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993 KiB

Open AccessArticle

Phosphorylation of Large T Antigen Regulates Merkel Cell Polyomavirus Replication

by Jason Diaz, Xin Wang, Sabrina H. Tsang, Jing Jiao and Jianxin You

Cancers 2014, 6(3), 1464-1486; https://doi.org/10.3390/cancers6031464 - 8 Jul 2014

Cited by 18 | Viewed by 8230

Abstract

Merkel Cell Polyomavirus (MCPyV) was recently discovered as a novel human polyomavirus that is associated with ~80% of Merkel Cell Carcinomas. The Large Tumor antigen (LT) is an early viral protein which has a variety of functions, including manipulation of the cell cycle [...] Read more.

Merkel Cell Polyomavirus (MCPyV) was recently discovered as a novel human polyomavirus that is associated with ~80% of Merkel Cell Carcinomas. The Large Tumor antigen (LT) is an early viral protein which has a variety of functions, including manipulation of the cell cycle and initiating viral DNA replication. Phosphorylation plays a critical regulatory role for polyomavirus LT proteins, but no investigation of MCPyV LT phosphorylation has been performed to date. In this report mass spectrometry analysis reveals three unique phosphorylation sites: T271, T297 and T299. In vivo replication assays confirm that phosphorylation of T271 does not play a role in viral replication, while modification at T297 and T299 have dramatic and opposing effects on LT’s ability to initiate replication from the viral origin. We test these mutants for their ability to bind, unwind, and act as a functional helicase at the viral origin. These studies provide a framework for understanding how phosphorylation of LT may dynamically regulate viral replication. Although the natural host cell of MCPyV has not yet been established, this work provides a foundation for understanding how LT activity is regulated and provides tools for better exploring this regulation in both natural host cells and Merkel cells. Full article

(This article belongs to the Special Issue Merkel Cell Carcinoma)

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Open AccessArticle

Inflammatory Cell Distribution in Primary Merkel Cell Carcinoma

by Rachel Wheat, Claudia Roberts, Tim Waterboer, Jane Steele, Jerry Marsden, Neil M. Steven and David J. Blackbourn

Cancers 2014, 6(2), 1047-1064; https://doi.org/10.3390/cancers6021047 - 6 May 2014

Cited by 16 | Viewed by 8817

Abstract

Merkel cell carcinoma (MCC) is an aggressive poorly differentiated neuroendocrine cutaneous carcinoma associated with older age, immunodeficiency and Merkel cell polyomavirus (MCPyV) integrated within malignant cells. The presence of intra-tumoural CD8+ lymphocytes reportedly predicts better MCC-specific survival. In this study, the distribution of [...] Read more.

Merkel cell carcinoma (MCC) is an aggressive poorly differentiated neuroendocrine cutaneous carcinoma associated with older age, immunodeficiency and Merkel cell polyomavirus (MCPyV) integrated within malignant cells. The presence of intra-tumoural CD8+ lymphocytes reportedly predicts better MCC-specific survival. In this study, the distribution of inflammatory cells and properties of CD8+ T lymphocytes within 20 primary MCC specimens were characterised using immunohistochemistry and multicolour immunofluorescent staining coupled to confocal microscopy. CD8+ cells and CD68+ macrophages were identified in 19/20 primary MCC. CD20+ B cells were present in 5/10, CD4+ cells in 10/10 and FoxP3+ cells in 7/10 specimens. Only two specimens had almost no inflammatory cells. Within specimens, inflammatory cells followed the same patchy distribution, focused at the edge of sheets and nodules and, in some cases, more intense in trabecular areas. CD8+ cells were outside vessels on the edge of tumour. Those few within malignant sheets typically lined up in fine septa not contacting MCC cells expressing MCPyV large T antigen. The homeostatic chemokine CXCL12 was expressed outside malignant nodules whereas its receptor CXCR4 was identified within tumour but not on CD8+ cells. CD8+ cells lacked CXCR3 and granzyme B expression irrespective of location within stroma versus malignant nodules or of the intensity of the intra-tumoural infiltrate. In summary, diverse inflammatory cells were organised around the margin of malignant deposits suggesting response to aberrant signaling, but were unable to penetrate the tumour microenvironment itself to enable an immune response against malignant cells or their polyomavirus. Full article

