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Oral carcinogenesis represents a multi-stage process which encompasses several genetic and molecular changes that promote the progression of oral potentially malignant disorders (OPMDs) to oral squamous cell carcinomas (OSCCs). A better understanding of critical pathways governing the progression of OMPDs to OSCCs is critical to improve oncologic outcomes in the future. Previous studies have identified an important role of tumor necrosis factor α (TNFα) and TNF receptor 1 (TNFR1) in the invasiveness of oral cancer cell lines. Here, we investigate the expression of TNFα and TNFR1 in human OPMDs that progress to OSCC compared to non-progressing OPMDs utilizing fluorescent immunohistochemistry (FIHC) to show increased TNFα/TNFR1 expression in progressing OPMDs. In order to interrogate the TNFα/TNFR1 signaling pathway, we utilized a 4-nitroquinoline 1-oxide (4-NQO) mouse model of oral carcinogenesis to demonstrate that TNFα/TNFR1 expression is upregulated in 4-NQO-induced OSCCs. TNFα neutralization decreased serum cytokines, inhibited the development of invasive lesions and reduced tumor-associated neutrophils in vivo. Combined, this data supports the role of TNFα in oral malignant transformation, suggesting that critical immunoregulatory events occur downstream of TNFR1 leading to malignant transformation. Our results advance the understanding of the mechanisms governing OSCC invasion and may serve as a basis for alternative diagnostic and therapeutic approaches to OPMDs and OSCC management.

Oral carcinogenesis represents a multi-stage process which encompasses several genetic and molecular changes that promote the progression of oral potentially malignant disorders (OPMDs) to oral squamous cell carcinomas (OSCCs). A better understanding of critical pathways governing the progression of OMPDs to OSCCs is critical to improve oncologic outcomes in the future. Previous studies have identified an important role of tumor necrosis factor α (TNFα) and TNF receptor 1 (TNFR1) in the invasiveness of oral cancer cell lines. Here, we investigate the expression of TNFα and TNFR1 in human OPMDs that progress to OSCC compared to non-progressing OPMDs utilizing fluorescent immunohistochemistry (FIHC) to show increased TNFα/TNFR1 expression in progressing OPMDs. In order to interrogate the TNFα/TNFR1 signaling pathway, we utilized a 4-nitroquinoline 1-oxide (4-NQO) mouse model of oral carcinogenesis to demonstrate that TNFα/TNFR1 expression is upregulated in 4-NQO-induced OSCCs. TNFα neutralization decreased serum cytokines, inhibited the development of invasive lesions and reduced tumor-associated neutrophils in vivo. Combined, this data supports the role of TNFα in oral malignant transformation, suggesting that critical immunoregulatory events occur downstream of TNFR1 leading to malignant transformation. Our results advance the understanding of the mechanisms governing OSCC invasion and may serve as a basis for alternative diagnostic and therapeutic approaches to OPMDs and OSCC management. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis with production of aberrant clones and a high cell apoptosis rate in Bone Marrow (BM). Macrophages are in charge of phagocytosis. Innate Immune cells and specific T cells are in charge of immuno-surveillance. Little is known on BM cell recruitment and activity as BM aspirate is frequently contaminated with peripheral blood. But some evidences suggest an active role of immune cells in protection against MDS and secondary leukemia. BM CD8+CD28- CD57+ T cells are directly cytotoxic and have a distinct cytokine signature in MDS, producing TNF-α, IL-6, CCL3, CCL4, IL-1RA. TNF-α; FAS-L, TRAIL... actively induce apoptosis of aberrant cells. On the other hand, TNF-α has ambiguous activity, increasing MDS related cytopenia and myelofibrosis together with TGF-b. IL-32 amplifies NK cytotoxicity but also the vicious circle of TNF-α production. Myeloid Derived Suppressing Cells (MDSC) are increased in MDS and have ambiguous role in protection/ progression of the diseases. CD33 is expressed on MDS and MDSC cells and is directly involved in MDSC activity. CD33 is a potential target for biotherapy. Other MDS stromal cells have feeding activity and can regulate proliferation too. MDS also has impact on Immunity and can favor chronic inflammation and emergence of auto-immune disorders.