Upregulation of Inflammatory Cytokines and Oncogenic Signal Pathways Preceding Tumor Formation in a Murine Model of T-Cell Lymphoma in Skin

Abstract

The tumor microenvironment, including its inflammatory components, regulates tumor progression. Herein, we explore the relationship between inflammation and the progression of T-cell lymphoma in the cutaneous microenvironment. Injection of MBL2 murine T lymphoma cells into ear skin of C57BL/6 and immunodeficient SCID/Beige mice resulted in tumor formation in only the latter group. However, induction of skin inflammation by one topical application of DNFB following MBL2 inoculation in C57BL/6 mice resulted in progressive high-grade lymphoma. The DNFB-regulated tumor formation was blocked by early, but not late, application of a potent topical corticosteroid. At 2 days after implantation, a 10-fold decrease in MBL2 cell apoptosis was detected in DNFB-treated ears compared with vehicle control. After DNFB treatment, Gr-1(high) neutrophils and F4/80(+) macrophages constituted the majority of tumor-infiltrating CD45(+) leukocytes. Depletion of macrophages by clodronate-containing liposomes blocked the tumor-promoting effect of DNFB. Transcriptional profiling of inflammatory cytokines and chemokines after DNFB treatment revealed robust changes in genes that are important in chemotaxis, proliferation, and apoptosis. Activation of oncogenic signal pathways, including NF-κB, was also detected. This work provides insights into the cellular and molecular pathways that mediate lymphoma progression and may have applicability to human cutaneous T-cell lymphomas.