Minichromosome maintenance (MCM) proteins are essential for the process of DNA replication, functioning as license components for the S-phase of cell-cycle initiation and further exerting weak helicase activity to unwind DNA from its supercoiled state at replication forks. The requirement for MCM proteins in cycling cells and their absence in quiescent ones supports evidence for their potential clinical application as cell proliferation markers. In the last few years, aside from their utility as cell proliferation markers, the assessment of MCM expression levels in diverse human malignancies has been the focus of extensive research in an aim to facilitate tumor diagnosis and prognosis in clinical settings. The present article aims to review the available data so far concerning the clinical significance of MCM protein expression in human neoplasia in comparison to conventional proliferative markers. A review of the literature revealed that MCM expression is associated with important clinicopathological parameters for patient management and also exhibits significant diagnostic and prognostic value in several malignancies. MCMs are characterized by higher specificity and sensitivity than the conventional proliferative markers, such as Ki-67 and PCNA, and are thus considered as diagnostic and prognostic tools of greater clinical significance in several types of human malignancy.

https://digitum.um.es/xmlui/bitstream/10201/42593/1/MCM%20proteins%20as%20diagnostic%20and%20prognostic%20tumor%20markers%20in%20the%20clinical%20setting.pdf

MCM proteins as diagnostic and prognostic tumor markers in the clinical setting

A number of biomarkers, particularly proteins that contribute to prognosis in diffuse large B cell lymphoma (DLBCL), have been identified. However, translation into accepted standards to predict survival has not yet been accomplished, primarily due to contradictory reports in the literature resulting from, among other factors, arbitrary methodologies used to set cut-off values for determining positivity. Some of these problems might be resolved by application of rational statistical methods for determination of cut-off scores. Herein, we critically address issues on in situ phenotypic prognostic tumor-related biomarkers in DLBCL with a particular and practical emphasis on tools for cut-off level determination, especially receiver operating characteristic curve analysis. Moreover, we candidly illustrate the application of these tools for efficient disease-specific survival prognostication on a tissue microarray collective of 240 primary DLBCL using the common prognostic biomarkers Bcl-2, Bcl-6, CD10, FOXP1, MUM1, and Cyclin E. Comparison of the results relative to disease-specific survival unequivocally showed the superior discriminatory power of the cut-off levels calculated by receiver operating curves and the Youden's index, compared to arbitrary cut-off values from the literature, advocating fundamental application of rational methods for determination of clinically relevant prognostic biomarkers' cut-off scores.

Prognostic immunophenotypic biomarker studies in diffuse large B cell lymphoma with special emphasis on rational determination of cut-off scores.

Cdc7 kinase – A new target for drug development

Background Chronic Lymphocytic Leukemia (CLL) pathogenesis has been linked to the prolonged survival and/or apoptotic resistance of leukemic B cells in vivo, and is thought to be due to enhanced survival signaling responses to environmental factors that protect CLL cells from spontaneous and chemotherapy-induced death. Although normally associated with cell migration, the chemokine, CXCL12, is one of the factors known to support the survival of CLL cells. Thus, the signaling pathways activated by CXCL12 and its receptor, CXCR4, were investigated as components of these pathways and may represent targets that if inhibited, could render resistant CLL cells more susceptible to chemotherapy. Methodology/principal findings To determine the downstream signaling targets that contribute to the survival effects of CXCL12 in CLL, we took a phosphoproteomics approach to identify and compare phosphopeptides in unstimulated and CXCL12-stimulated primary CLL cells. While some of the survival pathways activated by CXCL12 in CLL are known, including Akt and ERK1/2, this approach enabled the identification of additional signaling targets and novel phosphoproteins that could have implications in CLL disease and therapy. In addition to the phosphoproteomics results, we provide evidence from western blot validation that the tumor suppressor, programmed cell death factor 4 (PDCD4), is a previously unidentified phosphorylation target of CXCL12 signaling in all CLL cells probed. Additionally, heat shock protein 27 (HSP27), which mediates anti-apoptotic signaling and has previously been linked to chemotherapeutic resistance, was detected in a subset (approximately 25%) of CLL patients cells examined. Conclusions/significance Since PDCD4 and HSP27 have previously been associated with cancer and regulation of cell growth and apoptosis, these proteins may have novel implications in CLL cell survival and represent potential therapeutic targets. PDCD4 also represents a previously unknown signaling target of chemokine receptors; therefore, these observations increase our understanding of alternative pathways to migration that may be activated or inhibited by chemokines in the context of cancer cell survival.

/pdf/elucidating-the-cxcl12-cxcr4-signaling-network-in-chronic-57xs6muivz.pdf

Elucidating the CXCL12/CXCR4 signaling network in chronic lymphocytic leukemia through phosphoproteomics analysis.

Enabling replicative immortality and uncontrolled cell cycle are hallmarks of cancer cells. Minichromosome maintenance proteins (MCMs) exhibit helicase activity in replication initiation and play vital roles in controlling replication times within a cell cycle. Overexpressed MCMs are detected in various cancerous tissues and cancer cell lines. Previous studies have proposed MCMs as promising proliferation markers in cancers, while the prognostic values remain controversial and the underlying mechanisms remain unascertained. This review provides an overview of the significant findings regarding the cellular and tumorigenic functions of the MCM family. Besides, current evidence of the prognostic roles of MCMs is retrospectively reviewed. This work also offers insight into the mechanisms of MCMs prompting carcinogenesis and adverse prognosis, providing information for future research. Finally, MCMs in liver cancer are specifically discussed, and future perspectives are provided.

https://downloads.hindawi.com/journals/acp/2020/3750294.pdf

MCMs in Cancer: Prognostic Potential and Mechanisms.

BackgroundMinichromosome maintenance (MCM) proteins are essential for the initiation of DNA replication and have been found to be relevant markers for prognosis in a variety of tumours. The aim of this study was to assess the proliferative activity of diffuse large B-cell lymphoma (DLBCL) in tissue microarray (TMA) using one of the minichromosome maintenance proteins (Mcm2) and to explore its potential value to predict prognosis.MethodsImmunohistochemistry for Mcm2 was performed on TMAs constructed from 302 cases of DLBCL. A monoclonal mouse antibody was used after heat induced antigen retrieval. Mcm2 expression was scored quantitatively. Positivity for Mcm2 was defined as presence of nuclear expression of Mcm2 in greater than or equal to 40 % of tumour cells. A statistical analysis was carried out of the association of Mcm2 and the clinico-pathological characteristics.ResultsMcm2 expression was clearly evident in the nuclei of proliferating non-neoplastic cells and tumour cells. Positivity for Mcm2 was found in 46% (98/211) of analysable cases. A significant correlation existed between Mcm2 expression and presence of bulky disease (p = 0.003). Poor disease specific survival was observed in patients with DLBCL positive for Mcm2 expression in the univariate analysis (p = 0.0424).ConclusionMcm2 expression can be used to assess tumour proliferation and may be useful as an additional prognostic marker to refine the prediction of outcome in DLBCL.

Expression of minichromosome maintenance protein 2 as a marker for proliferation and prognosis in di

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Expression of minichromosome maintenance protein 2 as a marker for proliferation and prognosis in di