Emerging Evidence of Mast Cell Involvement in Oral Squamous Cell Carcinoma

Conclusion: Mast cells can promote tumour proliferation and aggressiveness via a plethora of secreted molecules and raised levels of such secretions as well as mast cell aggregation at Oral Squamous Cell Carcinoma sites is implicit of their involvement in progression of the pathology. There lacks, however, correlative data in the literature between mast cells and clinicopathological features such as tumour size, regional nodal involvement, or metastasis.

MC in modulating tumour growth-both positively and negativelyhas become a focus.

Tissue Distribution, Activation and Migration of Mast Cells in Oral Cancer
The altered tumour microenvironment induces changes in mast cell migration, activation and tissue distribution. Mast been demonstrated in a number of studies [5][6][7][8][9][10][11][12], and correlation between Mast Cell Density (MCD) and disease progression has also been reported [13][14][15]. In a slightly different vein Aromando, et al. [16] noted no change in total mast cell numbers in a hamster cheek pouch tissue during experimental carcinogenesis, but rather a decrease in MC in the adventitious tissue and an accumulation of MC in peritumoural and intratumoural stroma, as well as a reversion of the ratios of active/inactive MC in favour of the former [16]. Furthermore, differences in MCD between intratumoural and peritumoural stroma were evaluated, showing significantly higher MCD values in the peritumoural stroma than intratumoural, probably reflecting the migration of the cells from adventitious tissue as well as functional roles in Extracellular Matrix (ECM) degradation and induction of cell proliferation [16]. shown that, while both MCTC and MCT counts are significantly increased throughout the tumoural stroma, MCTC type predominates in the PT stroma, while MCT subtype predominates in the intratumoural stroma [17]. The authors hypothesise that the distribution of subpopulations reflects functional requirements: MCTC contain chymase, which plays a role in activation of Pro-Matrix Metalloproteinase-2 (MMP-2) and Pro-Matrix Metalloproteinase-9 (MMP-9) to their active MMP-2 and MMP-9 forms, respectively [18].
Both MMP-2 and MMP-9 possess the capacity to degrade type IV collagen [19], a significant component of the basement membrane and barrier to tumour invasion. Hence, the localisation of MCTC at tumour peripheries suggests an ECM remodelling role for these cells. Similarly, MCT predominance in the IT stroma suggests a role of these cells and their potent angiogenic mediator, tryptase [20] Transforming growth factor-beta (TGF-β) is synthesised and released by MC, and is increased in OSCC [5]. Its local roles are pleiotropic, including: its initially cytotoxic, but progression of the pathology. There lacks, however, correlative data in the literature between mast cells and clinicopathological features such as tumour size, regional nodal involvement, or metastasis. Eventually cytokinetic role in tumourigenesis [25] its action as a potent chemotactic factor for MC [28]; its role in angiogenesis; and its supposed part role in mediating a phenotypical change in tumours from CD34 + fibrocytes to alpha-smooth muscle antigen + (α-SMA + ) myofibroblasts [5]. ; hence a phenotypic shift away from CD34 + fibrocytes as they differentiate to alpha-SMA myofibroblasts, decreases repression of CD117 expression and consequently, allows MC migration and infiltration [5].

Mast Cells in Oral Cancer and Angiogenesis
Angiogenesis and neoangiogenesis are the processes of formation of new blood vessels from pre-existing blood vessels, and formation de novo, respectively. Tumour proliferation is limited by oxygen perfusion, and tissue oxygen perfusion greater than 2mm has been reported to be prohibitive of tumour growth

Mast Cells in Extracellular Matrix Remodelling in OSCC
An important feature of cancer progression is the ability to . MC tryptase itself has also been shown to directly exert gelatinase-like activity [56], and tryptase is also involved in the processing and activation of MMP-3 and MMP-1, the latter being dependent on the activation of the former [57,58].
Chymase is also capable of directly activating MMP-1 and MMP-3 [59]. Further MC chymase, but not tryptase, may directly cleave procollagen to fibril-forming collagen [60]. Hence MC contribute both directly and indirectly to processes which degrade the ECM.
In the context of oral cancer, MMP-9 expression has been shown to be upregulated in OSCC compared with healthy tissues, and significantly correlated with MCD [61]. Another study showed lip SCC samples that expressed higher MC counts also showed increased collagen degradation, assayed by picro-sirius staining [7]. MMP-9 has been associated with aggressive tumour growth, proteolytic processing of the ECM and activation of cytokines (such as TGF-β) [10]. MMP-9 is capable of processing type IV collagen of the basement membrane [62] and other ECM components, which are key events in tumour invasion and metastasis (see Fig. 1).
However, evidence supports a fluctuating role of MMP-9 in OSCC.
High MMP-9 expression has been shown to correlate with nodal involvement and metastasis, and poor prognosis in OSCC [63].
Meanwhile, Guttman et al. [64] reported no correlation between MMP-9 and tumour size or nodal involvement. Similarly, other authors reported that MMP-9 expression was not associated with clinical variables, such as tumour stage, recurrence rate, etc. [65].
Other data suggest that MMP-2 and MMP-2 expression significantly correlates with collagen degradation and local invasiveness, though this was not related to metastatic potential of the disease [66].
Meanwhile, it has been suggested that although MMP-2 and MMP-9 expression is high in OSCC, the ratio of active/inactive MMP-9 is low, suggesting MMP-2 is the gelatinase of greater importance in OSCC [67]. Conversely, MCs have also been implicated in collagen deposition. Vidal et al.
[10] observed the accumulation of MC in areas of fibrosis surrounding malignant minor salivary gland tumours and proposed the hypothesis that ECM remodelling, specifically collagen synthesis, may be mediated by MC.
A similar hypotheses have been made regarding odontogenic tumours [68] and breast cancers, in which it was suggested that tryptase played a role in collagen deposition [69]. Additionally, an association between MC and fibroblasts in the potentially malignant condition, oral submucous fibrosis, has been inferred [70,71].

Mast Cells and Tumour Proliferation, Invasion and Dissemination
Mast cells can precipitate mitogenicity in tumour cells directly  [16,77]. The proliferative consequence of tryptase-mediated PAR-2 activation has been reported in lung tissue, colon cancer and breast cancer [76,78], but few studies exist correlating MC with tumour cell proliferation in OSCC, and those that fail do to demonstrate a significant correlation [7]. A study pertaining to the potentially malignant oral condition actinic cheilits has, however, quantified COX-2, PAR-2, MC and tryptase in human actinic cheilitis tissues.
COX-2 is responsible for eicosanoid biosynthesis from arachidonic acid, and among the metabolites is Prostaglandin E2 (PGE2), which is also capable of promoting tumour proliferation [79]. The authors reported a significant correlation between tryptase-positive MC and PAR-2 expression, as well as COX-2 overexpression, inferring a role for tryptase in PAR-2 activation and COX-2 overexpression.
Increased MC counts have also been associated with higher levels of DNA synthesis in an experimental hamster oral carcinogenesis model, again implicating tryptase-mediated PAR-2 activation [16].

Conclusion
Mast cells are influenced by, and influence, malignant tumours.