(This article belongs to the Special Issue Merkel Cell Carcinoma)

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Open AccessArticle

Aberrant Promoter Hypermethylation of RASSF Family Members in Merkel Cell Carcinoma

by Antje M. Richter, Tanja Haag, Sara Walesch, Peter Herrmann-Trost, Wolfgang C. Marsch, Heinz Kutzner, Peter Helmbold and Reinhard H. Dammann

Cancers 2013, 5(4), 1566-1576; https://doi.org/10.3390/cancers5041566 - 18 Nov 2013

Cited by 21 | Viewed by 7238

Abstract

Merkel cell carcinoma (MCC) is one of the most aggressive cancers of the skin. RASSFs are a family of tumor suppressors that are frequently inactivated by promoter hypermethylation in various cancers. We studied CpG island promoter hypermethylation in MCC of RASSF2, RASSF5A, RASSF5C [...] Read more.

Merkel cell carcinoma (MCC) is one of the most aggressive cancers of the skin. RASSFs are a family of tumor suppressors that are frequently inactivated by promoter hypermethylation in various cancers. We studied CpG island promoter hypermethylation in MCC of RASSF2, RASSF5A, RASSF5C and RASSF10 by combined bisulfite restriction analysis (COBRA) in MCC samples and control tissue. We found RASSF2 to be methylated in three out of 43 (7%), RASSF5A in 17 out of 39 (44%, but also 43% in normal tissue), RASSF5C in two out of 26 (8%) and RASSF10 in 19 out of 84 (23%) of the cancer samples. No correlation between the methylation status of the analyzed RASSFs or between RASSF methylation and MCC characteristics (primary versus metastatic, Merkel cell polyoma virus infection, age, sex) was found. Our results show that RASSF2, RASSF5C and RASSF10 are aberrantly hypermethylated in MCC to a varying degree and this might contribute to Merkel cell carcinogenesis. Full article

(This article belongs to the Special Issue Merkel Cell Carcinoma)

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Review

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Open AccessReview

Mutational Analysis of Merkel Cell Carcinoma

by Derek J. Erstad and James C. Cusack, Jr.

Cancers 2014, 6(4), 2116-2136; https://doi.org/10.3390/cancers6042116 - 17 Oct 2014

Cited by 40 | Viewed by 8623

Abstract

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignancy that is associated with a poor prognosis. The pathogenesis of MCC is not well understood, and despite a recent plethora of mutational analyses, we have yet to find a set of signature mutations [...] Read more.

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignancy that is associated with a poor prognosis. The pathogenesis of MCC is not well understood, and despite a recent plethora of mutational analyses, we have yet to find a set of signature mutations implicated in the majority of cases. Mutations, including TP53, Retinoblastoma and PIK3CA, have been documented in subsets of patients. Other mechanisms are also likely at play, including infection with the Merkel cell polyomavirus in a subset of patients, dysregulated immune surveillance, epigenetic alterations, aberrant protein expression, posttranslational modifications and microRNAs. In this review, we summarize what is known about MCC genetic mutations and chromosomal abnormalities, and their clinical significance. We also examine aberrant protein function and microRNA expression, and discuss the therapeutic and prognostic implications of these findings. Multiple clinical trials designed to selectively target overexpressed oncogenes in MCC are currently underway, though most are still in early phases. As we accumulate more molecular data on MCC, we will be better able to understand its pathogenic mechanisms, develop libraries of targeted therapies, and define molecular prognostic signatures to enhance our clinicopathologic knowledge. Full article

(This article belongs to the Special Issue Merkel Cell Carcinoma)

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Open AccessReview

Merkel Cell Carcinoma in Immunosuppressed Patients

by Janice E. Ma and Jerry D. Brewer

Cancers 2014, 6(3), 1328-1350; https://doi.org/10.3390/cancers6031328 - 27 Jun 2014

Cited by 80 | Viewed by 7507

Abstract

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy. The infectivity of Merkel cell polyomavirus (MCPyV), an apparent agent in MCC development, may be exacerbated with impaired immune responses. This paper reviews relevant data regarding the role of immunosuppression in the [...] Read more.

