Abstract
Mast cells have been implicated in malignant processes, mainly through clinical correlative studies and by experiments performed using animals lacking mast cells due to defective c-kit signaling. However, mast cell-deficient mouse models based on c-kit defects have recently been questioned for their relevance. Here we addressed the effect of mast cells in a tumor setting by using transgenic Mcpt5-Cre+ R-DTA+ mice, in which the deficiency of mast cells is independent of c-kit defects. Melanoma cells (B16.F10) were administered either subcutaneously or intravenously into Mcpt5-Cre+ R-DTA+ mice or Mcpt5-Cre− R-DTA+ littermate controls, followed by the assessment of formed tumors. In the subcutaneous model, mast cells were abundant in the tumor stroma of control mice but were absent in Mcpt5-Cre+ R-DTA+ mice. However, the absence of mast cells did not affect tumor size. In contrast, after intravenous administration of B16.F10 cells, melanoma colonization of the lungs was markedly reduced in Mcpt5-Cre+ R-DTA+ vs. Mcpt5-Cre− R-DTA+ animals. Decreased melanoma colonization of the lungs in Mcpt5-Cre+ R-DTA+ animals was accompanied by increased inflammatory cell recruitment into the bronchoalveolar lavage fluid, suggesting that mast cells suppress inflammation in this setting. Further, qPCR analysis revealed significant alterations in the expression of Twist and E-cadherin in lungs of Mcpt5-Cre+ R-DTA+ vs. control Mcpt5-Cre− R-DTA+ animals, suggesting an impact of mast cells on epithelial-mesenchymal transition. In conclusion, this study reveals that mast cells promote melanoma colonization of the lung.
Highlights
Mast cells are well known for their devastating impact on allergic reactions, the most serious manifestation being anaphylactic shock [1, 2]
Our findings indicate that mast cells promote melanoma colonization of lungs, thereby introducing the possibility that mast cells have a role in melanoma metastasis
In this study we used mice in which Cre recombinase expression is driven by the promoter for Mcpt5 (Mcpt5-Cre+ mice), Mcpt5 ( denoted mouse mast cell protease 5) being a chymase that is restricted to mast cells of the connective tissue subtype (CTMCs; [37])
Summary
Mast cells are well known for their devastating impact on allergic reactions, the most serious manifestation being anaphylactic shock [1, 2]. Mast cell presence has in many cases been correlated with bad prognosis, suggesting that they are detrimental Examples of this scenario include squamous carcinomas [12, 13], nodular sclerotic-type Hodgkin’s lymphoma [14], Waldenströms macroglobulinemia [15] and prostate cancer [16]. Mast cell presence has in other cases been correlated with good prognosis, i.e. indicating that mast cells can be protective Examples of the latter include breast cancer [17, 18], non-small-cell lung carcinoma [19], www.impactjournals.com/oncotarget diffuse large B-cell lymphoma [20] and ovarian cancer [21]. Partly conflicting clinical findings have been published (reviewed in [10]), with some studies indicating a detrimental impact of mast cells [2224] whereas others have reported a positive correlation between mast cell presence and good prognosis [25]
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