A Methyl Deviation Index for Breast Cancer
DNA methylation analysis provides a promising avenue for identifying distinct breast cancer phenotypes using candidate gene measurements and microarray analyses. Killian et al (Am J Pathol 2011, 179:55–65) performed a large-scale DNA methylation analysis of breast cancers and benign parenchyma. A methyl deviation index (MDI) was calculated for each lesion relative to terminal ductal-lobular unit baseline. Group comparisons revealed that high-grade and short-survival estrogen receptor–positive (ER+) cancers had a significantly higher MDI than low-grade and long-survival ER+ cancers whereas ER− cancers had a significantly lower MDI. MDI showed superior prognostic performance to crude methylation levels, retaining prognostic significance in Cox multivariate analysis. Overall, MDI can be readily measured from routine breast pathology samples, correlates with aggressive cancer features, and is informative to estimate disease prognosis for ER+ primary invasive carcinomas.
Serum Enzymes Increase with Kupffer Cell Reduction
Macrophage colony-stimulating factor (M-CSF) directs differentiation of monocytes into Kupffer cells (KCs), which remove excess serum enzymes that are present following liver or muscle injury. Using three different animal models, Radi et al (Am J Pathol 2011, 179:240–247) asked whether increases in serum enzymes result from decreases in KCs in the apparent absence of hepatic or muscle injury. Antibody-mediated neutralization of M-CSF activity reduced the CD14+CD16+ monocyte population, depleted KCs, and increased serum enzyme levels in cynomolgus macaques. When rats were treated with clodronate liposomes, KCs were depleted and serum enzyme levels increased, again without evidence of tissue injury. Finally, in osteopetrotic (Csf1op/Csf1op) mice lacking functional M-CSF and having reduced levels of KCs, the levels of serum enzymes were higher than in wild-type littermates. Thus, depletion of KCs is associated with increased levels of short-lived serum enzymes, even in the absence of liver or muscle injury.
IL-17 Induces Pulmonary Pathogenesis during RSV Infection
Severe respiratory syncytial virus (RSV) infections cause airway damage, mucus hypersecretion, and Th2 cytokine production. Mukherjee et al (Am J Pathol 2011, 179:248–258) observed IL-17 levels in samples from severely ill infants with RSV infection and in a mouse model of RSV infection. In mice, neutralization of IL-17 during infection significantly reduced mucus production, inflammation, and viral load and significantly increased RSV-specific CD8+ T cells. T-bet, IFN-γ, eomesodermin, and granzyme B were significantly up-regulated after IL-17 blockade, and in vitro analyses suggest that IL-17 directly inhibits T-bet, eomesodermin, and IFN-γ in CD8+ T cells. In RSV-induced exacerbation of allergic airway responses, IL-17 neutralization significant decreased the exacerbated disease, reducing mucus production and Th2 cytokines levels as well as viral protein production. Together, these data reveal a pathogenic role for IL-17 in RSV-induced disease.
Stem Cells in This Old Heart of Mine
It is unknown whether defects in stem cell growth and differentiation contribute to myocardial aging and chronic heart failure (CHF) and whether a compartment of functional human cardiac stem cells (hCSCs) persists in the decompensated heart. Cesselli et al (Am J Pathol 2011, 179:349–366) address these questions by evaluating the properties of hCSCs in control and explanted hearts. Chronological age was a major predictor of five biomarkers of hCSC senescence: telomeric shortening, attenuated telomerase activity, telomere dysfunction-induced foci, and p21Cip1 and p16INK4a expression. CHF had similar consequences for hCSCs, suggesting that defects in the balance between cardiomyocyte mass and the pool of nonsenescent hCSCs may condition the evolution of the disease. These results demonstrate that telomere dysfunction in hCSCs is a biomarker of aging and heart failure.