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy. The infectivity of Merkel cell polyomavirus (MCPyV), an apparent agent in MCC development, may be exacerbated with impaired immune responses. This paper reviews relevant data regarding the role of immunosuppression in the development of MCC and describes modes of immunodeficient states. Because of the inherently low incidence rate of MCC, several case studies and series are also briefly mentioned to provide a more comprehensive summary of MCC in the setting of immunosuppression. We describe immunosuppressed patients who have experienced excessive UV radiation, organ transplantation, human immunodeficiency virus infection/AIDS, autoimmune diseases, and lymphoproliferative disorders. Iatrogenic forms of immunosuppression are also highlighted. Studies that quantify risks consistently report that individuals with a history of solid organ transplantation, autoimmune diseases, AIDS, and/or lymphoproliferative diseases have a significantly elevated risk of developing MCC. Overall, immunocompromised patients also appear to have an early onset and more aggressive course of MCC, with poorer outcomes. Recommendations for multidisciplinary approaches are proposed to effectively prevent and manage MCC in these patients. Full article

(This article belongs to the Special Issue Merkel Cell Carcinoma)

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Open AccessReview

Merkel Cell Polyomavirus: Molecular Insights into the Most Recently Discovered Human Tumour Virus

by Gabrielė Stakaitytė, Jennifer J. Wood, Laura M. Knight, Hussein Abdul-Sada, Noor Suhana Adzahar, Nnenna Nwogu, Andrew Macdonald and Adrian Whitehouse

Cancers 2014, 6(3), 1267-1297; https://doi.org/10.3390/cancers6031267 - 27 Jun 2014

Cited by 42 | Viewed by 15831

Abstract

A fifth of worldwide cancer cases have an infectious origin, with viral infection being the foremost. One such cancer is Merkel cell carcinoma (MCC), a rare but aggressive skin malignancy. In 2008, Merkel cell polyomavirus (MCPyV) was discovered as the causative agent of [...] Read more.

A fifth of worldwide cancer cases have an infectious origin, with viral infection being the foremost. One such cancer is Merkel cell carcinoma (MCC), a rare but aggressive skin malignancy. In 2008, Merkel cell polyomavirus (MCPyV) was discovered as the causative agent of MCC. It is found clonally integrated into the majority of MCC tumours, which require MCPyV oncoproteins to survive. Since its discovery, research has begun to reveal the molecular virology of MCPyV, as well as how it induces tumourigenesis. It is thought to be a common skin commensal, found at low levels in healthy individuals. Upon loss of immunosurveillance, MCPyV reactivates, and a heavy viral load is associated with MCC pathogenesis. Although MCPyV is in many ways similar to classical oncogenic polyomaviruses, such as SV40, subtle differences are beginning to emerge. These unique features highlight the singular position MCPyV has as the only human oncogenic polyomavirus, and open up new avenues for therapies against MCC. Full article

(This article belongs to the Special Issue Merkel Cell Carcinoma)

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Open AccessReview

Diagnosis and Management of Merkel Cell Carcinoma of the Head and Neck: Current Trends and Controversies

by Mark S. Swanson and Uttam K. Sinha

Cancers 2014, 6(3), 1256-1266; https://doi.org/10.3390/cancers6031256 - 27 Jun 2014

Cited by 8 | Viewed by 5648

Abstract

Merkel cell carcinoma is an aggressive neuroendocrine cutaneous malignancy with a predilection for regional and distant metastasis. This malignancy presents most commonly on the head and neck of elderly Caucasian males, with a higher prevalence in the immunosuppressed. A high index of suspicion [...] Read more.

