interleukin-8 and Carcinoma--Basal-Cell

Interleukin-17 (IL-17) and IL-22 have been reported to play critical roles in autoimmunity and inflammation but information about their role in cancer is limited. In this study, we investigated the role of IL-17 and IL-22 in the progression of human skin basal-cell carcinoma (BCC) and squamous-cell carcinoma (SCC). We found that both tumor types are infiltrated with an high number of IL-17(+) and IL-22(+) T lymphocytes, as demonstrated by immunohistochemistry and by FACS analysis performed on peritumoral T-cell lines isolated from skin biopsies. In vitro studies demonstrated that proliferation and migration of the BCC- and SCC-cell lines M77015 and CAL27 were increased by IL-17 and IL-22. Moreover, IL-17, alone or in combination with TNF-α, was able to induce the production of two cytokines important for tumor progression, IL-6 and IL-8, in CAL27. We also showed that IL-17 upregulated NF-κB signaling, while IL-22 activated the STAT3 pathway and the antiapoptotic AKT protein in M77015 and CAL27. Finally, in vivo experiments demonstrated that IL-17 and IL-22 enhanced tumor growth in nude mice injected with CAL27. Altogether, our findings indicate that high levels of IL-22 and IL-17 in the BCC and SCC microenvironment promote tumor progression.

Topics: Animals; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cell Line, Tumor; Female; Humans; Interleukin-17; Interleukin-22; Interleukin-6; Interleukin-8; Interleukins; Male; Mice; Mice, Nude; Neoplasm Proteins; NF-kappa B; Signal Transduction; Skin Neoplasms; Tumor Microenvironment

A subgroup of the transient receptor potential (TRP) channels, including vanilloid 1 (TRPV1), TRPV2, TRPV3, TRPV4, and TRP ankyrin 1 (TRPA1), is expressed in cutaneous peptidergic somatosensory neurons, and has been found in skin non-neuronal cells, such as keratinocytes. Different cancer cells express TRPs, where they may exert either pro- or antitumorigenic roles. Expression and function of TRPs in skin cancers have been, however, poorly investigated. Here, we have studied the distribution and expression of TRPs by immunohistochemistry and messenger RNA (mRNA) in human healthy skin and human keratinocytic tumors, including intraepidermal proliferative disorders (solar keratosis (SK) and Bowen's disease), and non-melanoma skin cancer (NMSC; basal cell and squamous cell carcinomas). Similar TRPV1, TRPV2, and TRPV3 staining was found in keratinocytes from healthy and tumor tissues. TRPA1 staining was increased solely in SK samples. However, the marked TRPV4 staining and TRPV4 mRNA expression, observed in healthy or inflamed skin, was abrogated both in premalignant lesions and NMSC. In a human keratinocyte cell line (HaCaT), TRPV4 stimulation released IL-8, which in turn downregulated TRPV4 expression. Selective reduction in TRPV4 expression could represent an early biomarker of skin carcinogenesis. Whether the cytokine-dependent, autocrine pathway that results in TRPV4 downregulation contributes to NMSC mechanism remains to be determined.

Topics: Adult; Aged; Aged, 80 and over; Autocrine Communication; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Interleukin-8; Keratinocytes; Keratosis; Male; Middle Aged; Precancerous Conditions; Skin Neoplasms; Tissue Banks; TRPV Cation Channels

The lack of a human papillomavirus (HPV)-infected skin cancer cell line has hampered the investigation of the interaction of UV and HPV in skin carcinogenesis. We identified a human basal cell carcinoma (BCC-1/KMC) cell line integrated with E6 and E7 genes of high-risk HPV type 18 and demonstrated that repression of E6 and E7 results in proliferation inhibition. Sublethal ultraviolet-B (UVB) irradiation induced the expressions of interleukin-6 (IL-6) and interleukin-8 (IL-8), as well as viral E6 and E7 genes, in BCC-1/KMC cells. When E6 and E7 expressions were inhibited, IL-6/IL-8 expressions were repressed. Furthermore, IL-6/IL-8 remained inducible by UVB irradiation when E6 and E7 were inhibited. These results indicated that IL-6 and IL-8 can be upregulated by viral E6 and E7 proteins without UVB irradiation. Moreover, chronic exposure to UVB upregulates IL-6 and IL-8 when E6/E7 is induced by UVB.

