endothelin-1 and Skin-Neoplasms

Melanoma is the most devastating form of skin cancer. The steady increase in the incidence of melanoma, its resistance to chemotherapy, together with its high potential to metastasize, have emphasized the importance of its prevention. It is becoming clear that solar ultraviolet radiation is a main culprit in the etiology of melanoma, the same as in basal and squamous cell carcinomas. It is commonly accepted that skin pigmentation and melanin content are principal determinants of the susceptibility to melanoma and other sun-induced skin cancers. Although this is generally true, however, prediction of melanoma risk based solely on pigmentary phenotype is not always precise and fails to identify high-risk individuals with dark skin color. Other important risk factors need to be considered and better defined, particularly DNA repair capacity. Emerging studies have revealed the role of melanoma susceptibility genes in regulating DNA repair, and indicated that melanoma patients have a lower DNA repair capacity than the general population. As the response of human melanocytes to ultraviolet radiation is modulated by an array of paracrine factors, we have focused our investigation on the role of melanocortins and the melanocortin 1 receptor, as well as endothelin-1, in this response. We have discovered novel roles for melanocortins and endothelin-1 as survival factors that rescue human melanocytes from ultraviolet radiation-induced apoptosis, and importantly enhance repair of DNA photoproducts and reduce the release of hydrogen peroxide that can cause oxidative stress. Our findings, together with epidemiological data showing that loss-of-function mutations in the melanocortin-1 receptor gene increase the risk of melanoma, substantiate the role of DNA repair in melanoma genesis, and suggest that responsiveness to melanocortins and endothelin-1 is important for melanoma prevention.

Topics: Apoptosis; Cell Survival; DNA Damage; DNA Repair; Endothelin-1; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; Melanins; Melanocytes; Melanoma; Oxidative Stress; Receptor, Melanocortin, Type 1; Risk Factors; Skin Neoplasms; Skin Pigmentation; Ultraviolet Rays

Melanocytes, after cell division, separate and migrate along the basement membrane; they extend their dendrites and establish multiple contacts with keratinocytes. Once adhesion is established, keratinocytes control melanocyte growth and expression of cell surface receptors. Most melanomas arise within the epidermis (melanoma in situ) and then invade across the basement membrane. These melanoma cells escape from control by keratinocytes through five major mechanisms: (1) downregulation of receptors important for communication with keratinocytes such as E-cadherin, P-cadherin, and desmoglein, which is achieved through growth factors such as hepatocyte growth factor, platelet-derived growth factor, and endothelin-1 produced by fibroblasts or keratinocytes; (2) upregulation of receptors and signaling molecules important for melanoma cell-melanoma cell and melanoma cell-fibroblast interactions such as N-cadherin, Mel-CAM, and zonula occludens protein-1; (3) deregulation of morphogens such as Notch receptors and their ligands; (4) loss of anchorage to the basement membrane because of an altered expression of cell-matrix adhesion molecules; (5) increased elaboration of metal-loproteinases. Thus, investigating normal melanocyte homeostasis helps us to better define how melanoma cells escape the microenvironment created by epidermal keratinocytes and how they develop new cellular partners in fibroblasts and endothelial cells, which support their growth and invasion.

Topics: Cadherins; Cell Communication; Cell Proliferation; Disease Progression; Endothelin-1; Hepatocyte Growth Factor; Homeostasis; Humans; MAP Kinase Signaling System; Melanocytes; Melanoma; Platelet-Derived Growth Factor; Skin; Skin Neoplasms; Skin Transplantation; Stem Cell Factor

