasia.1 MCs are known to be
multifunctional cells and recently shown that they can
act as effector elements of human innate immune system.
In fact, accumulation of MCs may be a part of generalized
inflammatory reaction described in some tumours, for
example, gastric carcinoma5 similar to physiological events
such as scars and ovulation. This tumour-induced inflammatory reaction including macrophages and fibroblasts could
establish a local microenvironment favouring tumour
progression via angiogenesis;6 and some of the angiogenic
factors may stimulate MC migration.7 And then the question
becomes is the MC really an active player or an innocent
passerby in a tumour stroma? It is really hard to know and
answer this at least for now.
Strikingly, mounting evidence indicates that MCs could
inhibit tumour growth similar to our in vitro experiments.
As described in a recent study, higher MC numbers is
associated with more indolent tumour growth, suggesting the possibility of tumour inhibitory effects of MCs.8
Another study also suggested the antitumour cytotoxicity
of MCs in colorectal cancer.9 Currently, believers in the
inhibitory role of MCs assume them as inhibitors of tumour
development through their pronecrolytic/apoptotic
granules, for example, TNF-, granzymes and chymase.2 4
In the past, TNF- was held primarily responsible from its
antitumour cytotoxicity.10
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There is an interesting speculation about the immunomodulatory effects of MC products in UV-irradiated skin that
they may contribute to the initiation and development of
human cutaneous malignant melanoma.11 However, I also
want to mention opposite immunomodulatory effects of
MC mediators, compatible with their antitumour effect. I
believe MC mediators cause different functions and the
coexistence of both MC subtypes including these mediators
contributes to the tissue homeostasis.12 For instance;
in a study, tryptase was thought to be a mediator causing
fibrosis, thus limiting tumour invasion, as well as an angiogenic, possibly contributing to a better chemotherapy
response of tumour cells.8 Moreover, mediators have
shown to influence various aspects of tumour biology and
the net effect of MC in the tumour progression is difficult
to evaluate. Although chymase induces apoptosis in different types of cells including endothelial cells involved
in the angiogenesis,13 tryptase is known to be a mitogenic
agent. MCs, like cytotoxic-killer cells, contain abundantly
serine proteases termed granzymes, including several
chymases in their granules, which is implicated in cellmediated cytotoxicity. Recently, cultured MCs have been
also proven to contain granzyme B and express Fas ligand
components of cell-mediated cytotoxicity.14 Chymase was
also shown to accumulate tumour-associated macrophages,
neutrophils and other inflammatory cells in vivo, suggesting
contribution to MC cytotoxicity indirectly.15 In summary,
MCs have the capability of fighting against tumour cells rather
than proliferating them. and their role in immunosurveillance
is recently discussed by us.16
In humans, peritumoral accumulation of MCs does not
always favour tumour progression such as in advanced
ovarian cancer, which peritumoral MC infiltration was demonstrated to predict for improved survival.8 Also, increased
MC density (MCD) was found to indicate a better survival
such as in breast and colorectal cancers.9 As opposed to
some studies;17 although significantly different numbers
of MCs were found in naevi compared to melanomas,
but no significant correlation could be identified regarding
clinical outcome.18 Some studies in mice showed that MCdeficient mouse had an increased tumour incidence compared
with normal. Consistent with this, in a study evaluating growth

