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Papers - Oba, Junna

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Multi-modal cancer cell-intrinsic molecular programs correlate with immunotherapy efficacy

J Oba

CANCER SCIENCE 112, 150-150 2021

The expression of cd74-regulated inflammatory markers in stage iv melanoma: Risk of cns metastasis and patient survival

Ogata D., Roszik J., Oba J., Kim S.H., Bassett R.L., Haydu L.E., Tanese K., Grimm E.A., Ekmekcioglu S.

Cancers (Cancers) 12 ( 12 ) 1 - 13 2020.12

Research paper (scientific journal), Accepted

Innate inflammatory features have been found in melanoma tumors from patients at all stages, and molecular analysis has identified definitive inflammatory proteins expressed by tumors cells in patients who presents the worst prognosis. We have previously observed weakened outcomes in patients with constitutive expression of inducible nitric oxide synthase (iNOS), macrophage migration inhibitory factor (MIF) and improved outcomes with CD74 expression in stage III melanoma. In our current study, we tested our hypothesis on CD74-regulated inflammatory markers’ expression in stage IV melanoma tumors whether the signature is associated with survival outcome and/or risk of developing CNS metastasis. We retrospectively identified 315 patients with stage IV melanoma. In a tissue microarray (TMA), we examined the expression of cells with CD74, its receptor MIF, and downstream inflammatory markers iNOS, nitrotyrosine (NT), cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES1). We analyzed the association of those inflammatory markers with overall survival time (OS) and time to CNS metastasis using Kaplan–Meier survival analyses. Our data validates CD74 as a useful prognostic tumor cell protein marker associated with favorable OS as in stage III melanomas, while the tumor NT expression strongly predicts an increased risk of developing CNS metastasis (p = 0.0008) in those patients.

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Non-corticosteroid adherence and itch severity influence perception of itch in atopic dermatitis

Takeuchi S., Oba J., Esaki H., Furue M.

Journal of Dermatology (Journal of Dermatology) 45 ( 2 ) 158 - 164 2018.02

Research paper (scientific journal), Accepted, ISSN 03852407

Topical corticosteroid phobia is an important problem in the treatment of atopic dermatitis as it can affect the ability to control disease severity and itch by reducing treatment adherence. Topical corticosteroid phobia often ends up even non-corticosteroid adherence. As such, non-corticosteroid adherence, disease severity and itch are likely to be associated with each other, but their relationship has yet to be thoroughly investigated. Thus, the purpose of this study is to investigate it in atopic dermatitis. Using data from 1190 participants in an Internet survey, we identified 255 non-corticosteroid users and 225 with moderate to severe itch who were defined as non-corticosteroid adherents. Corticosteroid users with the same itch categories (n = 878) served as controls. We also examined how itch severity affects the perception of itch in atopic dermatitis. Unexpectedly, non-corticosteroid adherents were less sensitive to the conditions to elicit itch such as perspiring, commuting homeward, drinking alcohol and wearing woolen clothes compared with the control. We also found that patients with severer itch were more sensitive to itch during/after bathing, when lying in bed, commuting homeward, studying/working, drinking alcohol, undressing, getting up in the morning, after a meal, ingesting piquant foods and when they were unoccupied, angry, busy, nervous, sad or enjoying themselves. In conclusion, we found that non-corticosteroid adherence and itch severity influence perception of itch in atopic dermatitis and discuss possible mechanisms underlying these results. The information obtained in this study may be useful for communication with and education of atopic dermatitis patients and their treatment in outpatient clinics.

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Trends in hepatocyte growth factor, insulin-like growth factor 1, thyroid-stimulating hormone, and leptin expression levels in uveal melanoma patient serum and tumor tissues: correlation to disease progression

Oba, J., Esmaeli, B., Ellerhorst, J. A., Lyons, G. R., Milton, D. R., Wang, W. L., Macedo, M. P., Lazar, A. J., Grimm, E. A. and Chattopadhyay, C.