Nitric oxide (NO) is an inorganic free radical gas which has cytostatic/cytotoxic actions in tumoral tissues, including gynecologic, breast, and colon cancer. Nitric oxide is also a multifunctional signaling molecule active in many cells of the body, including endothelial cells, macrophages, monocytes, hepatocytes, mast cells, osteoblasts, and astrocytes. Endothelin-1 (ET-1) is a 21-amino acid peptide that stimulates the proliferation of vascular smooth muscle cells, fibroblasts, and keratinocytes, and plays a role in the expression of proto-oncogenes (c-myc, c-fos), which precedes cell proliferation. Similar to NO, ET is secreted by different cell types, including macrophages, monocytes, hepatocytes, endothelial cells, vascular smooth muscle cells, and various tumor cells. Elevated ET-1 levels are observed in pulmonary, hepatocellular, and prostate cancers. Actinic keratosis (AK) and basal cell carcinoma (BCC) are common skin tumors with accentuated hyperkeratinization, hyperpigmentation, and keratinocyte proliferation.. To investigate plasma NOx (nitrite/nitrate -- the end products of NO metabolism), ET, and the NOx/ET ratio in patients with AK and BCC in comparison with healthy controls.. NOx, ET, and the NOx/ET ratio were measured in 13 patients with AK, 12 patients with BCC, and in 16 healthy controls.. Data analysis indicated a significant increase in plasma NOx, ET, and NOx/ET values in BCC patients in comparison with controls (P < 0.001, P < 0.05 and P < 0.001, respectively). Plasma ET levels in AK were also increased in comparison with controls (P < 0.001). When the two study groups (AK and BCC) were compared, a significant increase (P < 0.001) in the NOx/ET ratio in BCC was found.. The increased plasma ET and NOx levels in AK and, especially, BCC are probably the result of and/or reason for the accentuated hyperkeratinization, hyperpigmentation, and keratinocyte proliferation. The increased production of ET and NO by keratinocytes may function as growth and cytotoxic factors and potential mitogens, and may accelerate further proliferation of these skin tumors. In addition, the increased NOx/ET ratio probably reflects a disturbed equilibrium between these two substances, leading to cell damage and tumor promotion and proliferation.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Basal Cell; Endothelin-1; Endothelin-2; Female; Humans; Male; Middle Aged; Nitric Oxide; Porokeratosis; Probability; Prognosis; Reference Values; Sensitivity and Specificity; Skin Neoplasms

We report a 46-yr-old woman with a history of breast cancer who presented with diffuse myalgias, bone pain, and osteosclerosis. She was found to have recurrent breast cancer producing endothelin-1.. Acquired osteosclerosis can be caused by various disorders. Endothelin -1 is believed to contribute to osteosclerosis caused by breast cancer.. Although the bone marrow biopsy did not reveal breast cancer, she developed skin lesions consistent with metastatic breast cancer. She ultimately died from progressive disease. At autopsy immunohistochemistry for endothelin-1 was performed on a section from the L5 vertebral body.. The section from the L5 vertebral body showed small foci of cells consistent with metastatic carcinoma and a prominent sclerotic response. Immunohistochemistry for endothelin-1 was strongly positive.. Recurrent breast cancer may present with diffuse osteosclerosis. Endothelin-1 may be a paracrine factor responsible for increased bone formation and osteosclerosis.

Topics: Adenocarcinoma; Bone Neoplasms; Breast Neoplasms; Endothelin-1; Fatal Outcome; Female; Humans; Middle Aged; Osteosclerosis; Radiography; Skin Neoplasms

Giant congenital nevi are associated with clinical complications such as neurocutaneous melanosis and melanoma. Virtually nothing is known about why some individuals develop these lesions. We previously identified the sonic hedgehog (Shh) pathway regulator Cdon as a candidate nevus modifier gene. Here we validate this by studying Cdon knockout mice, and go on to establishing the mechanism by which Shh exacerbates nevogenesis. Cdon knockout mice develop blue nevi without the need for somatic melanocyte oncogenic mutation. In a mouse model carrying melanocyte NRAS

Topics: Animals; Endothelin-1; Female; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; Humans; Keratinocytes; Male; Melanocytes; Mice; Mice, Knockout; Neoplasms, Experimental; Nevus, Pigmented; Signal Transduction; Skin Neoplasms; Transcriptional Activation; Tumor Cells, Cultured; Up-Regulation

