Tokimasa Hida

Agouti protein, mahogunin, and attractin in pheomelanogenesis and melanoblast-like alteration of melanocytes: a cAMP-independent pathway

Melanocortin‐1 receptor (MC1R) and its ligands, α‐melanocyte stimulating hormone (αMSH) and agouti signaling protein (ASIP), regulate switching between eumelanin and pheomelanin synthesis in melanocytes. Here we investigated biological effects and signaling pathways of ASIP. Melan‐a non agouti (a/a) mouse melanocytes produce mainly eumelanin, but ASIP combined with phenylthiourea and extra cysteine could induce over 200‐fold increases in the pheomelanin to eumelanin ratio, and a tan‐yellow color in pelletted cells. Moreover, ASIP‐treated cells showed reduced proliferation and a melanoblast‐like appearance, seen also in melanocyte lines from yellow (Ay/a and Mc1re/ Mc1re) mice. However ASIP‐YY, a C‐terminal fragment of ASIP, induced neither biological nor pigmentary changes. As, like ASIP, ASIP‐YY inhibited the cAMP rise induced by αMSH analog NDP‐MSH, and reduced cAMP level without added MSH, the morphological changes and depigmentation seemed independent of cAMP signaling. Melanocytes genetically null for ASIP mediators attractin or mahogunin (Atrnmg‐3J/mg‐3J or Mgrn1md‐nc/md‐nc) also responded to both ASIP and ASIP‐YY in cAMP level, while only ASIP altered their proliferation and (in part) shape. Thus, ASIP–MC1R signaling includes a cAMP‐independent pathway through attractin and mahogunin, while the known cAMP‐dependent component requires neither attractin nor mahogunin.

Combined administration of basic fibroblast growth factor protein and the hepatocyte growth factor gene enhances the regeneration of dermis in acute incisional wounds

Hepatocyte growth factor (HGF) is a ligand for the c‐Met receptor tyrosine kinase. This study was aimed to characterize the role of the HGF gene combined with basic fibroblast growth factor (bFGF) protein in wound healing by administering both of them locally to acute incisional skin wounds created on the backs of rats. The bFGF protein and the HGF gene were administered intradermally after incisional surgery. Apoptotic cells in wound lesions were identified by the terminal deoxynucleotide transferase‐mediated nick‐end labeling method, as well as by immunological detection of active caspase‐3. While there was almost complete suppression of apoptosis with well‐organized wound healing in animals treated with the HGF gene, the combination of bFGF protein and the HGF gene paradoxically resulted in less scarring along with the promotion of apoptosis. Histopathological examination revealed that scar formation was least apparent in rats treated with both bFGF and the HGF gene compared with controls or those treated with the bFGF or the HGF gene alone. It is thought that the combined administration of bFGF and the HGF gene immediately after skin incision may make the healing process occur closer to tissue regeneration through the induction of apoptosis, which occurred 1 week after surgery. HGF supplementation through gene therapy combined with bFGF protein may be an effective strategy for treating wounds, as it increases the apparent regeneration of the dermis to allow for “scarless wound healing.”

Macrophage Inhibitory Cytokine-1: A New Player in Melanoma Development

Macrophage inhibitory cytokine-1 (MIC-1) is a divergent member of the TGF-beta superfamily. Although it has been reported to exhibit both tumorigenic and antitumorigenic activities, Boyle et al. report in this issue that MIC-1 expression was correlated with the tumorigenicity of melanoma cells. The elucidation of signaling pathways around MIC-1 might contribute to prospective targeting therapy for melanoma.

Circulating melanoma cells as a potential biomarker to detect metastasis and evaluate prognosis

TNM staging is mainly used to evaluate the prognosis of melanoma patients. Serum biomarkers such as 5‐S‐cysteinyldopa (5‐S‐CD) have occasionally been used but most do not respond until the tumour burden becomes high. Recently, circulating melanoma cells (CMC) have been reported as a possible new biomarker to detect metastasis, monitor treatment response and predict prognosis. The object of this exploratory study was to evaluate the efficacy of CMC to detect metastasis and predict prognosis by cross‐sectional and prospective observational analyses, respectively. Altogether 15 patients with stages II–IV melanoma were enrolled and CMC were enumerated by CellSearch system with cut‐off values of two cells/7.5 mL. Serum 5‐S‐CD and lactate dehydrogenase (LDH) were also measured. The sensitivity of CMC and 5‐S‐CD for the detection of metastasis was 33 and 50%, respectively. The combination of CMC and 5‐S‐CD showed a sensitivity of 67%, the best performance among CMC, 5‐S‐CD, LDH and any combination of two of the markers. Additionally, a 30‐month prospective observation showed that CMC could segregate patients with poorer prognosis. The median survival time for the patients with <2 CMC and those with ≥2 CMC was 19.5 and 4.5 months, respectively. The limitation of this study is the small sample size. These preliminary results indicate CMC may complement the efficacy of 5‐S‐CD to detect metastasis and can be a prognostic marker. Although there is still room for improvement to maximise the sensitivity, the CellSearch system is reproducible, standardised and suitable for multi‐centre studies.

