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Special Issue "Advances in Molecular Pathology"

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology".

Deadline for manuscript submissions: closed (30 November 2011)

Special Issue Editor

Guest Editor
Prof. Dr. Paul Fisch

Institute of Pathology, University Hospital Freiburg, Breisacher Strasse 115a, 79106 Freiburg, Germany

Special Issue Information

Dear Colleagues,

Molecular pathology is a medical subspecialty, increasingly localized between pathology and clinical medicine. Why may this somewhat provocative view be justified? Molecular pathology got its start in the last 10 to 20 years of the last century as a field with the primary goal of aiding pathologists in making the right diagnosis in difficult cases or to find out whether a lesion is neoplastic or reactive. Initially, PCR-based methods were developed that worked on paraffin material allowing the determination of clonality of immunoglobulin or T-cell receptor genes in lymphoid neoplasia, or even in nonlymphoid tissues such as myeloid proliferations or endometriosis using HUMARA. In parallel, RT-PCR and later Q-PCR from cDNA or FISH- based techniques became extremely useful methods to look for gene-fusions such as BCR-ABL and EWS-FLI1 in leukemias and sarcomas, or Q-PCR from DNA to find JAK2 mutations in myeloproliferative and myelodysplastic syndromes. Besides hematology and oncology, a considerable overlap has developed with microbiology, when looking for mycobacteria and other infectious agents in human tissues by PCR, and even with medical genetics, when looking for microsatellite instability in HNPCC or for the diagnosis of hemochromatosis. “Molecular pathology” in recent years is also becoming a tool for basic scientists and, lately for clinicians to look for minimal residual disease, determine prognosis and chose the best therapy. Examples for the latter are the analysis of mutations of KRAS in colon cancer, EGFR in lung cancer or CKIT in GIST as predictive markers. Novel technologies such as oligonucleotide arrays, whole genome sequencing and cDNA microarrays allow genomic analysis and gene expression profiling of tumor entities. They have the potential to revolutionize disease nomenclature, to better understand disease pathogenesis, help in treatment decisions and more accurately determine prognosis. On the other hand, rate limiting steps are the costs of these novel technologies in research and clinical applications and the need for effective cooperation between the departments of pathology, basic sciences, microbiology, virology, genetics, biometry/statistics, as well as clinical medicine.

Prof. Dr. Paul Fisch
Guest Editor

Keywords

  • microarrays
  • whole genome sequencing
  • predictive markers
  • minimal residual disease
  • PCR
  • FISH
  • disease pathogenesis
  • predictive markers

Published Papers (4 papers)