Endothelin-1 (ET-1) is a vasoactive peptide that also plays a role in the tanning response of the skin. Animal and cell culture studies have also implicated ET-1 in melanoma progression, but no association studies have been performed to link ET-1 expression and melanoma in humans. Here, we present the first in-vivo study of ET-1 expression in pigmented lesions in humans: an ET-1 immunohistochemical screen of melanocytic nevi, melanoma in situ lesions, invasive melanomas, metastatic melanomas, and blue nevi was performed. Twenty-six percent of melanocytic nevi and 44% of melanoma in situ lesions demonstrate ET-1 expression in the perilesional microenvironment, whereas expression in nevus or melanoma cells was rare to absent. In striking contrast, 100% of moderately to highly pigmented invasive melanomas contained numerous ET-1-positive cells in the tumor microenvironment, with 79% containing ET-1-positive melanoma cells, confirmed by co-staining with melanoma tumor marker HMB45. Hypopigmented invasive melanomas had reduced ET-1 expression, suggesting a correlation between ET-1 expression and pigmented melanomas. ET-1-positive perilesional cells were CD68-positive, indicating macrophage origin. Sixty-two percent of highly pigmented metastatic melanomas demonstrated ET-1 expression in melanoma cells, in contrast to 28.2% of hypopigmented specimens. Eighty-nine percent of benign nevi, known as blue nevi, which have a dermal localization, were associated with numerous ET-1-positive macrophages in the perilesional microenvironment, but no ET-1 expression was detected in the melanocytes. We conclude that ET-1 expression in the microenvironment increases with advancing stages of melanocyte transformation, implicating a critical role for ET-1 in melanoma progression, and the importance of the tumor microenvironment in the melanoma phenotype.

Topics: Animals; Endothelin-1; Female; Humans; Immunohistochemistry; Male; Melanoma; Neoplasm Invasiveness; Skin Neoplasms; Tumor Microenvironment

Topics: Apoptosis; Endothelin-1; Humans; Melanocytes; Melanoma; Neoplasms, Radiation-Induced; Radiation Tolerance; Receptor, Endothelin B; Signal Transduction; Skin Neoplasms; Ultraviolet Rays

Endothelin-1 is an autocrine growth factor for keratinocytes, an effect controlled by its A and B receptors, with no previous comparison of endothelin axis expression in inflammatory and neoplastic skin diseases showing keratinocyte proliferation. The aim of the study was to investigate endothelin-1 axis expression in skin lesions of psoriasis, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC).. This study included 40 subjects (8 patients with SCC, 12 patients with BCC, 10 patients with psoriasis, and 10 healthy controls). Biopsies from lesional skin of patients and normal skin of controls were examined immunohistochemically for endothelin-1 and its receptors A and B frequency and grade of expression.. Endothelin-1 and receptor A were detected in all patients with SCC and psoriasis, with a higher frequency and grade of expression than controls and BCC. The frequency of receptor B expression was significantly lower while higher staining grade was found in BCC (8.3%) rather than other studied groups.. A comparable higher frequency and grade of expression of endothelin-1 and its receptor A are documented in psoriasis and SCC than in BCC and controls denoting their involvement in keratinocyte proliferation in both diseases. Receptor A is the predominately expressed receptor in psoriasis and SCC.

Topics: Adolescent; Adult; Aged; Biopsy; Carcinoma, Squamous Cell; Endothelin-1; Female; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; Keratinocytes; Male; Middle Aged; Neoplasm Grading; Neoplasm Proteins; Neoplasms, Basal Cell; Psoriasis; Receptor, Endothelin A; Receptor, Endothelin B; Sampling Studies; Skin Neoplasms; Young Adult

Keratinocytes contribute to melanocyte transformation by affecting their microenvironment, in part through the secretion of paracrine factors. Here we report a loss of expression of nuclear receptor RXRα in epidermal keratinocytes during human melanoma progression. In the absence of keratinocytic RXRα, in combination with mutant Cdk4, cutaneous melanoma was generated that metastasized to lymph nodes in a bigenic mouse model. Expression of several keratinocyte-derived mitogenic growth factors (Et-1, Hgf, Scf, α-MSH and Fgf 2 ) was elevated in skin of bigenic mice, whereas Fas, E-cadherin and Pten, implicated in apoptosis, cellular invasion and melanomagenesis, respectively, were downregulated within the microdissected melanocytic tumors. We demonstrated that RXRα is recruited on the proximal promoter of both Et-1 and Hgf, possibly directly regulating their transcription in keratinocytes. These studies demonstrate the contribution of keratinocytic paracrine signaling during the cellular transformation and malignant conversion of melanocytes.

Topics: Animals; Cyclin-Dependent Kinase 4; Disease Progression; Endothelin-1; Epidermal Cells; Gene Expression Regulation; Hepatocyte Growth Factor; Humans; Keratinocytes; Melanoma; Mice; Mice, Transgenic; Paracrine Communication; Promoter Regions, Genetic; Retinoid X Receptor alpha; Skin Neoplasms

Endothelin (ET) B receptor (ET(B)R), which is overexpressed in human cutaneous melanomas, promotes tumorigenesis upon activation by ET-1 or ET-3, thus representing a potential novel therapeutic target. Hypoxia-inducible factor-1alpha (HIF-1alpha) is the transcriptional factor that conveys signaling elicited by hypoxia and growth factor receptors. Here, we investigated the interplay between ET axis and hypoxia in primary and metastatic melanoma cell lines. We report that under normoxic conditions, ET(B)R activation by ET-1/ET-3 enhances vascular endothelial growth factor (VEGF) up-regulation, cyclooxygenase (COX)-1/COX-2 protein expression and COX-2 promoter activity, prostaglandin E(2) (PGE(2)) production, and do so to a greater extent under hypoxia. Moreover, COX-1/COX-2 inhibitors block ET-induced PGE(2) and VEGF secretion, matrix metalloproteinase (MMP) activation, and cell invasion, indicating that both enzymes function as downstream mediators of ET-induced invasive properties. The ET(B)R selective antagonist BQ788 or transfection with ET(B)R small interfering RNA (siRNA) block the ET-mediated effects. ETs also increase HIF-1alpha expression under both normoxic and hypoxic conditions and its silencing by siRNA desensitizes COX-2 transcriptional activity, PGE(2) and VEGF production, and MMP activation in response to ET-3, implicating, for the first time, HIF-1alpha/COX as downstream targets of ET(B)R signaling leading to invasiveness. In melanoma xenografts, specific ET(B)R antagonist suppresses tumor growth, neovascularization, and invasiveness-related factors. Collectively, these results identify a new mechanism whereby ET-1/ET-3/ET(B)R axis can promote and interact with the HIF-1alpha-dependent machinery to amplify the COX-mediated invasive behavior of melanoma. New therapeutic strategies using specific ET(B)R antagonist could provide an improved approach to the treatment of melanoma by inhibiting tumor growth and progression.

Topics: Animals; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Endothelin-1; Endothelin-3; Enzyme Activation; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Matrix Metalloproteinases; Melanoma; Mice; Mice, Nude; Neoplasm Invasiveness; Promoter Regions, Genetic; Receptor, Endothelin B; RNA, Messenger; Skin Neoplasms; Transfection; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A

The cutaneous T-cell lymphomas (CTCL) are diseases characterised by cutaneous infiltrates of malignant, clonally expanded T-cells. Because individual genetic determination of angiogenetic and antioxidant properties of blood vessels could take part in responsibility to phototherapy in CTCL patients, the association of two frequent polymorphisms in endothelin-1 gene with phototherapy was tested.. 77 patients with CTCL, diagnosed and treated at the First Dermatological Clinic of St. Ann's Faculty Hospital Bmo (46 men and 31 women, median age 62, range 28-82 years) were included in the study. Diagnosis of CTCL according to the clinical picture was verified histologically. The genotype distributions and allelic frequencies between CTCL with phototherapy and those without phototherapy were compared. The 4A4A variant of -3A/-4A EDN1 is more frequent in patients treated with phototherapy (8/30 vs. 1/38, OR=10.13; P=0.01). The GA and AA genotypes of G8002A EDN1 polymorphism are more frequent in CTCL patients treated with phototherapy compared to those without it (15/23 vs. 7/32, OR=2.98; P=0.03).. Some polymorphic variants in EDN1 genes, a homozygote -4A-4A in -3A/-4A EDN1 and genotypes GA and GG in G8002A EDN1) seem to carry an advantage for phototherapy effectiveness in patients with CTCL.

Topics: Adult; Aged; Aged, 80 and over; Endothelin-1; Female; Humans; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Polymorphism, Genetic; PUVA Therapy; Skin Neoplasms; Ultraviolet Therapy