Fulminant bowel-associated dermatosis-arthritis syndrome that clinically showed necrotizing fasciitis-like severe skin and systemic manifestations

JEADV 2006, 20, 735–767

Carney Complex: Report of a Japanese Case Associated with Cutaneous Superficial Angiomyxomas, Labial Lentigines, and a Pituitary Adenoma

We report the case of a 12‐year‐old female patient who manifested multiple cutaneous angiomyxomas and labial pigmented lesions. Although the familial history was not confirmed in the present case, autosomal dominant inheritance has been reported to be involved in the pathogenesis of this condition. In addition to the cutaneous complications, magnetic resonance (MR) images revealed the presence of a pituitary adenoma, which provoked an elevation of serum growth hormone (GH) level. On the other hand, no significant symptoms such as cardiac myxoma, myxoid fibroadenoma of the breast, or adrenocortical complaints suggesting Cushing syndrome, were detected. In the Japanese literature, only a few cases of this disorder have been described in the form of brief reports. There have been only a few similar cases described in the dermatological field, except for one report diagnosed as Carney complex in 1990. Therefore, the present case seems to be the first Japanese case of typical Carney complex manifesting major clinical complications, including angiomyxomas, lentigines, and a pituitary adenoma, which induced endocrine overactivity.

Development of sarcoidosis during β-interferon therapy for melanoma.

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Rab7 is a critical mediator in vesicular transport of tyrosinase-related protein 1 in melanocytes

How melanosomal proteins such as enzymic proteins (tyrosinase and tyrosinase‐related proteins, Tyrps) and structural protein (gp100) are transported from Golgi to melanosomal compartments is not yet fully understood. A number of small GTPases have been found to be associated with melanosomes and we have identified one of them, Rab7, a regulator of vesicular transport, organelle motility, phospholipid signaling and cytosolic degradative machinery, as being involved in the transport of Tyrp1 from Golgi to stage I melanosomes. This study further characterizes the role of Rab7 as a regulator of differential sorting of melanosomal proteins in this process. Murine melanocytes were transiently transfected with a plasmid encoding either wild‐type (Rab7WT), constitutively active (Rab7Q67L) or dominant‐negative (Rab7N125I and Rab7T22N) Rab7. Through immunocytostaining and confocal laser scanning microscopy, we quantitatively compared the bio‐distribution of melanosomal proteins between Rab7WT‐expressing cells and mutant Rab7‐expressing cells. We also characterized their differential elimination from melanosomal compartments by Rab7 by utilizing a proteasome inhibitor, MG132. Our findings indicate that Rab7 plays an important role in differential sorting of tyrosinase, Tyrp1 and gp100 in early melanogenesis cascade, and that it is more specifically involved with Tyrp1 than tyrosinase and gp100 in the trafficking from Golgi to melanosomes and the specific exit from the degradative process.

Clinical and epidemiological analysis in 149 cases of rhododendrol-induced leukoderma

Rhododendrol‐induced leukoderma is an acquired depigmentation that develops mainly at the contact site after repeated use of skin‐whitening cosmetics containing rhododendrol. In most cases, cessation of further depigmentation or occurrence of repigmentation is observed after discontinuing the use of cosmetics. However, some patients develop vitiligo vulgaris through the spread of depigmentation into the non‐exposed areas. Our study aims to investigate the patient‐specific factors that may affect the extent of depigmentation or repigmentation, as well as development of vitiligo vulgaris. The degree of depigmentation of the face, neck and hands where exposed to rhododendrol was scored using photographs over time. The relationships between depigmentation score at first visit/improvement rate of depigmentation score and patient demographics were evaluated and three important clinical observations were made. First, repigmentation of the face was superior compared with that of the hands and neck, suggesting a possible role for the migration and differentiation of melanocyte stem cells from hair follicles, as a mechanism of repigmentation. Second, the intensity of rhododendrol exposure did not contribute to differences in the severity of depigmentation. This suggested a possibility of underlying genetic susceptibility to melanocyte cytotoxicity or immune reaction. Third, depigmentation score at first visit and past history of atopic dermatitis were significantly high in patients who developed vitiligo vulgaris. This suggested that severe chemical damage of melanocytes by rhododendrol leads to a higher risk of developing vitiligo vulgaris through the possible involvement of an immune reaction. These clinical observations may help to further understand the pathogenesis of rhododendrol‐induced leukoderma.

Serum cytokeratin 19 fragment 21‐1 is a useful tumor marker for the assessment of extramammary Paget's disease

Cytokeratin 19 fragment 21‐1 (CYFRA 21‐1) has been used as a tumor marker for several malignancies. However, to date, no studies have assessed whether CYFRA 21‐1 could be a useful marker for extramammary Pagets disease (EMPD). The present study aimed to evaluate the significance of CYFRA 21‐1 as a serum tumor marker for EMPD progression. Concentrations of serum CYFRA 21‐1 and carcinoembryonic antigen (CEA) in 13 cases of EMPD were measured prior to undergoing treatment at Sapporo Medical University Hospital from January 2014 to May 2016. Four of the 13 patients had lymph node metastases at diagnosis, but none had distant metastases. Immunohistochemistry indicated that all 13 primary tumors and four metastatic tumors in lymph nodes were positive for cytokeratin 19. Although none of the 13 patients showed high serum CEA levels, six patients (46.2%) had elevated serum CYFRA 21‐1. Furthermore, CYFRA 21‐1 was reduced in association with post‐treatment tumor reduction in all six patients. Among these six patients, four developed recurrence and metastasis during the follow‐up period. CYFRA 21‐1 was re‐elevated in all four of these patients; however, serum CEA was elevated only in the patient with distant metastasis. These results suggest that CYFRA 21‐1 is more sensitive compared with CEA, and can be useful as a tumor marker for evaluating tumor progression and treatment efficacy in patients with EMPD.