Melanoma Res 27 ( 2 ) 126 - 133 2017.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 1473-5636

This exploratory study was carried out to determine the expression levels of hepatocyte growth factor (HGF), insulin-like growth factor 1, thyroid-stimulating hormone (TSH), and leptin in serum and tumor samples from patients with uveal melanoma and to investigate the potential association of these expression levels with disease progression and patient survival. Seventeen patients, including nine nonmetastatic and eight metastatic, were included in the study. Eighteen healthy individuals served as controls. The levels of these four proteins in serum and tissue samples were determined by enzyme-linked immunosorbent assays and immunohistochemical staining, respectively. Associations between protein levels and survival, disease progression, and other clinicopathological factors were analyzed statistically. Serum levels of HGF were significantly higher and TSH levels were lower in uveal melanoma patients than in healthy individuals, but the level of neither protein differed significantly between metastatic and nonmetastatic groups. Of the four proteins tested, only serum TSH was significantly associated with patient survival. No correlation was observed between the tissue and serum levels of each protein. The levels of HGF in serum may be markers of uveal melanoma development. The prognostic and predictive values of these potential markers need to be determined in a larger cohort.

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Novel algorithmic approach predicts tumor mutation load and correlates with immunotherapy clinical outcomes using a defined gene mutation set

Roszik, J., Haydu, L. E., Hess, K. R., Oba, J., Joon, A. Y., Siroy, A. E., Karpinets, T. V., Stingo, F. C., Baladandayuthapani, V., Tetzlaff, M. T., Wargo, J. A., Chen, K., Forget, M. A., Haymaker, C. L., Chen, J. Q., Meric-Bernstam, F., Eterovic, A. K., Shaw, K. R., Mills, G. B., Gershenwald, J. E., Radvanyi, L. G., Hwu, P., Futreal, P. A., Gibbons, D. L., Lazar, A. J., Bernatchez, C., Davies, M. A. and Woodman, S. E.

BMC Med 14 ( 1 ) 168 2016.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 1741-7015

BACKGROUND: While clinical outcomes following immunotherapy have shown an association with tumor mutation load using whole exome sequencing (WES), its clinical applicability is currently limited by cost and bioinformatics requirements. METHODS: We developed a method to accurately derive the predicted total mutation load (PTML) within individual tumors from a small set of genes that can be used in clinical next generation sequencing (NGS) panels. PTML was derived from the actual total mutation load (ATML) of 575 distinct melanoma and lung cancer samples and validated using independent melanoma (n = 312) and lung cancer (n = 217) cohorts. The correlation of PTML status with clinical outcome, following distinct immunotherapies, was assessed using the Kaplan-Meier method. RESULTS: PTML (derived from 170 genes) was highly correlated with ATML in cutaneous melanoma and lung adenocarcinoma validation cohorts (R(2) = 0.73 and R(2) = 0.82, respectively). PTML was strongly associated with clinical outcome to ipilimumab (anti-CTLA-4, three cohorts) and adoptive T-cell therapy (1 cohort) clinical outcome in melanoma. Clinical benefit from pembrolizumab (anti-PD-1) in lung cancer was also shown to significantly correlate with PTML status (log rank P value < 0.05 in all cohorts). CONCLUSIONS: The approach of using small NGS gene panels, already applied to guide employment of targeted therapies, may have utility in the personalized use of immunotherapy in cancer.

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Uveal melanoma: From diagnosis to treatment and the science in between

Chattopadhyay, C., Kim, D. W., Gombos, D. S., Oba, J., Qin, Y., Williams, M. D., Esmaeli, B., Grimm, E. A., Wargo, J. A., Woodman, S. E. and Patel, S. P.

Cancer 122 ( 15 ) 2299 - 312 2016.08

Research paper (scientific journal), Accepted, ISSN 1097-0142

Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age-adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016;122:2299-2312. (c) 2016 American Cancer Society.

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Elevated Serum Leptin Levels are Associated With an Increased Risk of Sentinel Lymph Node Metastasis in Cutaneous Melanoma

Oba, J., Wei, W., Gershenwald, J. E., Johnson, M. M., Wyatt, C. M., Ellerhorst, J. A. and Grimm, E. A.

