The Human Cutaneous Squamous Cell Carcinoma Microenvironment Is Characterized by Increased Lymphatic Density and Enhanced Expression of Macrophage-Derived.

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The Human Cutaneous Squamous Cell Carcinoma Microenvironment Is Characterized by Increased Lymphatic Density and Enhanced Expression of Macrophage-Derived VEGF-C Dariush Moussai, Hiroshi Mitsui, Julia S. Pettersen, Katherine C. Pierson, Kejal R. Shah, Mayte Suárez-Fariñas, Irma R. Cardinale, Mark J. Bluth, James G. Krueger, John A. Carucci Journal of Investigative Dermatology Volume 131, Issue 1, Pages 229-236 (January 2011) DOI: 10.1038/jid.2010.266 Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Human cutaneous SCC is associated with increased lymphatic vessel density and characterized by the expression of LYVE-1 and VEGFR-3. Representative immunohistochemistry of LYVE-1 expression in (a) SCC and (b) normal skin. (c) Mean LYVE-1+ cell counts with standard error of the mean in SCC (black bar) and normal skin (gray bar) (n=10 for both groups). *P<0.05. (d) Immunofluorescence revealed colocalization of LYVE-1 (green) and VEGFR-3 (red) in SCC lymphatic endothelial cells. Scale bar=100μm. LYVE-1, lymphatic vessel endothelial hyaluronan receptor-1; SCC, squamous cell carcinoma; VEGFR-3, vascular endothelial growth factor receptor-3. Journal of Investigative Dermatology 2011 131, 229-236DOI: (10.1038/jid.2010.266) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Lymphatic endothelial cell (LEC)-associated gene signatures are present in squamous cell carcinoma (SCC) and in adjacent non-tumor-bearing skin compared with normal skin. The mean log fold change of published cancer-related angiogenic (Brentani), LEC-specific (Iritani_LEC), and vascular endothelial growth factor (VEGF) (VEGFPATHWAY) gene sets for SCC versus normal skin (black bars), peritumoral non-lesion (PTNL) versus normal skin (dark gray bars), and SCC versus PTNL (light gray bars). In the Iritani gene set, PTNL versus normal skin showed increased expression. **P<0.005. Journal of Investigative Dermatology 2011 131, 229-236DOI: (10.1038/jid.2010.266) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Vascular endothelial growth factor (VEGF)-C, VEGF-D, Prox-1, Flt-4, neuropilin-2 (NRP-2), podoplanin (PDPN), and IL-8 are expressed in the squamous cell carcinoma (SCC) microenvironment. The relative mRNA expression of (a) VEGF-C, (b) VEGF-D, (c) PROX-1, (d) Flt-4, (e) NRP-2, (f) PDPN, and (g) IL-8 relative to human acidic ribosomal protein in SCC (black bars), peritumoral non-lesion (PTNL, gray bars), and normal skin (white bars). Data are expressed as relative gene expression+SEM. *P<0.05, ***P<0.0005. Journal of Investigative Dermatology 2011 131, 229-236DOI: (10.1038/jid.2010.266) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Squamous cell carcinoma (SCC)-associated macrophages express vascular endothelial growth factor-C (VEGF-C). (a) CD163+ macrophages (green) and (b) CD68+ macrophages (green) colocalized with VEGF-C (red) shown as yellow. (c) Triple-labeled immunofluorescence revealed the presence of CD163+ cells (blue) that expressed both CD68 (green) and VEGF-C (red). Triple-positive cells (CD163+CD68+VEGF-C+) appear white. Scale bar=100μm. (d) VEGF-C mRNA expression in normal epidermis (EPI, n=3), actinic keratosis (AK)-like dysplasia (AK-like dysplasia, n=3), SCC in situ (SCCIS, n=3), invasive SCC (n=3), and inflammatory infiltrate (INF, n=5). P<0.01 for the following comparisons with VEGF-C: INF versus normal epidermis, INF versus AK-like dysplasia, and INF versus SCCIS. Journal of Investigative Dermatology 2011 131, 229-236DOI: (10.1038/jid.2010.266) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions