Abstract
BackgroundThe importance of the malignant cell environment to its growth and survival is becoming increasingly apparent, with dynamic cross talk between the neoplastic cell, the leukocyte infiltrate and the stroma. Most cancers are accompanied by leukocyte infiltration which, contrary to an anticipated immuno-protective role, could be contributing to tumour development and cancer progression. Epstein-Barr virus (EBV) associated cancers, including nasopharyngeal carcinoma and Hodgkin's Disease, show a considerable leukocyte infiltration which surrounds the neoplastic cells, raising the questions as to what role these cells play in either restricting or supporting the tumour and what draws the cells into the tumour. In order to begin to address this we have studied a transgenic model of multistage carcinogenesis with epithelial expression of the EBV primary oncoprotein, latent membrane protein 1 (LMP1). LMP1 is expressed particularly in the skin, which develops a hyperplastic pathology soon after birth.ResultsThe pathology advances with time leading to erosive dermatitis which is inflamed with a mixed infiltrate involving activated CD8+ T-cells, CD4+ T-cells including CD4+/CD25+/FoxP3+ Treg cells, mast cells and neutrophils. Also significant dermal deposition of immunoglobulin-G (IgG) is observed as the pathology advances. Along with NF-kappaB activation, STAT3, a central factor in inflammation regulation, is activated in the transgenic tissue. Several inflammatory factors are subsequently upregulated, notably CD30 and its ligand CD153, also leukocyte trafficking factors including CXCL10, CXCL13, L-selectin and TGFβ1, and inflammatory cytokines including IL-1β, IL-3 and the murine IL-8 analogues CXCL1, CXCL2 and CXCL5-6, amongst others. The crucial role of mature T- and/or B-lymphocytes in the advancing pathology is demonstrated by their elimination, which precludes mast cell infiltration and limits the pathology to an early, benign stage.ConclusionsLMP1 can lead to the activation of several key factors mediating proliferation, angiogenesis and inflammation in vivo. With the initiation of an inflammatory programme, leukocyte recruitment follows which then itself contributes to the progressing pathology in these transgenic mice, with a pivotal role for B-and/or T-cells in the process. The model suggests a basis for the leukocyte infiltrate observed in EBV-associated cancer and its supporting role, as well as potential points for therapeutic intervention.
Highlights
The importance of the malignant cell environment to its growth and survival is becoming increasingly apparent, with dynamic cross talk between the neoplastic cell, the leukocyte infiltrate and the stroma
The most striking phenotype presents in the hairless skin regions, the ears of the mice. This preneoplastic phenotype has been categorised into five recognisable and predictable stages, from stage 1 (St1) showing mild hyperplasia with increased vascularisation to stage 5 (St5) displaying severe hyperplasia with necrosis and tissue degeneration, which can lead to acanthosis, hyperkeratosis and occasional carcinoma [20]
In agreement with the IHC analysis, a greater proportion of CD45+ leukocytes were present in the transgenic ear tissue compared to the controls with between 60% and 80% CD45+ cells in the transgenic samples compared with 2% to 7% in non-transgenic sibling control (NSC) samples
Summary
The importance of the malignant cell environment to its growth and survival is becoming increasingly apparent, with dynamic cross talk between the neoplastic cell, the leukocyte infiltrate and the stroma. Most cancers are accompanied by leukocyte infiltration which, contrary to an anticipated immuno-protective role, could be contributing to tumour development and cancer progression. Epstein-Barr virus (EBV) associated cancers, including nasopharyngeal carcinoma and Hodgkin’s Disease, show a considerable leukocyte infiltration which surrounds the neoplastic cells, raising the questions as to what role these cells play in either restricting or supporting the tumour and what draws the cells into the tumour. Almost all cancers are accompanied by leukocyte infiltration, the significance of which has recently come under increasing scrutiny as to whether these cells work to eradicate the malignant cell, or whether they act to support it. Soluble B-cell-derived factors have been shown to increase inflammatory cell recruitment and co-ordinately carcinogenic progression in a K14.HPV16:E6/E7 transgenic mouse model of epithelial carcinogenesis [5]. It is becoming increasingly clear that the ability of tumour cells themselves to secrete and/or respond to cytokines and chemokines can provide a survival advantage [6]
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