Merkel cell carcinoma is an aggressive neuroendocrine cutaneous malignancy with a predilection for regional and distant metastasis. This malignancy presents most commonly on the head and neck of elderly Caucasian males, with a higher prevalence in the immunosuppressed. A high index of suspicion must be maintained due to the often asymptomatic presentation. Lip tumors, scalp tumors, local invasion, nodal metastasis, distant metastasis, and lymphovascular invasion are poor prognostic factors. Up to 8.7% of patients present with distant metastasis, and PET-CT is an accurate staging tool with a 90% sensitivity. Combined aggressive surgical resection with adjuvant radiotherapy affords the best regional control rates. The regional lymphatics must be addressed with either sentinel lymph node biopsy, surgery, or elective radiation due to the risk of occult metastasis. Addition of chemotherapy has no proven benefit in locoregional control. Full article

(This article belongs to the Special Issue Merkel Cell Carcinoma)

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Open AccessReview

Systemic Therapy for Merkel Cell Carcinoma: What’s on the Horizon?

by Guilherme Rabinowits

Cancers 2014, 6(2), 1180-1194; https://doi.org/10.3390/cancers6021180 - 16 May 2014

Cited by 13 | Viewed by 7702

Abstract

Merkel cell carcinoma is an aggressive neuroendocrine skin cancer that usually affects elderly patients. Despite being uncommon, incidence has been steadily increasing over the last two decades, likely due to increased awareness, better diagnostic methods and aging of the population. It is currently [...] Read more.

Merkel cell carcinoma is an aggressive neuroendocrine skin cancer that usually affects elderly patients. Despite being uncommon, incidence has been steadily increasing over the last two decades, likely due to increased awareness, better diagnostic methods and aging of the population. It is currently one of the most lethal cutaneous malignancies, with a five-year overall survival of approximately 50%. With the better understanding of the molecular pathways that lead to the development of Merkel cell carcinoma, there has been an increasing excitement and optimism surrounding novel targeted therapies, in particular to immunotherapy. Some of the concepts surrounding the novel targeted therapies and currently ongoing clinical trials are reviewed here. Full article

(This article belongs to the Special Issue Merkel Cell Carcinoma)

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Open AccessReview

Merkel Cell Carcinoma of the Eyelid and Periocular Region

by Helen Merritt, Matthew C. Sniegowski and Bita Esmaeli

Cancers 2014, 6(2), 1128-1137; https://doi.org/10.3390/cancers6021128 - 9 May 2014

Cited by 22 | Viewed by 13453

Abstract

Merkel cell carcinoma (MCC) in the eyelid and periocular region can be treated surgically, in most cases, with preservation of the eye and reasonable visual function. Adjuvant radiation therapy, sentinel lymph node biopsy, and chemotherapy should be considered for MCC of the eyelid [...] Read more.

Merkel cell carcinoma (MCC) in the eyelid and periocular region can be treated surgically, in most cases, with preservation of the eye and reasonable visual function. Adjuvant radiation therapy, sentinel lymph node biopsy, and chemotherapy should be considered for MCC of the eyelid and periocular region, especially for larger tumors that are T2b or more advanced and lesions that present with regional nodal or distant metastasis. Full article

(This article belongs to the Special Issue Merkel Cell Carcinoma)

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Open AccessReview

Molecular Imaging and Therapy of Merkel Cell Carcinoma

by Volkan Beylergil and Jorge A. Carrasquillo

Cancers 2014, 6(2), 1020-1030; https://doi.org/10.3390/cancers6021020 - 29 Apr 2014

Cited by 3 | Viewed by 6896

Abstract

Several molecular imaging modalities have been evaluated in the management of Merkel cell carcinoma (MCC), a rare and aggressive tumor with a high tendency to metastasize. Continuous progress in the field of molecular imaging might improve management in these patients. The authors review [...] Read more.

Several molecular imaging modalities have been evaluated in the management of Merkel cell carcinoma (MCC), a rare and aggressive tumor with a high tendency to metastasize. Continuous progress in the field of molecular imaging might improve management in these patients. The authors review the current modalities and their impact on MCC in this brief review article. Full article

(This article belongs to the Special Issue Merkel Cell Carcinoma)

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