Decrease in mast cells in
oral squamous cell
carcinoma: Possible failure
in the migration of these
cells.
Oral Oncol. 2007 May;43(5):484-90. Epub 2006 Sep 18
Author:
Oliveira-Neto HH, Leite AF, Costa NL, Alencar RC, Lara
VS, Silva TA, Leles CR, Mendonca FE, Batista AC.
Commentary of abspathology
A B Schütz, Ph.D.
Dentist, Pharmacist, Master in Oral Pathology at the Federal
University of Rio de Janeiro (UFRJ), Doctor in Oral Pathology at
the Bauru School of Dentistry, University of Sao Paulo
(FOB/USP), Brazil. Address reprint request to Dr. Antonio
Beltrao Schütz, José Bonifácio 2598/103, telephone: (055)
3221-6763, CEP: 97 015-450, Santa Maria, RS, Brazil.
Again, to read this another article of my ex-colleague at
the Bauru School of Dentistry, Lara, VS, whose results
caused me strangeness, was a pleasant surprise and
made to return me to mind my doctoral study at the
Bauru School of Dentistry at the Sao Paulo University
(USP).
With relation to Professor Lara, we first meeting was
in the memorable reunion of the Brazilian Society of
Stomatology, in Curitiba, 1988. In that time, was
student of the first year of post-graduation in Oral
Pathology at the Federal University of Rio de Janeiro
(FOUFRJ), at the staff of the professor José Carlos
Borges Teles, and the Professor Lara, student of the
last year of graduation at the FOB/USP, presented a
clinic case organized by the Professor Consolaro. As
disagree of an aspect of the presentation, asked her;
responding me, “I do not say”. Moment in that thought,
“She will certainly be a Brazilian Professor”. Past 20
years, she has the greater grade in the Brazilian
academic hierarchy and I am outside it.
But as in that time, some aspects of the article
published by Lara, VS and colleagues that disagree
must be better explicated.
When I write or read a scientific article, the first step
is to compare its results with the knowledge about
general pathology, and, afterwards, with the results of
other publications.
So, this enthusiastic article promotes us interesting
results and conclusions, such as: “the decrease in
MC numbers in pre-malignant and malignant oral
lesions may be related to the migration failure of
these cells, possibly reflecting an important
modification in the microenvironment during tumor
initiation and progression” because there are articles
published proving the augment of the number of this
cells as well as that the MC subpopulations may
contribute to lip SCC progression. While intra-tumoral
MC (T) may stimulate angiogenesis; peri-tumoral MC
(TC) may promote extra cellular matrix degradation and
tumor progression at the invasion front in lip squamous
cell carcinoma (Rojas; Spencer, Martinez; Maurelia;
Rudolph, 2005)1. A significant correlation between MC
(mast cells) and microvascular densities was observed
in oral SCC (r = 0.5; P = 0.012). The MC and
microvascular counts were significantly higher in oral
SCC than in hyperkeratosis and normal oral mucosa (P
< 0.05), suggesting that MCs may upregulate tumor
angiogenesis in oral SCC, perhaps via MC tryptase
(Iamaroon; Pongsiriwet; Jittidecharaks; Pattanaporn;
Prapayasatok, 2003) 2
The upward migration and degranulation is continued
progressively during the 12- and 14-week periods of
DMBA application in correlation with the progression of
the tumor. By 16 weeks of treatment with the
carcinogen, more mast cells had migrated closer to the
invasive carcinoma, and many had degranulated. In the
connective tissue mast cells were fully packed with
many granules, and some mast cells were in proximity
to macrophages and eosinophils, demonstrating that
there is a positive correlation between developing
carcinomas and mast cell density. Mast cell migration
towards the carcinoma and degranulation were also
evident (Flynn; Schwartz ;Shklar,1991)3.