Medicine (Baltimore) 95 ( 11 ) e3073 2016.03

Research paper (scientific journal), Accepted, ISSN 1536-5964

The metabolic hormone leptin has been implicated in the pathogenesis of various malignancies and may contribute to the high rate of cancer in obese individuals. We reported that leptin and its receptor are expressed by melanoma tumors and cell lines, and that leptin stimulates proliferation of cultured melanoma cells. Here, we tested the hypothesis that leptin contributes to early melanoma progression by assessing its association with sentinel node positivity in cutaneous melanoma patients. The study enrolled 72 patients who were scheduled to undergo lymphatic mapping and sentinel node biopsy. Fasting blood was obtained before surgery, and serum leptin levels were measured by enzyme-linked immunosorbent assay (ELISA) with a "raw" (assay value) and an "adjusted" value (raw value divided by body mass index). Leptin levels and other clinicopathologic parameters were compared between sentinel node positive and negative groups. Logistic regression models were used to predict sentinel node status using leptin and other relevant clinical parameters. The raw and adjusted leptin levels were significantly higher in the 15 patients with positive sentinel nodes. These findings could not be attributed to differences in body mass indices. Univariate models revealed raw leptin, adjusted leptin, Breslow thickness, and mitotic rate as significant predictors of sentinel node status. Leptin levels and Breslow thickness remained significant in multivariate models. Survival and follow-up analysis revealed more aggressive disease in diabetic patients. Elevated serum leptin levels predict sentinel node metastasis in melanoma. Validation of this finding in larger cohorts should enable better stratification of early stage melanoma patients.

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Early Tumor-Infiltrating Dendritic Cells Change their Characteristics Drastically in Association with Murine Melanoma Progression

Nakahara, T., Oba, J., Shimomura, C., Kido-Nakahara, M. and Furue, M.

J Invest Dermatol 136 ( 1 ) 146 - 53 2016.01

Research paper (scientific journal), Accepted, ISSN 1523-1747

Dendritic cells (DCs) have a critical effect on the outcome of adaptive immune responses against growing tumors. Tumor-infiltrating dendritic cells (TIDCs) play diverse roles in the regulation of tumor regression or growth, but the characteristics that distinguish those effects are obscure. In this study, we investigated the frequency, phenotype, and function of TIDCs over time from early stages of melanoma growth in mice. Flow cytometric analysis revealed that the tumors were infiltrated by a significant population of CD11c(+) major histocompatibility complex II(+) DCs, especially at an early stage of tumor growth. The allogeneic stimulatory capacity of TIDCs increased with tumor growth, whereas this capacity of DCs in lymph nodes decreased. TIDCs harvested at an early stage of melanoma (early TIDCs) accelerated tumor growth, but those harvested at a late stage (late TIDCs) delayed tumor progression when they were coinjected with melanoma cells. Furthermore, coinjection of early TIDCs failed to induce full immunocompetent maturation of CD8(+) T cells, with much lower expression of IFN-gamma, granzyme B, and perforin within the tumor microenvironment. In conclusion, TIDCs change their characteristics from an immunoinhibitory to an immunostimulatory phenotype over time in association with tumor progression.

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CD10-Equipped Melanoma Cells Acquire Highly Potent Tumorigenic Activity: A Plausible Explanation of Their Significance for a Poor Prognosis

Oba, J., Nakahara, T., Hashimoto-Hachiya, A., Liu, M., Abe, T., Hagihara, A., Yokomizo, T. and Furue, M.

