Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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Tumor Stroma and Melanoma Progression Depends on Host Endothelial Cell Derived SDF-1
Zeshaan N. Maan, MBBS, MSc, MRCS, Michael S. Hu, MD, MS, MPH, Alexander J. Whittam, BA, Lauren H. Fischer, MD, Dominik Duscher, MD, Graham G. Walmsley, BA, Arnetha J. Whitmore, BA, Michael T. Longaker, MD, MBA, Geoffrey C. Gurtner, MD, FACS.
Stanford University School of Medicine, Stanford, CA, USA.

PURPOSE:
The surrounding vascularized stroma of malignant cells provides a microenvironment critical for tumor development and subsequent progression of cancer. Understanding the signaling mechanisms governing the microenvironment and its interplay with tumor cells has the potential to inform more efficient tools for cancer management. Stromal-derived factor-1 (SDF-1) has been implicated in regulating stem cell microenvironments and also appears to be involved in cancer biology, though its specific role remains unclear. Utilizing newly developed murine models, we investigated the role of host endothelial derived SDF-1 in mediating endothelial-fibroblast interactions during tumor stroma formation and cancer progression.
METHODS:
Murine B16 melanoma cells were seeded onto a pullulan-collagen hydrogel, which were subcutaneously implanted in endothelial cell specific SDF-1 knockout (eKO), fibroblast specific SDF-1 KO (fKO), fibroblast specific CXCR4 (SDF-1 receptor) KO (frKO), and floxed control mice. The mice were photographed and weighed and had their tumor size measured at regular intervals. After 28 days, tumors were harvested, weighed and processed for histology. The effects of SDF-1 on fibroblast behavior and angiogenic profile were assessed in vitro.
RESULTS:
eKO mice demonstrated significantly reduced tumor burden compared to fKO, frKO, and control mice, in terms of height (*p<0.05), weight (*p<0.05) and volume (*p<0.05). SDF-1 increased fibroblast proliferation (*p<0.001), migration (*p=0.002), and survival (*p<0.05) in vitro. Co-culture demonstrated that decreased endothelial production of SDF-1 significantly reduced fibroblast expression of VEGF (*p<0.05) and FGF-2 (*p<0.05) in vitro.
CONCLUSIONS:
Endothelial cell SDF-1 (eSDF-1) plays a pivotal role in cancer biology, regulating the fibroblast expression of angiogenic cytokines, VEGF and FGF-2, and modulating fibroblast proliferation and survival capacity. Collectively, our findings show that eSDF-1 modulates tumor stroma formation and vascular potential, thereby governing tumor progression.


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