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Research

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Open AccessArticle Analysis of Snail-1, E-Cadherin and Claudin-1 Expression in Colorectal Adenomas and Carcinomas
Int. J. Mol. Sci. 2012, 13(2), 1632-1643; doi:10.3390/ijms13021632
Received: 23 November 2011 / Revised: 16 January 2012 / Accepted: 17 January 2012 / Published: 2 February 2012
Cited by 13 | PDF Full-text (330 KB) | HTML Full-text | XML Full-text
Abstract
We report the expression of Snail-1, E-cadherin and claudin-1 by indirect immunohistochemistry in colonic neoplasia. Snail-1 is a zinc finger transcription factor expressed in cells that already have undergone almost complete epithelial-mesenchymal transition (EMT) and have already evaded from the tumor. The [...] Read more.
We report the expression of Snail-1, E-cadherin and claudin-1 by indirect immunohistochemistry in colonic neoplasia. Snail-1 is a zinc finger transcription factor expressed in cells that already have undergone almost complete epithelial-mesenchymal transition (EMT) and have already evaded from the tumor. The main mechanism by which Snail induces EMT is downregulation of E-cadherin, of which expression was shown to be frequently downregulated in many different types of tumors, where it accompanies the invasiveness and metastatic behavior of malignant cells. Moreover, Snail-1 may downregulate the expression of claudin-1, a cell-cell adhesion protein which plays a likely role in progression and dissemination during tumorigenesis. Snail-1 was expressed in both carcinoma and adenoma cells with histologically normal epithelium in the mucosa, adjacent to the tumors, without significant differences, and predominant strong intensity of staining. Statistically significant differences were revealed between normal and tumorous epithelium (p = 0.003) at the subcellular level, where the shift of the protein to the cytoplasm with combined cytoplasmic/nuclear or pure cytoplasmic expression was observed. E-cadherin expression was present in 100% of cases of both adenocarcinomas and adenomas, with prevailing strong membranous immunoreactivity and no differences between protein expression in tumors and normal mucosa. Predominating strong positivity of claudin-1 was detected in tumor cells of adenocarcinomas and adenomas. Marked differences were seen in protein localization, where membranous staining, typical for nontumorous epithelium, changed to combined membranous/cytoplasmic expression in adenocarcinomas (p = 0.0001) and adenomas (0.0002), in which cytoplasmic shift was associated with a higher degree of dysplasia. Furthermore, membranous/cytoplasmic localization was more frequent in the carcinoma group (87%) in comparison with adenomas (51%) (p = 0.0001). We conclude that dystopic subcellular localizations of Snail-1 and claudin-1 may participate in changes of cellular morphology and behavior which might be associated with altered effectory pathways of proteins and thus substantially contribute to the cancer development. Full article
(This article belongs to the Special Issue Advances in Molecular Pathology)
Open AccessArticle Distribution and Clinical Significance of Th17 Cells in the Tumor Microenvironment and Peripheral Blood of Pancreatic Cancer Patients
Int. J. Mol. Sci. 2011, 12(11), 7424-7437; doi:10.3390/ijms12117424
Received: 8 August 2011 / Revised: 12 October 2011 / Accepted: 19 October 2011 / Published: 28 October 2011
Cited by 26 | PDF Full-text (596 KB) | HTML Full-text | XML Full-text
Abstract
This study was designed to investigate the distribution of Th17 cells in the tumor microenvironment and peripheral blood of pancreatic cancer patients, its clinical significance, and the expression profile of Th17 cell-associated cytokines. The percentage of Th17 cells detected by flow cytometry [...] Read more.
This study was designed to investigate the distribution of Th17 cells in the tumor microenvironment and peripheral blood of pancreatic cancer patients, its clinical significance, and the expression profile of Th17 cell-associated cytokines. The percentage of Th17 cells detected by flow cytometry analysis (FACS) was significantly higher in 46 pancreatic tumor tissues (5.28 ± 1.65%) compared with corresponding adjacent normal tissues (2.57 ± 0.83%) (P = 0.031). In addition, the percentage of Th17 cells was significantly higher in stage III-IV tumors than stage I-II tumors (P = 0.039). The percentage of Th17 cells in peripheral blood of 20 pancreatic cancer patients (3.99 ± 1.15%) was significantly higher than 15 healthy volunteers (1.98 ± 0.57%) (P = 0.027). Immunohistochemistry (IHC) was performed to detect IL-17+ cells in 46 pancreatic tumor tissues, as well as expression of CD34 in 24 tumor tissues. IL-17 was shown to mainly locate in cytoplasm, and the frequency of IL-17+ cells in tumor tissues (39/46) was higher than control (29/46). The presence of IL-17+ cells in tumor tissues was associated with tumor, node, and metastasis (TNM) stage, and lymph node metastasis (P = 0.012 and P = 0.009) but not with patient sex, age, tumor size, and histological grade (P > 0.05). Interestingly, distribution of Th17 cells in tumor tissues was positively correlated with microvessel density (MVD) (r = 0.86, P = 0.018). Furthermore, the median survival time of patients with high and low level of IL-17+ cells frequency was 14.5 and 18.5 months respectively (P = 0.023). The serum levels of Th17 cell-associated cytokines, IL-17 and IL-23 in 20 pancreatic patients detected by enzyme-linked immunosorbent assay (ELISA) were 69.2 ± 28.5 pg/mL and 266.5 ± 98.1 pg/mL, respectively, which were significantly higher than 15 healthy volunteers (P = 0.015 and P = 0.02). Moreover, levels of IL-17 and IL-23 were significantly higher in stage III-IV tumors than stage I-II tumors (P = 0.04 and P = 0.036). This study suggests that increase in Th17 cells frequency and its related cytokines levels in pancreatic tumor tissues may indicate involvement in the invasion and metastasis of pancreatic cancer, which may thereby affect patient prognosis. Therefore, Th17 cells and related cytokines may be served as important immune indicators for predicting the prognosis of pancreatic cancer patients. Full article
(This article belongs to the Special Issue Advances in Molecular Pathology)