PLoS One 11 ( 2 ) e0149285 2016

Research paper (scientific journal), Accepted, ISSN 1932-6203

CD10 has been widely used in cancer diagnosis. We previously demonstrated that its expression in melanoma increased with tumor progression and predicted poor patient survival. However, the mechanism by which CD10 promotes melanoma progression remains unclear. In order to elucidate the role of CD10 in melanoma, we established CD10-overexpressing A375 melanoma cells and performed DNA microarray and qRT-PCR analyses to identify changes in the gene expression profile. The microarray analysis revealed that up-regulated genes in CD10-A375 were mostly involved in cell proliferation, angiogenesis, and resistance to apoptosis; down-regulated genes mostly belonged to the categories associated with cell adhesion and migration. Accordingly, in functional experiments, CD10-A375 showed significantly greater cell proliferation in vitro and higher tumorigenicity in vivo; CD10 enzymatic inhibitors, thiorphan and phosphoramidon, significantly blocked the tumor growth of CD10-A375 in mice. In migration and invasion assays, CD10-A375 displayed lower migratory and invasive capacity than mock-A375. CD10 augmented melanoma cell resistance to apoptosis mediated by etoposide and gemcitabine. These findings indicate that CD10 may promote tumor progression by regulating the expression profiles of genes related to cell proliferation, angiogenesis, and resistance to apoptosis.

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Pruritus of patients with atopic dermatitis in daily life and their experience of therapeutic effects: results of a web-based questionnaire survey

Takeuchi, S., Oba, J., Esaki, H. and Furue, M.

Br J Dermatol 173 ( 1 ) 250 - 2 2015.07

Research paper (scientific journal), Accepted, ISSN 1365-2133

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Inflammatory IL-1beta-driven JNK activation in stage III melanoma

Qin, Y., Milton, D. R., Oba, J., Ding, Z., Lizee, G., Ekmekcioglu, S. and Grimm, E. A.

Pigment Cell Melanoma Res 28 ( 2 ) 236 - 9 2015.03

Research paper (scientific journal), Accepted, ISSN 1755-148X (Electronic)

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Expression of programmed death receptor ligand 1 in melanoma may indicate tumor progression and poor patient survival

Oba, J., Nakahara, T., Abe, T., Hagihara, A., Moroi, Y. and Furue, M.

J Am Acad Dermatol 70 ( 5 ) 954 - 6 2014.05

Research paper (scientific journal), Accepted, ISSN 1097-6787

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The prognostic value of a reverse transcriptase-PCR assay of sentinel lymph node biopsy for patients with cutaneous melanoma: a single-center analysis in Japan

Ito, T., Moroi, Y., Oba, J., Nakahara, T., Takeuchi, S., Uchi, H., Takahara, M., Masuda, T. and Furue, M.

Melanoma Res 22 ( 1 ) 38 - 44 2012.02

Research paper (scientific journal), Accepted, ISSN 1473-5636

Sentinel lymph node biopsy (SLNB) is the standard of care for staging melanoma. However, limited research has been carried out on the prognostic value of SLNB in patients with primary cutaneous melanoma in Asian countries. The objective is to evaluate the efficacy of SLNB in Japanese patients with primary cutaneous melanoma and to elucidate whether reverse transcriptase (RT)-PCR analysis of sentinel lymph nodes (SLNs) is valuable for predicting patient outcome. A total of 101 patients with primary cutaneous melanoma underwent SLNB at the Department of Dermatology, Kyushu University (Fukuoka, Japan), between May 2001 and December 2009. The removed nodes were stained with hematoxylin-eosin and with immunohistochemical stains for HMB-45, tyrosinase, MART-1, and MITF and multiple-mRNA marker (MART-1, tyrosinase, and GP-100) RT-PCR assays were conducted. The following clinicopathological variables were evaluated: age, sex, histological type, tumor site, Breslow thickness, disease-free survival (DFS), and melanoma-specific survival (MSS). Several parameters were analyzed for DFS and MSS using the Kaplan-Meier method and Cox proportional hazards model. The success rate of identifying SLNs was 98% (99 of 101 cases). Tumor-positive SLNs were significantly correlated with higher Breslow thickness, stage, tumor subtype, and tumor site. Patients with tumor-positive SLNs had a significantly shorter MSS and DFS than those with tumor-negative SLNs (P=0.0153 and 0.0004, respectively). Patients with at least two positive markers in the RT-PCR assay had a significantly shorter DFS than those with less than one marker (P=0.013). SLNB and multimarker RT-PCR analysis are useful for predicting the prognosis of patients with melanoma.