2006 The Author. Journal compilation 2006 European Society of Veterinary Dermatology. 17; 284286

Letter to the Editor

of pulmonary metastases of B16 melanoma; lung metastases were significantly decreased in controls, compared
to a MC-free animal, W/Wv mice.19 In another study done
with B16 melanoma cells in two strains of MC-deficient
mice suggested that the MC dependence of antitumour
resistance.20 MCD and its significance in tumour development are recently argued by us in detail.21
Like this study1 although MCs have been implicated in
neoplastic angiogenesis and consequently poor prognosis,
some other studies showed that peritumoral MC infiltration
with high microvessel density (MVD) could be a marker of
predicting for improved survival in ovary and oral squamous
carcinomas. In some mice studies, no significant difference
between MC-deficient and -sufficient ones was found for
the angiogenesis.22 Neoplastic angiogenesis is a complex
process, including macrophages23 eosinophils, stromal,
endothelial progenitor as well as tumour cells. It is also
mediated by different kinds of mediators released from
different cells including tumour as well as MCs. Essentially
heparin-like molecules; IL-8, SCF, b-FGF, TGF-, angiopoietins
and histamine, were believed to be responsible from
neovascularization. Angiogenic cooperation was also reported
in a tumour stroma between different mediators such as
PGF2, vascular endothelial growth factor and thymidine
phosphorylase. Other contributory characteristics tumour
cells such as in melanomas, for example, IL-324 and substance
P expressions should also be considered. For instance, SP
also is known to potentiate neoangiogenesis.25 As a result,
in this chaotic environment, the MCs genuine role in tumourassociated angiogenesis is very difficult to define. MVD
and its significance in tumour prognosis is also lately
discussed by us.26
Although a monoclonal antibody against the endothelial
cell marker factor VIII was used in this study1 to identify MVD,
no standardized scheme is yet available to assess the
angiogenesis. Heterogeneity of endothelial cell marker
expressions even in a tumour is well known.27 CD105,
proliferation marker, proved to be superior to pan-endothelial
cell markers (e.g. CD31/CD34, etc.)28 Utilizing these markers
facilitates the vascular status estimation, but may not show
the angiogenic status. Some tumours are vascularized
without significant angiogenesis by vascular mimicry.29
As a result, although I believe in prognostic significance
of MCD and MVD in tumours, more explanatory in vitro/in
vivo studies are necessary to define MCs genuine role in
the tumour stroma.
ner zdemir, MD
Division of Allergy and Immunology
Department of Pediatrics
Cincinnati Childrens Hospital Medical Center
University of Cincinnati College of Medicine
5th floor, Location C, MC 2000
3333 Burnet Avenue
Cincinnati, OH 45229-3039
E-mail: Oner.Ozdemir@cchmc.org
oner.ozdemir.md@gmail.com

References
1. Mukaratirwa S, Chikafa L, Dliwayo R et al. Mast cells and angiogenesis in canine melanomas: malignancy and clinicopathological
factors. Veterinary Dermatology 2006; 17: 1416.

