angiogenin and Skin-Neoplasms

Imiquimod (IMQ) is a synthetic Toll-like receptor (TLR7/8) ligand that can trigger antiviral and antitumor activities. Despite evidence of potent therapeutic effects, the clinical use of IMQ in melanoma is impeded by incomplete understanding of its mechanisms of action. Mice and humans differ in many aspects of immunity, including TLR7 expression patterns, thus impeding the use of mouse models in translating discoveries into clinical applications. In this article, we investigated the mechanisms behind IMQ effects in vivo in a human context of melanoma and immunity using an innovative melanoma-bearing humanized mouse model. In this model, IMQ strongly inhibited melanoma tumor development through prompt mobilization of plasmacytoid dendritic cells and by triggering their cytotoxic functions, and through upregulation of expression of type 1 IFN response genes. IMQ also drastically impeded tumor vascularization by inducing the downregulation of angiogenic factors vascular endothelial growth factor, angiogenin, IL-8, and fibroblast growth factor. Our results revealed the short- and long-term multifactorial effects of IMQ converging toward inhibition of melanoma development. By providing a better understanding of the mechanisms of action of IMQ in melanoma, our study opens the way for its further clinical use in the treatment of metastatic melanoma.

Topics: Administration, Topical; Aminoquinolines; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Dendritic Cells; Disease Models, Animal; Down-Regulation; Fibroblast Growth Factors; Humans; Imiquimod; Interleukin-8; Melanoma; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Middle Aged; Neovascularization, Pathologic; Ribonuclease, Pancreatic; Skin Neoplasms; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Hemangiomas are characterized by rapid growth but slow regression. Prognosis and treatment urgently require the identification of serum markers to determine the proliferative potential of hemangiomas.. Using four pairs of tissue from the proliferative and involution stages of the same hemangiomas, the authors performed cDNA microarray experiments to study differential expression of genes between proliferative hemangiomas and involuting hemangiomas. Among these genes, the authors searched for possible serum markers. A novel analysis process was used to screen for up-regulated genes encoding secreted proteins. Next, the mRNA and protein expression in hemangiomas and serum levels in patients with hemangiomas were validated by quantitative reverse-transcriptase polymerase chain reaction, immunohistochemistry, Western blotting, and enzyme-linked immunosorbent assay.. Sixty-two up-regulated genes were detected in proliferative hemangiomas. Angiogenin, a key angiogenesis factor induced by hypoxia, was found to be a possible serum marker. Angiogenin mRNA and protein expression were validated by quantitative reverse-transcriptase polymerase chain reaction, immunohistochemistry, and Western blotting. An enzyme-linked immunosorbent assay confirmed that angiogenin serum levels correlate with the hemangioma stage. Moreover, receiver operating characteristic curve analysis indicates a high sensitivity and specificity of angiogenin for discriminating between proliferative hemangiomas and the control group and patients with venous malformations.. The authors report for the first time that angiogenin may be a useful serum marker for hemangiomas, and report a novel analysis process that might efficiently screen for potential serum markers of tumors by cDNA microarray analysis.

Topics: Biomarkers; Blotting, Western; Child, Preschool; Enzyme-Linked Immunosorbent Assay; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Hemangioma; Humans; Immunohistochemistry; Infant; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; Ribonuclease, Pancreatic; ROC Curve; Skin Neoplasms; Up-Regulation

Angiogenin is a member of the ribonuclease superfamily that is associated with the angiogenic process. Angiogenesis is regarded as an important step to support primary and metastatic tumor growth. In cutaneous T cell lymphoma (CTCL), angiogenesis in lesional skin is increased, suggesting that interaction between tumor cells and their microvasculature are likely to occur during progression of CTCL. Patients with hematological malignancies show increased serum angiogenin levels, which are related with poor overall survival. To investigate possible roles of angiogenin in development of CTCL, we measured serum angiogenin levels in 36 patients with CTCL and 21 healthy controls by enzyme-linked immunosorbent assay. We also investigated angiogenin mRNA and protein expression in lesional skin of CTCL by quantitative RT-PCR and immunohistochemistry. Serum angiogenin levels in patients with CTCL were significantly higher than those in healthy controls. When classified with types of skin lesions, serum angiogenin levels were elevated only in erythrodermic CTCL patients. Angiogenin mRNA expression levels in lesional skin were significantly elevated in erythrodermic CTCL compared to normal skin. Immunohistochemical study revealed that angiogenin was expressed by keratinocytes, endothelial cells, and infiltrating lymphocytes in CTCL. Our results suggest that enhanced angiogenin expression may be related with a poor prognosis of erythrodermic CTCL. As angiogenin acts as an inhibitor of polymorphonuclear leukocyte degranulation, angiogenin may also be linked to impaired host defense in erythrodermic CTCL.

Topics: Adult; Female; Humans; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Neovascularization, Pathologic; Ribonuclease, Pancreatic; RNA, Messenger; Skin; Skin Neoplasms

This work was conducted to find out new potential serum markers and study their role as predictive factors in patients with metastatic melanoma. Serum samples from 68 patients with stage IV malignant melanoma were collected just before current treatment and screened for 79 different cytokines by using a multi-cytokine array. Angiogenin, which is a protein capable of promoting angiogenesis, was found to be markedly elevated among a sub-group of patients with progressive disease (PD) and thus was subjected to further analysis. The mean serum angiogenin level was 270 ng/ml and the median 236 ng/ml (STD 163 ng/ml). Concentrations were significantly higher among men than in women (P = 0.031), whereas patient's age, site of the primary tumour, Clark's or Breslow's classifications were not associated with angiogenin levels. Patients with only lymph node metastases had markedly lower angiogenin levels than those with metastases at other sites (P = 0.05). High angiogenin levels were significantly (P = 0.015; Kruskal-Wallis) associated with poor treatment response with chemoimmunotherapy. Treatment-related survival (TRS) was shorter (10 months) in patients with above-median values than in those with below-median levels (19 months, P = NS). Cox multivariate regression model was used to control for the confounding by the classical prognostic factors of melanoma (age, sex, disease burden, performance score, site of metastases). Disease burden was the only variable that remained in the model as a significant independent predictor of TRS (P = 0.044). These data suggest that serum angiogenin levels might be of predictive value in the evaluation of treatment response for patients with stage IV melanoma.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Female; Humans; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Ribonuclease, Pancreatic; Skin Neoplasms; Survival Analysis; Treatment Outcome; Tumor Burden