Topics: Carcinoma, Basal Cell; Cell Line, Tumor; Cell Proliferation; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Viral; Humans; Inflammation; Interleukin-6; Interleukin-8; Oncogene Proteins, Viral; Papillomavirus E7 Proteins; RNA Interference; RNA, Small Interfering; Skin Neoplasms; Ultraviolet Rays; Up-Regulation

Both neurotrophins and chemorepellents are involved in the elongation and sprouting of itch-associated C-fibers in the skin. Nerve growth factor (NGF) and semaphorin 3A (Sema3A) are representatives of these two types of axon-guidance factors, respectively.. We investigated the effects of calcium concentration and histamine on the expression of NGF and Sema3A in normal human epidermal keratinocytes (NHEK) and normal human fibroblasts (NHFb).. NHEK and NHFb were cultured under different calcium concentrations (0.15-0.9 mM) with or without histamine, and the expression of mRNA for NGF and SEMA3A was assessed by real-time PCR analysis. An immunohistochemical study was performed for Sema3A using normal skin and skin cancer specimens.. In NHEK, SEMA3A expression was elevated by high calcium concentration and reduced by low calcium condition, while NGF expression was not dependent on calcium. Their expressions were unchanged by calcium in NHFb. Immunohistochemically, keratinocytes in the prickle layer of normal epidermis and squamous cell carcinoma cells were positive for Sema3A, sparing basal cells and suprabasal cells. The addition of histamine to NHEK at 10 μg/ml enhanced SEMA3A expression but depressed NGF expression. In NHFb, however, histamine decreased both NGF and SEMA3A levels.. Sema3A inhibits C-fiber elongation/sprouting in the upper layers of the epidermis, where calcium concentration is high, thereby determining the nerve endings. Histamine reduces Sema3A production by fibroblasts, allowing C-fibers to elongate in the dermis. In contrast, the histamine-augmented keratinocyte production of Sema3A might suppress C-fiber elongation and exaggerated pruritus.

Topics: Calcium; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cells, Cultured; Fibroblasts; Granulocyte-Macrophage Colony-Stimulating Factor; Histamine; Humans; Interleukin-8; Keratinocytes; Nerve Fibers, Unmyelinated; Nerve Growth Factor; Oligopeptides; RNA, Messenger; Semaphorin-3A; Skin

Mast cells are increasingly present in the lesional skin of chronic skin inflammatory diseases including psoriasis and basal cell carcinoma (BCC). It has previously been shown that proteinase-activated receptor (PAR)-2 is expressed by mast cells, and tryptase is a potent activator of this receptor. In this study, skin biopsies from both healthy-looking and lesional skin of patients with psoriasis and superficial spreading BCC were collected and the expression of PAR-2 immunoreactivity in tryptase-positive mast cells was analysed. PAR-2 expression was confirmed in vitro in different mast cell populations. Cord-blood derived mast cells (CBMC) were stimulated with a PAR-2 activating peptide, 2-furoyl-LIGRLO-NH(2). Consequently, IL-8 and histamine production was analysed in the supernatants. We observed a significant increase in the percentage of mast cells expressing PAR-2 in the lesional skin of psoriasis and BCC patients compared with the healthy-looking skin. HMC-1.2, LAD-2 and CBMC mast cells all expressed PAR-2 both intracellularly and on the cell surface. CBMC activation with the PAR-2 activating peptide resulted in an increased secretion of IL-8, but no histamine release was observed. Furthermore, both PAR-2 and IL-8 were co-localized to the same tryptase-positive mast cells in the lesional BCC skin. These results show that mast cells express increased levels of PAR-2 in chronic skin inflammation. Also, mast cells can be activated by a PAR-2 agonist to secrete IL-8, a chemokine which can contribute to the progress of inflammation.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Basal Cell; Female; Humans; Interleukin-8; Male; Mast Cells; Middle Aged; Psoriasis; Receptor, PAR-2; Skin Neoplasms; Up-Regulation; Young Adult

Psoriasin (S100A7) has originally been described to be expressed by psoriatic keratinocytes possibly as a result of altered differentiation and inflammation. As psoriasin was found to be overexpressed in human breast and bladder cancer suggesting a role in tumour progression, we investigated the expression of psoriasin in human epithelial skin tumours.. Realtime reverse transcription-polymerase chain reaction experiments were performed to analyse the mRNA-expression levels of psoriasin together with involucrin as a marker for epithelial differentiation and interleukin-8 (IL-8) as a marker for inflammation in skin biopsy samples from patients with precancerous skin lesions (PSL, n = 6), squamous cell carcinoma (SCC, n = 11), basal cell carcinoma (BCC, n = 17), and healthy controls (n = 10).. Unexpectedly, mRNA expression levels for Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) revealed a variation of up to 600-fold in all cDNA-samples under investigation, indicating that GAPDH is not suitable as a housekeeping gene in human skin samples. Psoriasin mRNA expression was significantly up-regulated in samples of PSL, SCC and BCC. In situ hybridisation and immunohistochemical examinations identified psoriasin mRNA and protein expression in the differentiated layers of the epidermis. IL-8 mRNA expression was significantly up-regulated in SCC, however, there was no correlation between elevated levels of psoriasin and the expression of IL-8.. Similar to the findings in breast and bladder cancer, the up-regulation of psoriasin might play a role in the progression of skin cancer. The expression of psoriasin in human skin tumours seems to be independent from differentiation and inflammation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Calcium-Binding Proteins; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Child; Female; Gene Expression Regulation, Neoplastic; Glyceraldehyde-3-Phosphate Dehydrogenases; Humans; Immunohistochemistry; In Situ Hybridization; Interleukin-8; Male; Middle Aged; Precancerous Conditions; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm; S100 Calcium Binding Protein A7; S100 Proteins; Skin Neoplasms; Up-Regulation