Basal cell carcinoma (BCC) is the most prevalent malignant skin tumor. In Asian patients, marked pigmentation in BCC lesions is often observed. Recently, endothelins (ETs) have been implicated to participate in the pigmentation process of BCC. Therefore, we set out to investigate the involvement of ET in the pigmentation process of BCC and the potential regulators in the pigmentation pathway. We explored the effects of an established BCC cell line on melanocytes. The growth factor profiles of BCC culture supernatant and effects of supernatant on melanocytes were documented. Potential regulators involved in the pigmentation pathway were also studied. The immunohistochemical staining of pigmented and non-pigmented BCC specimens was performed to confirm our in vitro findings. Our results showed that BCC supernatant contained significant amount of ET-1, basic fibroblast growth factor, and nerve growth factor. Furthermore, BCC supernatant stimulated melanin formation of cultured melanocytes. Addition of ET-receptor antagonist abrogated the melanogenic effect of BCC supernatant on melanocytes. Introduction of UVB irradiation decreased the ET-1 secretion by BCC cells. Immunohistochemical staining of the pigmented facial BCC specimens showed prominent expression of ET-1 on pigmented BCC, while the non-pigmented facial BCC specimens showed little ET-1 reactivity. Tumor necrosis factor-alpha (TNF-alpha) staining showed little expression on BCC specimens, regardless of pigmentation status. In summary, our results indicate that enhanced ET-1 expression in pigmented BCC plays an important role in the hyperpigmentation of this tumor. Moreover, this enhanced ET-1 cascade showed little correlation with UV irradiation and TNF-alpha expression in our study.

Topics: Carcinoma, Basal Cell; Cell Movement; Cell Survival; Cells, Cultured; Culture Media, Conditioned; Endothelin-1; Fibroblast Growth Factor 2; Humans; Immunohistochemistry; Keratinocytes; Melanocytes; Nerve Growth Factor; Pigmentation; Skin Neoplasms

The endothelin pathway plays a critical role in melanoma tumor progression by a variety of mechanisms that enhance tumor cell growth, invasion, and metastasis. Here, we investigate the effect of this pathway on CXC chemokine expression in human melanoma cells and melanocytes. As determined by ELISA, endothelin-1 (ET-1) induces CXCL1 and CXCL8 secretion in three human melanoma cell lines in a concentration-dependent fashion. These responses are mediated by the endothelin-B receptor and are sustained over a 40 h time course. ET-1 does not induce CXCL1 secretion in primary human melanocytes but ET-3, an endothelin isoform, induces a low level of CXCL1 secretion in certain cultures. Neither ET-1 nor ET-3 induces secretion of CXCL8 in primary human melanocytes; thus, this response may be specific for melanocytic cells that have undergone malignant transformation. We have previously demonstrated that ET-1 induces changes in the expression of adhesion molecules in melanoma cells such that invasion and metastasis are favored. This study demonstrates that ET-1 additionally induces secretion of CXC chemokines critical for melanoma metastasis and tumor progression.

Topics: Cell Line, Tumor; Chemokine CXCL1; Chemokines, CXC; Dose-Response Relationship, Drug; Endothelin-1; Endothelin-3; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-8; Melanocytes; Melanoma; Receptor, Endothelin B; Skin Neoplasms

Melanoma cell adhesion molecule (MCAM) is a cell-surface adhesion molecule expressed on over 70% of metastatic melanoma cells but not expressed in normal melanocytes invivo. Protein levels of MCAM correlate with aggressive invasive behavior of melanoma cells in vitro and invivo. Here we demonstrate that endothelin-1 (ET-1) upregulates MCAM protein in primary human melanocytes. MCAM upregulation by ET-1 occurs irrespective of degree of melanocyte pigmentation and is dose-responsive. The drug BQ788 is an endothelin-B (ET(B)) receptor antagonist and inhibits upregulation of MCAM by ET-1. In addition, endothelin-3 (ET-3) and N-succinyl-[Glu9, Ala11, 15]-ET-1-1620, both selective ET(B) agonists, are potent upregulators of MCAM. These demonstrate a critical role for the ET(B) receptor in the upregulation of MCAM by ET-1 and related isoforms. MCAM mRNA abundance is also increased by ET-1 stimulation, thus the mechanism of MCAM protein upregulation may occur at the level of transcription. Our previous studies have demonstrated that ET-1 downregulates E-cadherin in melanocytes and melanoma cells. Since E-cadherin is a melanoma invasion suppressor, and MCAM is a melanoma invasion promoter, ET-1 may promote melanoma invasion and metastasis through the regulation of adhesion molecule expression.