2. zdemir , Savasan S. Short and long-term mast cell mediated

cytotoxicity against NK/LAK sensitive and resistant cells. Proceedings of Pediatric Academic Societies (PAS) 2005; 57: 1531
[Abstract].
3. zdemir . Human mast cell cytotoxicity against human lymphoma
and myeloid leukemia cells. Journal of Allergy and Clinical Immunology
2006; 117: S17 [Abstract].
4. Chng S, Wallis RA, Yuan L, et al. Mast cells and cutaneous
malignancies. Modern Pathology 2006; 19: 14959.
5. Caruso RA, Fedele F, Rigoli L, et al. Mast cell interaction with tumor
cells in small early gastric cancer: ultrastructural observations.
Ultrastructural Pathology 1997; 21: 17381.
6. Kamate C, Baloul S, Grootenboer S et al. Inflammation and
cancer, the mastocytoma P815 tumor model revisited: triggering of
macrophage activation in vivo with pro-tumorigenic consequences.
International Journal of Cancer 2002; 100: 5719.
7. Gruber BL, Marchese MJ, Kew R. Angiogenic factors stimulate
mast-cell migration. Blood 1995; 86: 248893.
8. Chan JK, Magistris A, Loizzi V et al. Mast cell density, angiogenesis,
blood clotting, and prognosis in women with advanced ovarian
cancer. Gynecological Oncology 2005; 99: 205.
9. Tan SY, Fan Y, Luo HS et al. Prognostic significance of cell infiltrations of immunosurveillance in colorectal cancer. World Journal
of Gastroenterology 2005; 11: 12104.
10. Clarke GR, Shirzadeh H, Pang G et al. TNF-alpha is not the sole
mediator of WEHI-164 tumour cell killing in natural cytotoxicity.
Cytokine 1997; 9: 25462.
11. Grimbaldeston MA, Pearce AL, Robertson BO et al. Association
between melanoma and dermal mast cell prevalence in sununexposed skin. British Journal of Dermatology 2004; 150: 895
903.
12. zdemir . The role of mast cell and mast cell subtypes (MC (T)
and MC (CT) in tumor angiogenesis. European Journal of Cardiothoracic Surgery 2006; 29: 6389.
13. Latti S, Leskinen M, Shiota N et al. Mast cell-mediated apoptosis
of endothelial cells in vitro: a paracrine mechanism involving
TNF-alpha-mediated down-regulation of bcl-2 expression. Journal
of Cell Physiology 2003; 195: 1308.
14. Wagelie-Steffen AL, Hartmann K, Vliagoftis H et al. Fas ligand
(FasL, CD95L, APO-1L) expression in murine mast cells. Immunology
1998; 94: 56974.
15. He S, Walls AF. Human mast cell chymase induces the accumulation of neutrophils, eosinophils and other inflammatory cells in vivo.
British Journal of Pharmacology 1998; 125: 1491500.
16. zdemir . Immunosurveillance function of human mast cell?
World Journal of Gastroenterology 2005; 11: 70546.
17. Ribatti D, Vacca A, Ria R et al. Neovascularisation, expression of
fibroblast growth factor-2, and mast cells with tryptase activity
increase simultaneously with pathological progression in human
malignant melanoma. European Journal of Cancer 2003; 39: 666
74.
18. Schadendorf D, Kohlmus C, Gawlik C et al. Mast cells in melanocytic tumours. Archives of Dermatological Research 1995; 287:
4526.
19. Schittek A, Issa HA, Stafford JH et al. Growth of pulmonary
metastases of B16 melanoma in mast cell-free mice. Journal of
Surgery Research 1985; 38: 248.
20. Van Loveren H, Den Otter W, Meade R et al. A role for mast cells
and the vasoactive amine serotonin in T cell-dependent immunity
to tumors. Journal of Immunology 1985; 134: 12929.
21. zdemir . Mast cell density, angiogenesis, and their significance
in tumor development. Gynecological Oncology 2006; 100: 6289.
22. Ghosh AK, Hirasawa N, Ohtsu H et al. Defective angiogenesis in
the inflammatory granulation tissue in histidine decarboxylasedeficient mice but not in mast cell-deficient mice. Journal of
Experimental Medicine 2002; 195: 97382.
23. Ono M, Torisu H, Fukushi J et al. Biological implications of
macrophage infiltration in human tumor angiogenesis. Cancer
Chemotherapy and Pharmacology 1999; 43 (Suppl. ): S6971.
24. Reed JA, McNutt NS, Bogdany JK et al. Expression of the mast
cell growth factor interleukin-3 in melanocytic lesions correlates

2006 The Author. Journal compilation 2006 European Society of Veterinary Dermatology.

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Letter to the Editor

with an increased number of mast cells in the perilesional stroma:

implications for melanoma progression. Journal of Cutaneous
Pathology 1996; 23: 495505.
25. Khare VK, Albino AP, Reed JA. The neuropeptide/mast cell secretagogue substance P is expressed in cutaneous melanocytic lesions.
Journal of Cutaneous Pathology 1998; 25: 210.
26. zdemir . Mast cell density, neoplastic angiogenesis and their
prognostic importance. Digestive and Liver Disease 2006; 38:
356.
27. Eberhard A, Kahlert S, Goede V et al. Heterogeneity of angiogen-

286

esis and blood vessel maturation in human tumors: implications

for antiangiogenic tumor therapies. Cancer Research 2000; 60:
138893.
28. Tanaka F, Otake Y, Yanagihara K et al. Evaluation of angiogenesis
in non-small cell lung cancer: comparison between anti-CD34
antibody and anti-CD105 antibody. Clinical Cancer Research
2001; 7: 34105.
29. Pezzella F, Pastorino U, Tagliabue E et al. Non-small-cell lung
carcinoma tumor growth without morphological evidence of neoangiogenesis. American Journal of Pathology 1997; 151: 141723.

2006 The Author. Journal compilation 2006 European Society of Veterinary Dermatology.