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Expression of CD10 predicts tumor progression and unfavorable prognosis in malignant melanoma

Oba, J., Nakahara, T., Hayashida, S., Kido, M., Xie, L., Takahara, M., Uchi, H., Miyazaki, S., Abe, T., Hagihara, A., Moroi, Y. and Furue, M.

J Am Acad Dermatol 65 ( 6 ) 1152 - 60 2011.12

Research paper (scientific journal), Accepted, ISSN 1097-6787

BACKGROUND: CD10 expression in malignant melanoma (MM) has been reported to increase according to tumor progression and metastasis; however, its association with patient outcome has not been clarified. OBJECTIVE: We examined the immunohistochemical expression of CD10 in MM to determine whether or not it could serve as a marker for tumor progression and prognosis. METHODS: A total of 64 formalin-fixed, paraffin-embedded samples of primary MM were immunostained for CD10. Similarly, 40 samples of melanocytic nevus and 20 of metastatic MM were analyzed for comparison. The following clinicopathologic variables were evaluated: age, gender, histologic type, tumor site, Breslow thickness, Clark level, the presence or absence of ulceration and tumor-infiltrating lymphocytes, and survival. Statistical analyses were performed to assess for associations. Several parameters were analyzed for survival using the Kaplan-Meier method and Cox proportional hazards model. RESULTS: Immunohistochemical analysis revealed that 34 of 64 cases (53%) of primary MM expressed CD10, compared with 15 of 20 cases (75%) of metastatic MM and only 4 of 40 cases (10%) of nevus. There was a significant positive relationship between CD10 expression and Breslow thickness, Clark level, and ulceration. Univariate analysis revealed 4 significant factors for shorter survival periods: CD10 expression, high Breslow thickness, high Clark level, and the presence of ulceration (P < .01 each). In multivariate analysis, CD10 expression was revealed to be a statistically significant and independent prognostic factor. LIMITATIONS: The major limitation was the small sample size. CONCLUSION: CD10 expression may serve as a progression marker and can predict unfavorable prognosis in patients with MM.

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Clinicopathologic and prognostic significance of SATB1 in cutaneous malignant melanoma

Chen, H., Takahara, M., Oba, J., Xie, L., Chiba, T., Takeuchi, S., Tu, Y., Nakahara, T., Uchi, H., Moroi, Y. and Furue, M.

J Dermatol Sci 64 ( 1 ) 39 - 44 2011.10

Research paper (scientific journal), Accepted, ISSN 1873-569X (Electronic)

BACKGROUND: Special AT-rich sequence-binding protein-1 (SATB1), a new type of gene regulator, has been reported to be expressed in several human cancers and may have malignant potential. However, no data on SATB1 expression and its relationship to tumor progression in cutaneous malignant melanoma (CMM) has yet been reported. OBJECTIVE: We examined the immunohistochemical expression of SATB1 in CMM to determine whether it could serve as a prognostic marker. METHODS: A total of 97 samples of primary CMM and controls were immunostained for SATB1. The following clinicopathologic variables were evaluated: age, gender, subtype, SATB1 expression, Breslow thickness, Clark level, presence of ulceration, lymph node metastasis, distant metastasis, and survival. Statistical analyses were performed to assess for associations. Several parameters were analyzed for survival using the Kaplan-Meier method and Cox proportional-hazards model. RESULTS: Forty cases (85.1%) of CMM showed positive staining for SATB1 by immunohistochemistry. The intensity of SATB1 staining was significantly higher in CMM than in nevus NV and normal skin (NS) (P < 0.01). High SATB1 expression was significantly correlated with Breslow thickness, Clark level, mortality, presence of ulceration, and lymph node metastasis (P < 0.01). Moreover, Kaplan-Meier analysis revealed that SATB1 overexpression was significantly associated with worse survival (P < 0.01). Further univariate analysis and multivariate regression analysis indicated that SATB1 expression was an independent prognostic marker for CMM (P = 0.03). CONCLUSIONS: The overexpression of SATB1 correlated with metastatic potential of CMM and is a novel independent prognostic marker for predicting outcome.

