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.

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The precise mechanisms governing invasion at the leading edge of SCC and its subsequent metastasis are not fully understood. We aimed to define the cancer related molecular changes that distinguish non-invasive tumor from invasive SCC. To this end, we combined laser capture microdissection with cDNA microarray analysis. We defined invasion-associated genes as those differentially regulated only in invasive SCC nests, but not in actinic keratosis or in situ SCC, compared to normal epidermis. There were 383 up- and 354 down-regulated genes in the “invasion set.” SCC invasion was characterized by aberrant expression of various proteolytic molecules. We noted increased expression of MMP7 and IL-24 in invasive SCC. IL-24 induced the expression of MMP7 in SCC cells in culture. In addition, blocking of MMP7 by a specific antibody significantly delayed the migration of SCC cells in culture. These results suggest a possible contribution of IL-24 to SCC invasion via enhancing focal expression of MMP7, though IL-24 has been suggested to have anti-tumor growth effects in other cancer types. Identification of regional molecular changes that regulate cancer invasion may facilitate the development of new targeted treatments for aggressive cancer.

Dysplastic nevi (DNs), also known as Clark's nevi or atypical moles, are distinguished from common melanocytic nevi by variegation in pigmentation and clinical appearance, as well as differences in tissue patterning. However, cellular and molecular differences between DNs and common melanocytic nevi are not completely understood. Using cDNA microarray, quantitative RT-PCR, and immunohistochemistry, we molecularly characterized DNs and analyzed the difference between DNs and common melanocytic nevi. A total of 111 probesets (91 annotated genes, fold change > 2.0 and false discovery rate < 0.25) were differentially expressed between the two lesions. An unexpected finding in DNs was altered differentiation and activation of epidermal keratinocytes with increased expression of hair follicle-related molecules (keratin 25, trichohyalin, ribonuclease, RNase A family, 7) and inflammation-related molecules (S100A7, S100A8) at both genomic and protein levels. The immune microenvironment of DNs was characterized by an increase of T helper type 1 (IFNγ) and T helper type 2 (IL13) cytokines as well as an upregulation of oncostatin M and CXCL1. DUSP3, which regulates cellular senescence, was identified as one of the disease discriminative genes between DNs and common melanocytic nevi by three independent statistical approaches and its altered expression was confirmed by immunohistochemistry. The molecular and cellular changes in which the epidermal-melanin unit undergoes follicular differentiation as well as upregulation of defined cytokines could drive complex immune, epidermal, and pigmentary alterations.

To understand the development of new psoriasis lesions, we studied a group of moderate-to-severe psoriasis patients who experienced a relapse after ceasing efalizumab (anti-CD11a, Raptiva, Genentech). There were increased CD3+ T cells, neutrophils, CD11c+ and CD83+ myeloid dendritic cells (DCs), but no increase in CD1c+ resident myeloid DCs. In relapsed lesions, there were many CD11c+CD1c−, inflammatory myeloid DCs identified by TNFSF10/TRAIL, TNF, and iNOS. CD11c+ cells in relapsed lesions co-expressed CD14 and CD16 in situ. Efalizumab induced an improvement in many psoriasis genes, and during relapse, the majority of these genes reversed back to a lesional state. Gene Set Enrichment Analysis (GSEA) of the transcriptome of relapsed tissue showed that many of the gene sets known to be present in psoriasis were also highly enriched in relapse. Hence, on ceasing efalizumab, T cells and myeloid cells rapidly enter the skin to cause classic psoriasis.Trial registrationClinicaltrials.gov NCT00115076

CD200 expression on local blood vessels may promote tumor progression by suppressing CD200R myeloid cells during diapedesis. These data highlight a previously unrecognized mechanism of immune evasion by SCC and may provide guidance for the development of targeted therapy.

Background: To compare glycemic variability (GV) indices between patients with fibrocalculous pancreatic diabetes (FCPD) and type 2 diabetes mellitus (T2D) using continuous glucose monitoring (CGM). Methods: We measured GV indices using CGM (iPro™2 Professional CGM, Medtronic, USA) data in 61 patients each with FCPD and T2D who were matched for glycated hemoglobin A1c (HbA1c) and duration of diabetes. GlyCulator2 software was used to estimate the CGM-derived measures of GV (SD, mean amplitude of glycemic excursion [MAGE], continuous overall net glycemic action [CONGA], absolute means of daily differences [MODD], M value, and coefficient of variance [%CV]), hypoglycemia (time spent below 70 mg/dL, AUC below 70 mg/dL, glycemic risk assessment diabetes equation hypoglycemia, Low Blood Glucose Index), and hyperglycemia (time spent above 180 mg/dL at night [TSA > 180], AUC above 180 mg/dL [AUC > 180], glycemic risk assessment diabetes equation hyperglycemia, High Blood Glucose Index [HBGI], and J index). The correlation of GV indices with HbA1c, duration of diabetes, and demographic and biochemical parameters were also assessed. Results: All the CGM-derived measures of GV (SD, MAGE, CONGA, MODD, and %CV), except M value, were significantly higher in the FCPD group than in the T2D group ( P < 0.05). Measures of hyperglycemia (TSA >180, AUC >180, HBGI, and J index) were significantly higher in the FCPD group than in the T2D group ( P < 0.05). The measures of hypoglycemia were not significantly different between the two groups. All the hyperglycemia indices showed a positive correlation with HbA1c in both groups. Conclusions: FCPD is associated with higher GV than is T2D. The findings of higher postprandial glycemic excursions in patients with FCPD could have potential therapeutic implications.