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This month in AJP| Volume 181, ISSUE 5, P1483, November 2012

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This Month in AJP

    Open AccessPublished:September 19, 2012DOI:https://doi.org/10.1016/j.ajpath.2012.09.002

        Biomarkers Found for Human Metaplasia and Gastric Cancer

        Early diagnosis and curative resection are associated with increased survival in gastric cancer patients. Yet, a majority of gastric cancers are still diagnosed at later stages. Sousa et al (Am J Pathol 2012, 181:1560−1572) uncovered novel biomarkers LTF and DNMT1 for spasmolytic polypeptide-expressing metaplasia and intestinal metaplasia, respectively, by generating proteome profiles using formalin-fixed, paraffin-embedded samples of interstitial-type gastric cancer, metaplasia, and normal mucosa by combining peptide isoelectric focusing and liquid chromatography-mass spectrometry/mass-spectrometry analysis. The authors further established that the loss of LTF or DMBT1 expression in gastric tumors correlates with a poor prognosis.

        Large Oncosomes and Aggressiveness in Prostate Cancer

        Oncosomes are tumor-derived microvesicles that transmit signaling complexes between cell and tissue compartments. Di Vizio et al (Am J Pathol 2012, 181:1573−1584) demonstrated that such oncosomes contain metalloproteinases, RNA, caveolin-1, and the GTPase ADP-ribosylation factor 6 and are biologically active toward tumor cells, endothelial cells, and fibroblasts. Flow cytometry-based methods can selectively sort and analyze large oncosomes in mouse prostate cancer models and human tumor tissues, demonstrating a correlation with tumor progression in mice. Aside from establishing techniques for the visualization, isolation, quantification, and characterization of large tumor vesicles in tissues and in the circulation, these findings suggest a mechanism of conditioning tumor microenvironment and distant site by migrating tumor cells, thereby potentiating advanced disease.

        Necrostatin-1 Therapy for Retinal Detachment

        Necroptosis, or programmed necrosis, is important in embryonic development and pathophysiology as well as neuronal cell death. Dong et al (Am J Pathol 2012, 181:1634−1641) investigated the role of the necroptosis inhibitor necrostatin-1 on photoreceptor survival and functional experimental retinal detachment in rats. By introducing necrostatin-1 into the subretinal space at the time of retinal detachment and 6 hours later, they observed that necrostatin-1 directly protected neurons by specifically inhibiting necroptotic cell death, inhibited receptor interacting protein kinase phosphorylation induction after retinal detachment, attenuated retinal degeneration, preserved retinal thickness, rescued neurons in the outer retinal layers, and reduced functional impairment after retinal detachment. There is therefore a promising therapeutic role for necrostatin-1 in protecting photoreceptors from necroptosis and improving functional outcome.

        TIMP-3 Predicts Survival and Relapse in Non–Small Cell Lung Cancer

        Tissue inhibitor of metalloproteinase-3 (TIMP-3) is essential for limiting inflammation. Wu et al (Am J Pathol 2012, 181:1796−1806) hypothesized that TIMP-3 loss would induce chronic inflammation, promoting tumor malignancy in human papillomavirus (HPV)-infected non–small cell lung cancer. TIMP-3 loss was more frequent in HPV 16/18-positive tumors than in E6-negative tumors. Promoter hypermethylation resulted in decreased TIMP-3 expression, leading to cell invasion and anchorage-independent growth due to increased IL-6 production in otherwise E6-negative TL4 and CL-10 lung cancer cells expressing E6. Patients with low-TIMP-3/high-IL-6 tumors had shorter overall survival and relapse-free survival periods than patients with high-TIMP-3/low-IL-6 tumors. TIMP-3 may serve as a prognostic marker for tumor recurrence in patients after surgical resection, and its loss may promote tumor malignancy, subsequent relapse, and poor survival in patients with HPV-infected non–small cell lung cancer.

        miR-200c Inhibits Melanoma Progression

        The role of miRNAs in melanoma progression and drug resistance has not been well studied. Liu et al (Am J Pathol 2012, 181:1823−1835) analyzed the role of miR-200c in melanoma progression and demonstrated that miR-200c is down-regulated in melanomas compared with melanocytic nevi. miR-200c overexpresion in melanoma cells resulted in decreased cell proliferation, migratory capacity, and drug resistance that could be rescued by Bmi-1 overexpression; down-regulation of BMI-1, ABCG2, ABCG5, and MDR1 with a concomitant increase in E-cadherin levels and in vivo inhibition of melanoma xenograft growth and metastasis with decreased BMI-1 expression and E-cadherin levels in tumors were also observed. Thus, miR-200c represents a critical target for increasing melanoma sensitivity to clinical therapies.