Basal cell carcinoma (BCC) is the most common malignant tumor of the skin. Although an increase in mast cell infiltration was observed in BCC lesions, definite evidence of an active role of mast cells in the pathogenesis of BCC is still lacking. BCC is accompanied by cellular infiltrates. Moreover, the stroma in the BCC lesions is characterized by an increased number of mast cells and increased vascularity. The aim of this study was to elucidate the probable role of mast cells in BCC, especially focusing on the relationship between mast cells and lymphocytic infiltration as well as angiogenesis.. We examined the expression and distribution of VEGF, IL-8 and RANTES in 16 nodular BCC lesions by immunohistochemistry. We also examined the lymphocyte subset, and the correlation between VEGF expression and microvessel density in the BCC lesion. mRNA expression of IL-8 and RANTES was examined by the reverse transcriptase-polymerase chain reaction.. T cells, especially CD4+/CD45RO+ memory T cells were the predominant infiltrating lymphocyte population in BCC lesions. An increased number of tryptase+ cells (mast cells) was found in the stroma. VEGF+/IL-8+/RANTES+ cells were also found abundantly in the stroma of all BCC lesions. The number of VEGF+, IL-8+ and RANTES+ cells was significantly higher than that in controls. By immunohistochemistry of serial sections, tryptase+ cells were found to express VEGF, IL-8 or RANTES. Messenger RNA expression of IL-8 and RANTES was also observed in the BCC lesions.. This study suggests that mast cells may play an active role in the angiogenesis of BCC through the production of VEGF and IL-8. Furthermore, mast cells may also regulate lymphocytic infiltration through the production of IL-8 and RANTES.

Topics: Aged; Aged, 80 and over; Carcinoma, Basal Cell; Chemokine CCL5; Endothelial Growth Factors; Female; Humans; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Interleukin-8; Lymphocyte Subsets; Lymphokines; Male; Mast Cells; Microcirculation; Middle Aged; Neovascularization, Pathologic; RNA, Messenger; RNA, Neoplasm; Skin Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

We examined leukocyte counts and ex vivo cytokine response of whole blood to lipopolysaccharide (LPS) or lipoteichoic acid (LTA) in patients under low-dose molgramostim therapy. Patients were injected subcutaneously daily for ten days with 1 microg/kg (n=9) or 2 microg/kg (n=14) molgramostim. Leukocytosis was observed in all patients, but only the eosinophil fraction was significantly increased in relation to other leukocyte populations. Ex vivo IFN-gamma release was decreased and IL-10 and IL-1ra secretion were increased in response to LPS or LTA. Thus, in non-neutropenic patients, leukocytosis can already be initiated by low doses of molgramostim. The ex vivo cytokine data suggest that these doses prime blood towards a systemic anti-inflammatory response.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Basal Cell; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Head and Neck Neoplasms; Humans; Interferon-gamma; Interleukin 1 Receptor Antagonist Protein; Interleukin-10; Interleukin-6; Interleukin-8; Leukocytes; Lipopolysaccharides; Male; Middle Aged; Recombinant Proteins; Sialoglycoproteins; Teichoic Acids; Time Factors

In the past, interleukin-8 (IL-8) could be demonstrated within keratinocytes in normal epidermis and inflammatory skin diseases, like psoriasis and eczema. Using monoclonal antibodies, the distribution of IL-8 immunoreactivity was inversely related to the density of inflammatory infiltrate. Other in vitro observations indicated IL-8 to be a growth factor for keratinocytes. These results prompted an immunohistochemical examination of IL-8 immunoreactivity in malignant and semimalignant epithelial tumours of human skin. Whereas IL-8 could not be detected within the transformed cells of epithelial tumours or melanoma, some tumour cells within well differentiated squamous cell carcinoma and Bowen's disease showed IL-8 immunoreactivity. Thus, loss of IL-8 immunoreactivity can be a sign of malignant transformation. This indicates an important role in growth regulation as well as terminal differentiation of human keratinocytes.

Topics: Bowen's Disease; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Humans; Immunohistochemistry; Interleukin-8; Keratinocytes; Melanoma; Skin; Skin Neoplasms