This result aims in the oppose direction of the
conclusion of Lara et al. (2007)4, proving a correlation
between o development of squamous cell carcinoma
and mast cell density, possibly via rise of the
expression of MC tryptase (Iamaroon; Pongsiriwet;
Jittidecharaks; Pattanaporn et al., 2003),3 protease
able to increase the expression and to activate
Urokinase-type plasminogen activator (Yasuda et al.,
2005)5, which has been correlated which process of
invasion and metastatic dissemination, via activation
urokinase-type plasminogen activator receptor (uPAR)
in lingual squamous cell carcinomas (Wang; Guo; Wei;
Dong; Wu, 2005).6
In addition, mast cells are able to synthesize the
urokinase plasminogen activator as well as to express
its receptor (Bankl et al., 1999).7 Also synthesize and
secrete various collagenase involved in the process of
invasion (Di Girolamo; Wakefield, 2000)8. Of these,
proteases (MMPs, cathepsin c, d and serine proteases)
secreted from mast cells facilitate several steps in
cancer progression (McKerrow; Bhargava; Hansell;
Huling et al., 2000)9. In oral carcinoma, the balance
between proteinases and their inhibitors controls the
tissue degradation at each stage of tumor invasion and
metastasis (Baker; Leaper; Hayter; Dickenson, 2006)10.
Several matrix metalloproteinases (MMPs) have
showed to play an important role in the invasion and
metastasis of oral squamous cell carcinoma (SCC).
MMP-2 and MMP-9 are capable of degrading type-IV
collagen, which is a major component of basement
membrane. Activation ratio MMP-2 was significantly
elevated in patients with lymph node metastasis than
patients without lymph node metastasis (P = 0.005)
(Patel; Shah; Rawal; Desai et al., 2005)11.
Under pathologic conditions, such as occur in mast
tumor cells, (Leibman; Lana; Hansen; Powers et al.
2000)12 or head and neck squamous cell carcinoma,
(Franchi; Massi; Santucci; Masini et al., 2006)13 mast
cell are too able to synthesize and to secrete MMP2
and MMP9. Of these, MMP9 is able to promote to
activation of NOS synthase (oxide nitric synthase),
whose product ON (oxide nitric) is a diatomic free
radical molecule that has been implicated in tumor
angiogenesis and progression of head and neck
squamous cell carcinoma (HNSCC).13
Mast cell deficiency in HPV16 mice significantly
attenuates keratinocyte hyperproliferation and
activation of angiogenesis, thus supporting the concept
that inflammation, and in particular activation of
sentinel mast cells and release of their factors,
functionally contribute to early neoplastic development
in HPV16 mice (de Visser; Korets; Coussens ).14
However, in Lara et al.’s study,4 the number of MC
was verified to be decreased in leukoplakia and OSCC
(P=0.31) in relation to the control (oral mucosa). This
result must be seen with suspension, considering that
of the 14 articles published, correlating mast cells and
oral squamous cell, published in Entrez PubMed, is the
unique that verified decrease in number of mast cells
comparatively to oral mucosa.
There is only an article reporting that in oral
carcinoma the number of mast cell, in spite of being
increased in relation to oral mucosa, was decreased in
relation to squamous cell carcinoma identified in other
localizations, suggesting to be, at least in part, the
explication for more aggressive behavior of some
neoplasm in oral cavity.
That there is the rise of the number of mast cells
(MC), during the devolvement and progression of the
oral carcinogenesis is pacific, question itself, however,
if the increase of these cells (MC) might be considered
or not the good prognostic factor because has been
reported, in some cases of oral squamous cell
carcinomas, greater survival rate and decreased
incidence of metastasis, in lesions showing increase in
the number of macrophages and mast cells (Ranieri;
Labriola; Achille; Florio et al., 2002).15
On the other hand, the presence of mast cell in the
proximity of macrophages and eosinophils must be
considered as an unfavorable prognostic factor, same
in well differentiated squamous cell carcinoma
(Horiuchi; Mishima; Ohsawa; Sugimura; Aozasa,
1999),16 also opposing itself the conclusion of the freedocent thesis of another Professor at the Pathology
IComment of abspathology) Department, at the
Bauru School of Dentistry, Denise Tostes de Oliveira
(Catwoman), who concluded to be eosinophilia a good
factor prognostic to the well differentiated oral
squamous cell carcinoma.