        Linked Article

        • Large Oncosomes in Human Prostate Cancer Tissues and in the Circulation of Mice with Metastatic Disease
          The American Journal of PathologyVol. 181Issue 5
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            Oncosomes are tumor-derived microvesicles that transmit signaling complexes between cell and tissue compartments. Herein, we show that amoeboid tumor cells export large (1- to 10-μm diameter) vesicles, derived from bulky cellular protrusions, that contain metalloproteinases, RNA, caveolin-1, and the GTPase ADP-ribosylation factor 6, and are biologically active toward tumor cells, endothelial cells, and fibroblasts. We describe methods by which large oncosomes can be selectively sorted by flow cytometry and analyzed independently of vesicles <1 μm.
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        • Necrostatin-1 Protects Photoreceptors from Cell Death and Improves Functional Outcome after Experimental Retinal Detachment
          The American Journal of PathologyVol. 181Issue 5
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            Necroptosis is a recently discovered programmed necrosis. Evidence demonstrated the importance of necroptosis in neuronal cell death. Necrostatin-1 is a specific inhibitor of necroptosis. In this study, we investigated the role of necrostatin-1 on photoreceptor survival and functional protection after experimental retinal detachment (RD) in rats. Necrostatin-1/inactive analogue of necrostatin-1 was introduced into the subretinal space at RD induction and 6 hours afterward, respectively. We found that necrostatin-1 attenuated retinal histopathological damage and reduced plasma membrane breakdown (a morphological hallmark of necroptosis) in outer retinal layers.
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        • Loss of TIMP-3 Promotes Tumor Invasion via Elevated IL-6 Production and Predicts Poor Survival and Relapse in HPV-Infected Non–Small Cell Lung Cancer
          The American Journal of PathologyVol. 181Issue 5
          • Preview
            Human papillomavirus (HPV) 16/18 E6 oncoprotein is expressed in lung tumors and is associated with p53 inactivation. The tissue inhibitor of metalloproteinase 3 (TIMP-3) is essential for limiting inflammation; therefore, we expected that TIMP-3 loss might induce chronic inflammation, thereby promoting tumor malignancy as well as poor survival and relapse in patients with HPV-infected non–small cell lung cancer. In this study, the loss of TIMP-3 by loss of heterozygosity and/or promoter hypermethylation was more frequent in HPV16/18 E6–positive tumors than in E6-negative tumors.
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        • Proteomic Profiling of Paraffin-Embedded Samples Identifies Metaplasia-Specific and Early-Stage Gastric Cancer Biomarkers
          The American Journal of PathologyVol. 181Issue 5
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            Early diagnosis and curative resection are the predominant factors associated with increased survival in patients with gastric cancer. However, most gastric cancer cases are still diagnosed at later stages. Since most pathologic specimens are archived as FFPE samples, the ability to use them to generate expression profiles can greatly improve cancer biomarker discovery. We sought to uncover new biomarkers for stomach preneoplastic metaplasias and neoplastic lesions by generating proteome profiles using FFPE samples.
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        • miR-200c Inhibits Melanoma Progression and Drug Resistance through Down-Regulation of Bmi-1
          The American Journal of PathologyVol. 181Issue 5
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            MicroRNAs (miRNAs) are short noncoding RNAs that play crucial roles in tumorigenesis and tumor progression. Melanoma is the most aggressive skin cancer that is resistant or rapidly develops resistance to a variety of chemotherapeutic agents. The role of miRNAs in melanoma progression and drug resistance has not been well studied. Herein, we demonstrate that miR-200c is down-regulated in melanomas (primary and metastatic) compared with melanocytic nevi. Overexpression of miR-200c in melanoma cells resulted in significantly decreased cell proliferation and migratory capacity as well as drug resistance.
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          Open Access