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Expression of milk fat globule epidermal growth factor-VIII may be an indicator of poor prognosis in malignant melanoma

Oba, J., Moroi, Y., Nakahara, T., Abe, T., Hagihara, A. and Furue, M.

Br J Dermatol 165 ( 3 ) 506 - 12 2011.09

Research paper (scientific journal), Accepted, ISSN 1365-2133

BACKGROUND: Milk fat globule epidermal growth factor-VIII (MFG-E8) is a secreted protein that binds phosphatidylserine and promotes apoptotic cell ingestion by phagocytes, mediating the immune tolerance and maintenance of homeostasis. A recent study has shown that MFG-E8 expression in human melanoma is increased with tumour progression; however, the effect of its expression on patient survival has not yet been clarified. OBJECTIVE: To analyse MFG-E8 expression in melanoma, and to determine whether it can serve as a marker for diagnosis, tumour progression and/or prognosis. METHODS: MFG-E8 expression was examined by immunohistochemistry in 60 primary melanomas, 22 metastatic lesions and 30 benign naevi. The following clinicopathological variables were evaluated: age, gender, histological type, tumour site, Breslow thickness, Clark's level, the presence or absence of ulceration and tumour-infiltrating lymphocytes, and survival periods. Statistical analyses were performed to assess associations and melanoma-specific survival. RESULTS: MFG-E8 expression was significantly higher in primary and metastatic melanoma than in naevus. Furthermore, it increased according to tumour progression and metastasis. Patients with MFG-E8 expression in primary tumours had significantly shorter survival periods than those without MFG-E8 expression. Univariate and multivariate analyses revealed that MFG-E8 expression was a statistically significant and independent prognostic factor. CONCLUSION: MFG-E8 expression may serve as a tumour progression marker and can predict an unfavourable prognosis in patients with melanoma.

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CD10 expressed by fibroblasts and melanoma cells degrades endothelin-1 secreted by human keratinocytes

Xie, L., Moroi, Y., Takahara, M., Tsuji, G., Oba, J., Hayashida, S., Takeuchi, S., Shan, B., Uchi, H. and Furue, M.

Eur J Dermatol 21 ( 4 ) 505 - 9 2011.07

Research paper (scientific journal), Accepted, ISSN 1167-1122

Endothelin-1 (ET-1) is a potent multifunctional peptide linked to wound healing, pigmentation, carcinogenesis, and fibrosclerotic processes in the skin. Whereas ET-1 was thought to be digested by receptor-mediated endocytosis, it is also reported to be biochemically degraded by the neutral endopeptidase CD10 using kidney homogenates. Although keratinocytes (KC) and fibroblasts (Fb) are sources of both ET-1 and CD10, respectively, there is no report investigating the direct association between CD10 expression and its function in relation to ET-1 degradation in the skin. CD10 expression in melanoma cells is associated with clinical prognosis, suggesting an important role in the invasive and metastatic potential of melanoma cells. Here, cultured KC produced much higher amounts of ET-1 than did cultured Fb or melanoma cells. In contrast, KC and A375 melanoma cells did not express CD10, while Fb, SK-MEL-28 and G361 melanoma cells constitutively expressed CD10. KC-derived ET-1 was down-modulated by both CD10-positive Fb and CD10-positive melanoma cells, and the inhibition was partially reversed under substitution conditions using CD10-knockdown Fb or CD10-knockdown melanoma cells. This indicates that CD10 on cultured Fb and melanoma cells is biochemically active in the degradation or down-modulation of ET-1 secreted from KC. These findings may lead to better understanding of skin homeostasis and of the malignant potential of melanoma.

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Expression of c-Kit, p-ERK and cyclin D1 in malignant melanoma: an immunohistochemical study and analysis of prognostic value

Oba, J., Nakahara, T., Abe, T., Hagihara, A., Moroi, Y. and Furue, M.