Besides, in other localizations, the MC count may be
associated with tumor differentiation and prognosis of
squamous cell carcinoma, considering that, this count,
in the patients with poorly differentiated HCC, was
obviously higher than that with well differentiated
(P<0.01) (Peng; Deng; Yang; Xie; Li; Li; Feng, 2005).17
Similar result was verified in squamous cell carcinoma
of the esophagus, where both MVD (micro vessels
density) and MCD (mast cell density) were associated
with the depth of wall invasion, lymph node metastasis,
and tumor progression (stage). A significant correlation
was noted between MVD and MCD values (r = 0.72).
The prognosis was significantly worse in patients with
high MVD (> or = 92) and high MCD (> or = 18) values
(Elpek; Gelen; Aksoy; Erdogan; Dertsiz; Demircan;
Keles, 2001).18
Current evidence suggests that mast cells contribute
to the tumorigenesis of cutaneous malignancies
through four mechanisms. (1) Immunosuppression:
Ultraviolet-B radiation, the most important initiator of
cutaneous malignancies, such as in Lip, activating
mast cells. Upon irradiation of the skin, trans-urocanic
acid in the epidermis isomerizes to cis-urocanic acid,
which stimulates neuropeptide release from neural cfibers. These neuropeptides in turn trigger histamine
secretion from mast cells, leading to suppression of the
cellular immune system. (2) Angiogenesis: Mast cells
are the major source of vascular endothelial growth
factor in basal cell carcinoma and malignant
melanoma. Vascular endothelial growth factor is one of
the most potent angiogenic factors, which also induces
leakage of other angiogenic factors across the
endothelial cell wall into the matrix. Mast cell proteases
reorganize the stroma to facilitate endothelial cell
migration. As well, heparin, the dominant mast cell
proteoglycan, assists in blood-borne metastasis. (3)
Degradation of extracellular matrix: Through its own
proteases, and indirectly via interaction with other cells,
mast cells participate in degradation of the matrix,
which is required for tumor spread. (4) Mitogenesis:
Mast cell mediators including fibroblast growth factor-2
and interleukin-8 are mitogenic to melanoma cells
(Ch'ng; Wallis; Yuan; Davis; Tan, 2006).19
Current evidence supports an accessory role for mast
cells in the development and progression of cutaneous
malignancies. One of these mechanisms are mitogenic
kinin peptides formed by the serine protease, tissue
kallikrein (TK1), which stimulate the proliferation of
tumour cells and, by increasing vascular permeability,
enhance metastasis (Dlamini, Bhoola, 2005).20
The attempt of the immune response to the neoplasm
antigens, which, in great majority of the cases, does
not detain it, is able to activate mast cell to production
of reactive oxygen species (ROS) and reactive nitrogen
oxide species (RNOS), including nitric oxide, in the
inflammatory front; explicating, at least in part, the
increase of the number of mast cell, as well as of other
inflammatory cells in oral carcinoma, such as
eosinophils, without any relation with a good
prognostic.
In addition, the simple process inflammatory not
immune, in response to ulceration and necrosis, may
attract MC, for the generation of pro-inflammatory
cytokines and growth factors chemotatic for these cells
(MC), such as eosinophil chemotactic factor (ECF) or
the mast cell-associated tetrapeptides of the eosinophil
chemotactic factor of anaphylaxis (ECF-A) identified
yet in 1978 in extracts of anaplastic carcinomas, also
associated to metastatic lesions and the response to
radiation of the tumor (Goetzl; Tashjian; Rubin;
Austen, 1978 ).21
So, we hypnotize that the increase in the number
mast cells in oral squamous cell carcinoma,
comparatively to oral mucosa, has relation with the
processes of migration, invasion and angiogenesis
verified during the development and progression of this
neoplasm, whose mechanisms, at least in part, show
relation with the production of metalloproteinases and
other proteinases able to induce to synthesis and
secretion of chemistries mediators, such as nitric oxide
(NO) and urokinase plasminogen activator (uPA),
directly involved in these processes, as well as in the
metastatic dissemination. However, the relation of the
increase of the number mast cells with the clinical
course of the neoplasm and/or prognostic must be still
better studied, particularly in anaplastic oral
carcinomas.
The text will continue
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