Tyrosinase immunoreactivity in formalin‐fixed, paraffin‐embedded primary and metastatic melanoma: frequency and distribution

Hofbauer, Günther F.L.; Kamarashev, Jivko; Geertsen, Ralf; Böni, R.; Dummer, Reinhard

doi:10.1111/j.1600-0560.1998.tb01720.x

Cited by 137 publications

(115 citation statements)

References 21 publications

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“…21 Levels of tyrosinase correlate inversely with melanoma clinical stage. 22 These data suggest that the normal melanogenesis program is inhibited in melanoma cells. 23 We examined the roles of BRAF and INK4A lesions in melanoma cells.…”

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confidence: 75%

Effects on proliferation and melanogenesis by inhibition of mutant BRAF and expression of wild‐type INK4A in melanoma cells

Rotolo

Diotti

Gordon

et al. 2005

Intl Journal of Cancer

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Activating BRAF mutations and loss of wild-type INK4A expression both occur at high frequencies in melanomas. Here, we present evidence that BRAF and INK4A have different effects on melanogenesis, a marker of melanocytic differentiation. Human melanoma cell line 624Mel harbors mutations in both BRAF and INK4A. The in vitro and in vivo growth of these cells was inhibited by either reduced expression of mutant BRAF using stable retroviral RNA interference (RNAi) or retrovirus-mediated stable expression of wild-type INK4A cDNA. Consistent with the observed growth inhibition, phosphorylation of S780 and S795 in pRB, both CDK4/6 targets, was suppressed in cells expressing either mutant BRAF RNAi or wild-type INK4A. Interestingly, melanoma cells expressing mutant BRAF RNAi had increased pigmentation, produced more mature melanosomes and melanin and expressed higher levels of tyrosinase and tyrosinase-related protein-1, whereas melanogenesis was not induced by wild-type INK4A. We found that the melanocyte lineage-specific master control protein microphthalmia-associated transcription factor was upregulated by inhibition of mutant BRAF, which may be the cause for the melanogenic effect of BRAF RNAi. The results suggest that, although both BRAF and INK4A lesions promote cell growth and tumor formation, mutant BRAF may also induce dedifferentiation in melanoma cells. ' 2005 Wiley-Liss, Inc. Key words:T1796A BRAF; INK4A; melanogenesis; differentiation; melanoma Melanoma is becoming one of the most prevalent malignancies with a dismal prognosis. Further understanding of melanoma biology is required to design better strategies in the treatment of this devastating disease. BRAF mutations have been identified in 70% of human malignant melanomas.1 A T1796A transversion in axon 15, resulting in a V599E substitution in the BRAF kinase domain, accounts for >90% of BRAF mutations detected in melanoma samples.1 BRAF is a component of the RAS-RAF-MEK-ERK signaling pathway that plays essential roles in cell proliferation, differentiation and survival.2 BRAF is one of 3 members of the RAF family, 2 which are serine/threonine kinases that transduce regulatory signals from RAS through MEK to ERK.V599E BRAF has increased kinase activity; causes intrinsic ERK activation in cultured NIH3T3 cells, COS cells and human melanocytes; and leads to elevated transforming activity of cultured NIH3T3 cells and human melanocytes.1,3-5 Suppression of V599E BRAF expression has been reported to cause inhibition of melanoma cell proliferation and survival in vitro and in vivo. 6-8Apart from BRAF mutation, most melanoma cells have lost expression of wild-type INK4A, through either DNA deletion/mutation or promoter hypermethylation.9-12 INK4A encodes the cell cycle regulator p16INK4A , which binds to and inhibits CDK4/6 and promotes cell cycle arrest via the RB tumor-suppressor pathway.13,14 Consistent with a tumor-suppressor role of INK4A in melanomas, a germline R24C mutation in CDK4 has been identified in familial melanoma patients. 15,16 This mutation ...

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confidence: 75%

Effects on proliferation and melanogenesis by inhibition of mutant BRAF and expression of wild‐type INK4A in melanoma cells

Rotolo

Diotti

Gordon

et al. 2005

Intl Journal of Cancer

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“…However, a cautionary note regarding the fine specificity of these serological reagents, which is best exemplified by mAb 57B, should be made. Although 57B was generated as an anti-MAGE-A3 mAb, 16,19 it was later regarded as a poly-MAGE reagent 15,38 and is now considered reactive with MAGE-A4. 39 The problems in defining the specificity of these mAbs may be most likely due to the high degree of homology between several of the CT antigens.…”

Section: Discussionmentioning

confidence: 99%

“…12,13 MAGE expression has been found in a wide array of neoplastic lesions and is most prevalent in malignant melanomas, several types of carcinomas, and certain sarcomas. [14][15][16][17][18][19][20] NY-ESO-1 21,22 has been isolated in esophageal carcinoma but has also been found in several other malignancies, such as melanoma; neuroblastoma; carcinoma of the ovary, breast, and lung; and in synovial sarcoma. [23][24][25][26][27][28][29] The CT7 antigen was identified by the SEREX approach using a melanoma cell line SK-MEL37 and allogeneic sera from a melanoma patient.…”