J Dermatol Sci 62 ( 2 ) 116 - 23 2011.05

Research paper (scientific journal), Accepted, ISSN 1873-569X (Electronic)

BACKGROUND: The mitogen-activated protein kinase (MAPK) signaling pathway is one of the major cascades that are crucial for the initiation and progression of melanoma; however, the influence of these signaling molecules on patient survival has not been clarified. OBJECTIVE: The purpose of this study was to analyze the protein expression of MAPK signaling molecules in melanoma, and to correlate the expression status with clinicopathologic parameters. METHODS: Expression of c-Kit, phosphorylated ERK (p-ERK), and cyclin D1 was examined by immunohistochemistry in 78 primary melanomas, 24 metastatic lesions, and in 42 benign nevi. The following clinicopathologic variables were evaluated: age, gender, histologic type, tumor site, Breslow thickness, Clark's level, ulceration, and survival period. Statistical analyses were performed for assessment of associations and melanoma-specific survival. RESULTS: The expression of c-Kit, p-ERK, and cyclin D1 was significantly higher in primary melanomas than in nevi. c-Kit immunoreactivity was highest in thin (Tis-pT2) melanomas, and showed a significant reduction with tumor progression and metastasis. The expression of p-ERK was high in all stages of melanoma. Cyclin D1 positivity increased significantly according to tumor progression, but decreased in metastases. A significant correlation between p-ERK and cyclin D1 expression was observed. Survival analysis failed to detect any trends towards shorter or longer survival among patients expressing either c-Kit, p-ERK or cyclin D1. CONCLUSIONS: The expression of c-Kit, p-ERK, and cyclin D1 might help to differentiate thin melanoma from melanocytic nevus, but it appears to lack prognostic potential.

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CD10-bearing fibroblasts may inhibit skin inflammation by down-modulating substance P

Xie, L., Takahara, M., Nakahara, T., Oba, J., Uchi, H., Takeuchi, S., Moroi, Y. and Furue, M.

Arch Dermatol Res 303 ( 1 ) 49 - 55 2011.01

Research paper (scientific journal), Accepted, ISSN 1432-069X (Electronic)

Substance P (SP) is a multipotent neuropeptide that affects the proliferation, activation and motility of keratinocytes and fibroblasts (Fbs). SP in pulmonary and synovial cells is degraded by CD10, a 90- to 110-kDa cell surface zinc-dependent metalloprotease. However, the expression and function of CD10 in human dermal Fbs have not yet been investigated in vivo and in vitro specifically with reference to SP. Our immunohistologic study revealed moderate to strong fibroblastic CD10 expression in the majority of psoriasis vulgaris (16/16), chronic eczema (15/16), lichen planus (18/20) and atopic dermatitis (4/5). Keratinocytes showed no CD10 expression in vivo and in vitro. Cultured Fbs constitutively expressed CD10 and SP. CD10 expression was augmented by external interleukin (IL)-1beta and IL-22, but not by IL-8 and IL-17A in Fbs. SP production was enhanced in CD10 knockdown-Fbs (CD10ND-Fbs) compared with control-Fbs. In the presence of IL-1beta or IL-22, the enhancement of SP production was more prominent in CD10ND-Fbs than in control-Fbs, suggesting the down-modulating activity of CD10 on SP in cytokine-mediated inflammation. In conclusion, fibroblastic CD10 expression may down-regulate skin inflammation by degrading SP or reducing its level in the dermal microenvironment.

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Aberrant expression of CD10 in ground-glass-like multinucleated giant cells of multicentric reticulohistiocytosis

Tashiro, A., Takeuchi, S., Nakahara, T., Oba, J., Tsujita, J., Fukushi, J., Kiryu, H., Oda, Y., Xie, L., Yan, X., Takahara, M., Moroi, Y. and Furue, M.

J Dermatol 37 ( 11 ) 995 - 7 2010.11

Research paper (scientific journal), Accepted, ISSN 1346-8138

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