Review

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Open AccessReview Epigenetic Disregulation in Oral Cancer
Int. J. Mol. Sci. 2012, 13(2), 2331-2353; doi:10.3390/ijms13022331
Received: 6 December 2011 / Revised: 9 February 2012 / Accepted: 13 February 2012 / Published: 21 February 2012
Cited by 23 | PDF Full-text (368 KB) | HTML Full-text | XML Full-text
Abstract
Squamous cell carcinoma of the oral region (OSCC) is one of the most common and highly aggressive malignancies worldwide, despite the fact that significant results have been achieved during the last decades in its detection, prevention and treatment. Although many efforts have [...] Read more.
Squamous cell carcinoma of the oral region (OSCC) is one of the most common and highly aggressive malignancies worldwide, despite the fact that significant results have been achieved during the last decades in its detection, prevention and treatment. Although many efforts have been made to define the molecular signatures that identify the clinical outcome of oral cancers, OSCC still lacks reliable prognostic molecular markers. Scientific evidence indicates that transition from normal epithelium to pre-malignancy, and finally to oral carcinoma, depends on the accumulation of genetic and epigenetic alterations in a multistep process. Unlike genetic alterations, epigenetic changes are heritable and potentially reversible. The most common examples of such changes are DNA methylation, histone modification, and small non-coding RNAs. Although several epigenetic changes have been currently linked to OSCC initiation and progression, they have been only partially characterized. Over the last decade, it has been demonstrated that especially aberrant DNA methylation plays a critical role in oral cancer. The major goal of the present paper is to review the recent literature about the epigenetic modifications contribution in early and later phases of OSCC malignant transformation; in particular we point out the current evidence of epigenetic marks as novel markers for early diagnosis and prognosis as well as potential therapeutic targets in oral cancer. Full article
(This article belongs to the Special Issue Advances in Molecular Pathology)
Open AccessReview Tumor Heterogeneity: Mechanisms and Bases for a Reliable Application of Molecular Marker Design
Int. J. Mol. Sci. 2012, 13(2), 1951-2011; doi:10.3390/ijms13021951
Received: 2 December 2011 / Revised: 23 January 2012 / Accepted: 1 February 2012 / Published: 13 February 2012
Cited by 31 | PDF Full-text (737 KB) | HTML Full-text | XML Full-text
Abstract
Tumor heterogeneity is a confusing finding in the assessment of neoplasms, potentially resulting in inaccurate diagnostic, prognostic and predictive tests. This tumor heterogeneity is not always a random and unpredictable phenomenon, whose knowledge helps designing better tests. The biologic reasons for this [...] Read more.
Tumor heterogeneity is a confusing finding in the assessment of neoplasms, potentially resulting in inaccurate diagnostic, prognostic and predictive tests. This tumor heterogeneity is not always a random and unpredictable phenomenon, whose knowledge helps designing better tests. The biologic reasons for this intratumoral heterogeneity would then be important to understand both the natural history of neoplasms and the selection of test samples for reliable analysis. The main factors contributing to intratumoral heterogeneity inducing gene abnormalities or modifying its expression include: the gradient ischemic level within neoplasms, the action of tumor microenvironment (bidirectional interaction between tumor cells and stroma), mechanisms of intercellular transference of genetic information (exosomes), and differential mechanisms of sequence-independent modifications of genetic material and proteins. The intratumoral heterogeneity is at the origin of tumor progression and it is also the byproduct of the selection process during progression. Any analysis of heterogeneity mechanisms must be integrated within the process of segregation of genetic changes in tumor cells during the clonal expansion and progression of neoplasms. The evaluation of these mechanisms must also consider the redundancy and pleiotropism of molecular pathways, for which appropriate surrogate markers would support the presence or not of heterogeneous genetics and the main mechanisms responsible. This knowledge would constitute a solid scientific background for future therapeutic planning. Full article
(This article belongs to the Special Issue Advances in Molecular Pathology)

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