Topics: Antigens, CD; CD146 Antigen; Endothelin B Receptor Antagonists; Endothelin-1; Gene Expression; Humans; Kinetics; Melanocytes; Melanoma; Neural Cell Adhesion Molecules; Oligopeptides; Piperidines; RNA, Messenger; Skin Neoplasms; Tumor Cells, Cultured; Up-Regulation

Normal human melanocytes respond to endothelin-1 with induced proliferation and differentiation. Whereas in cultured melanoma cells the predominant endothelin receptor, ET(B)-R, is consistently downregulated, ET(B)-R upregulation was recently reported for melanoma tumors. Contrary to the pro-survival activity described for endothelin in vascular cells, a proapoptotic activity of endothelin-1 has been reported for melanoma cells, in previous studies. We therefore investigated the role of endothelin for melanoma cells with respect to apoptosis and proliferation. Treatment with 10 nM endothelin-1 was a strong mitogenic signal for normal human melanocytes, which responded with a 4-6-fold increase of thymidine incorporation, whereas the response was only 1.2-fold for SK-Mel-19, the melanoma cell line characterized by the highest ET(B)-R expression, and it was even less in other cell lines. Determination of the apoptotic rates revealed that endothelin-1 significantly reduced basic apoptotic rates to 75% both in SK-Mel-19 and in normal melanocytes. After cell synchronization, an antiapoptotic effect of endothelin-1 was seen in five of seven cell lines investigated. In the cell line Bro, which showed no response and which lacks ET(B)-R expression, responsibility could be restored by overexpression of ET(B)-R after stable transfection, indicating that the effectors of the endothelin-1 signal cascade were active in these cells, and that the antiapoptotic effect of endothelin-1 is mediated in a receptor-specific way. This antiapoptotic activity of endothelin for melanoma cells combined with upregulation of endothelin receptors in the tumor may be a crucial step for melanoma progression.

Topics: Apoptosis; Cell Division; Down-Regulation; Endothelin-1; Gene Expression Regulation, Neoplastic; Humans; Melanocytes; Melanoma; Receptor, Endothelin B; Receptors, Endothelin; Skin Neoplasms; Transfection; Tumor Cells, Cultured

Haemangiosarcomas of animals are reported mainly in the dog and cat and less commonly in the cow, horse, pig and goat, but no cases have been reported in sheep. These tumours occur more commonly in internal sites than in the subcutis. A large mass in the right flank of a 6-year-old Sardinian sheep showed histopathological features of a haemangiosarcoma. The antibodies anti-Factor VIII-related antigen (FVIII-RAg) and anti-CD31 did not react immunohistochemically with either the normal or the neoplastic endothelial cells, whereas endothelin-1 strongly labelled both the normal and the neoplastic cells at different stages of differentiation. The results emphasize the usefulness of endothelin-1 as a vascular marker in sheep, particularly in the immunohistochemical detection of neoplastic endothelial cells.

Topics: Animals; Biomarkers, Tumor; Endothelin-1; Fatal Outcome; Hemangiosarcoma; Immunohistochemistry; Neoplasm Recurrence, Local; Sheep; Sheep Diseases; Skin Neoplasms

The origin of diffuse melanosis resulting from metastatic melanoma is unknown. We examined the light microscopic and ultrastructural changes in the skin of an affected 35-year-old woman and determined the peripheral blood levels of melanocyte growth factors. A total of 7 biopsy specimens were examined by light and electron microscopy and immunohistology (S-100, HMB45, MART1, CD68, MAC387). Serum/plasma levels of melanocyte growth factors of the patient were determined by enzyme-linked immunosorbent assays and compared with those of normal volunteers (n = 10) and amelanotic patients with metastatic melanoma (n = 10), matched to the UICC stage of the affected patient. Hyperpigmented but otherwise apparently normal skin of the patient displayed epidermal melanocyte hyperplasia, increased melanogenesis, and dermal pigment stored in histiocytes and other cells along with extracellular deposits. Blood levels of alpha-melanocyte stimulating hormone, hepatocyte growth factor, and endothelin-1 were significantly elevated in the affected patient. Aberrant production of these factors may not only be responsible for activation of the pigment system in diffuse melanosis of metastatic melanoma, but also for increased proliferation, motility, and pigment incontinence of normal and malignant melanocytes.

Topics: Adult; alpha-MSH; Case-Control Studies; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Fatal Outcome; Female; Growth Substances; Hepatocyte Growth Factor; Humans; Immunohistochemistry; Melanoma; Melanosis; Skin Neoplasms

Topics: Arteriovenous Shunt, Surgical; Biomarkers, Tumor; Endothelin-1; Hemangiosarcoma; Humans; Kidney Transplantation; Male; Middle Aged; Renal Dialysis; Skin Neoplasms