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confidence: 99%

Expression of cancer–testis antigens in endometrial carcinomas using a tissue microarray

et al. 2005

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Cancer-testis (CT) antigens are expressed in a variety of malignant tumors, but in normal adult tissue, they are only expressed in testicular germ cells. Owing to this tumor-associated expression pattern, these antigens are of major interest as potential targets for immunotherapy and possibly for diagnostic purposes. This study was performed to analyze the expression of four CT antigens, NY-ESO-1, MAGE-A3, MAGE-A4, and CT7/MAGE-C1, in endometrial carcinoma using immunohistochemistry, and to correlate expression with histologic subtypes, grade, and expression of WT1 and p53. Formalin-fixed paraffin-embedded tissues of 130 endometrial carcinomas of the following types and grades were analyzed using a tissue microarray: 85 endometrioid carcinomas (FIGO grade 1, 39; grade 2, 11; and grade 3, 35), 18 papillary serous carcinomas, 12 clear cell carcinomas, 13 malignant mixed mullerian tumors, one mucinous adenocarcinoma, and one undifferentiated carcinoma. The following anti-CT monoclonal antibodies/antigens were studied by immunohistochemistry: monoclonal antibody ES121/NY-ESO-1, monoclonal antibody M3H67/MAGE-A3, monoclonal antibody 57B/ MAGE-A4, and monoclonal antibody CT7-33/CT7. The CT expression data were compared to WT1 and p53 protein expression as analyzed in a previous study. Positive staining with anti-CT monoclonal antibodies was graded as follows: focal, o5% positive cells; 1 þ , 5-25% cells; 2 þ , 26-50% cells; 3 þ , 51-75%; and 4 þ , 475% cells. The 3 þ and 4 þ staining patterns were considered homogeneous patterns of potential clinical significance and were scored positive for statistical analysis. In low-grade tumors, the most immunoreactivity was seen with mAb M3H67 but little labeling was observed with the other monoclonal antibodies. In high-grade tumors, monoclonal antibodies M3H67 (25%), 57B (23%), and CT7-33 (20%) showed the highest reactivity, while ES121 showed the lowest immunoreactivity (6%). The staining pattern was mostly heterogeneous. Statistical significance was found solely for the correlation of monoclonal antibody 57B staining and p53 expression. No correlation was found for any anti-CT monoclonal antibody staining and clinical stage or for anti-CT staining and WT1 expression. CT antigens CT7, MAGE-A3 and MAGE-A4, but not NY-ESO-1, are expressed in high-grade endometrial carcinomas, and expression of MAGE-A4 is correlated with the presence of overexpressed p53.

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“…Thus, knowledge about the patterns of expression of each in individual tumors is essential. In addition, prior studies have been disadvantaged by small sample numbers (14,15) and limited numbers of antigens tested (12,14,15,21). Finally, very limited information is available about the changes that occur in the expression of each antigen during the progression of melanoma in individual patients.…”

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confidence: 99%

Tumor Antigen Expression in Melanoma Varies According to Antigen and Stage

Barrow

Browning

MacGregor

et al. 2006

Clinical Cancer Research

214

194

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Purpose: Melanoma cells express antigens that can induce T-cell and antibody responses.Obtaining a detailed understanding of antigen expression in primary and metastatic melanoma is essential if these molecules are to be useful targets for immunotherapy of melanoma. Experimental Design: Malignant melanomas (n = 586) from 426 patients were typed for antigen expression. Multiple samples were available from 86 individuals, enabling analysis of antigen expression patterns over time. Paraffin-embedded samples were tested by immunohistochemistry for the presence of the differentiation antigens: gp100, Melan-A, tyrosinase, and the ''cancer/testis'' antigens MAGE-A1, MAGE-A4, and NY-ESO-1. Results: Samples were primary tumors (n = 251), lymph node metastases (n = 174), s.c. metastases (n = 71), and distant metastases (n = 90). The differentiation antigens were strongly expressed in 93% to 95% of tumors regardless of stage. In contrast, the frequency of cancer/ testis antigen expression in primary tumors for MAGE-A1, MAGE-A4, and NY-ESO-1 was lower (20%, 9%, and 45%, respectively). MAGE-A1 and MAGE-A4 were acquired with advancing disease (to 51% and 44% in distant metastases, respectively) but not NY-ESO-1, which remained positive in 45%. MAGE-A1 expression was twice as prevalent in ulcerated primaries as in nonulcerated primaries (30% versus 15%; P = 0.006) and in thicker as opposed to thin melanomas (26% versus 10%; P = 0.1). Conclusions: This large series describes patterns of antigen expression in melanoma and their evolution over time. This will help inform decisions about selection of patients and target antigens for melanoma immunotherapy clinical trials.

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Tyrosinase immunoreactivity in formalin‐fixed, paraffin‐embedded primary and metastatic melanoma: frequency and distribution

Cited by 137 publications

References 21 publications

Effects on proliferation and melanogenesis by inhibition of mutant BRAF and expression of wild‐type INK4A in melanoma cells

Effects on proliferation and melanogenesis by inhibition of mutant BRAF and expression of wild‐type INK4A in melanoma cells

Expression of cancer–testis antigens in endometrial carcinomas using a tissue microarray

Tumor Antigen Expression in Melanoma Varies According to Antigen and Stage

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