title: The human cutaneous squamous cell carcinoma microenvironment is characterized by increased lymphatic density and enhanced expression of macrophage-derived VEGF-C.
abstract: Metastases from primary cutaneous squamous cell carcinoma (SCC) account for the majority of the ∼10,000 non-melanoma skin cancer deaths in the United States annually. We studied lymphangiogenesis in human SCC because of the potential link to metastasis. SCC samples were stained for lymphatic endothelial vessel marker LYVE-1 and positive cells were counted and compared with cells in normal skin. Gene set enrichment analysis and reverse transcription (RT)-PCR were performed on SCC, on adjacent non-tumor-bearing skin, and on normal skin to determine the differential expression of lymphangiogenesis-associated genes. Laser capture microdissection (LCM) was performed to isolate tumor cells and tumor-associated inflammatory cells for further gene expression analysis. Immunofluorescence was performed to determine the source of vascular endothelial growth factor-C (VEGF-C) in the tumor microenvironment. We found increased lymphatic density and reorganized lymphatic endothelial vessels in the dermis immediately adjacent to SCC nests. RT-PCR confirmed the presence of VEGF-C in skin immediately adjacent to SCC. LCM confirmed the increased expression of VEGF-C, the SCC inflammatory infiltrate. The presence of CD163(+)/CD68(+)/VEGFC(+) cells and absence of VEGF-C expression by CD3(+) or CD11C(+) cells suggested that VEGF-C is derived from tumor-associated macrophages. Clarification of mechanisms governing SCC-mediated lymphangiogenesis may identify potential targets for therapeutic intervention against aggressive or inoperable disease.
authors.affiliation: Department of Dermatology, Weill Medical College of Cornell University, New York, New York, USA.
authors.forename: Dariush
authors.initials: D
authors.lastname: Moussai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mitsui
authors.forename: Julia S
authors.initials: JS
authors.lastname: Pettersen
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Pierson
authors.forename: Kejal R
authors.initials: KR
authors.lastname: Shah
authors.forename: Mayte
authors.initials: M
authors.lastname: Suárez-Fariñas
authors.forename: Irma R
authors.initials: IR
authors.lastname: Cardinale
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Bluth
authors.forename: James G
authors.initials: JG
authors.lastname: Krueger
authors.forename: John A
authors.initials: JA
authors.lastname: Carucci
mesh_terms: D001706:Biopsy; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D042583:Lymphangiogenesis / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics; D018613:Microscopy, Confocal; D039943:Neuropilin-2 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism*; D000098853:Podoplanin
chemical_list: D008562:Membrane Glycoproteins; D039943:Neuropilin-2; D042582:Vascular Endothelial Growth Factor C; C117468:PDPN protein, human; D000098853:Podoplanin