Modeling Colon Adenocarcinomas in 3D
Normal fibroblasts and cancer-associated fibroblasts (CAFs) display distinct gene expression signatures that may influence tumor cell migration, proliferation, and survival during tumor progression. To test this hypothesis, Dolznig et al (Am J Pathol 2011, 179:487–501) established a three-dimensional (3D) cell culture system using human colon tumor cells grown as multicellular spheroids that were subsequently co-cultured with normal fibroblasts or CAFs in collagen I gels. In this model, genes involved in invasion, extracellular matrix remodeling, inflammation, and angiogenesis were differentially regulated. The modular setup, reproducibility, and robustness of the system allow identification of target molecules involved in signaling pathways that mediate paracrine interactions in the tumor microenvironment as well as validation of such targets during tumor growth and invasion in the supporting stroma.
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Published online: June 06, 2011
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© 2011 American Society for Investigative Pathology. Published by Elsevier Inc.
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- Effects of Age and Heart Failure on Human Cardiac Stem Cell FunctionThe American Journal of PathologyVol. 179Issue 1
- PreviewCurrently, it is unknown whether defects in stem cell growth and differentiation contribute to myocardial aging and chronic heart failure (CHF), and whether a compartment of functional human cardiac stem cells (hCSCs) persists in the decompensated heart. To determine whether aging and CHF are critical determinants of the loss in growth reserve of the heart, the properties of hCSCs were evaluated in 18 control and 23 explanted hearts. Age and CHF showed a progressive decrease in functionally competent hCSCs.
- Full-Text
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- A Methyl-Deviator Epigenotype of Estrogen Receptor–Positive Breast Carcinoma Is Associated with Malignant BiologyThe American Journal of PathologyVol. 179Issue 1
- PreviewWe broadly profiled DNA methylation in breast cancers (n = 351) and benign parenchyma (n = 47) for correspondence with disease phenotype, using FFPE diagnostic surgical pathology specimens. Exploratory analysis revealed a distinctive primary invasive carcinoma subclass featuring extreme global methylation deviation. Subsequently, we tested the correlation between methylation remodeling pervasiveness and malignant biological features. A methyl deviation index (MDI) was calculated for each lesion relative to terminal ductal-lobular unit baseline, and group comparisons revealed that high-grade and short-survival estrogen receptor–positive (ER+) cancers manifest a significantly higher MDI than low-grade and long-survival ER+ cancers.
- Full-Text
- Preview
- Modeling Colon Adenocarcinomas in Vitro: A 3D Co-Culture System Induces Cancer-Relevant Pathways upon Tumor Cell and Stromal Fibroblast InteractionThe American Journal of PathologyVol. 179Issue 1
- PreviewActivated tumor stroma participates in tumor cell growth, invasion, and metastasis. Normal fibroblasts and cancer-associated fibroblasts (CAFs) have been shown to display distinct gene expression signatures. This molecular heterogeneity may influence the way tumor cells migrate, proliferate, and survive during tumor progression. To test this hypothesis and to better understand the molecular mechanisms that control these interactions, we established a three-dimensional (3D) human cell culture system that recapitulates the tumor heterogeneity observed in vivo.
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- Increased Serum Enzyme Levels Associated with Kupffer Cell Reduction with No Signs of Hepatic or Skeletal Muscle InjuryThe American Journal of PathologyVol. 179Issue 1
- PreviewMacrophage colony-stimulating factor (M-CSF) is a hematopoietic growth factor that is responsible for the survival and proliferation of monocytes and the differentiation of monocytes into macrophages, including Kupffer cells (KCs) in the liver. KCs play an important role in the clearance of several serum enzymes, including aspartate aminotransferase and creatine kinase, that are typically elevated as a result of liver or skeletal muscle injury. We used three distinct animal models to investigate the hypothesis that increases in the levels of serum enzymes can be the result of decreases in KCs in the apparent absence of hepatic or skeletal muscle injury.
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- IL-17–Induced Pulmonary Pathogenesis during Respiratory Viral Infection and Exacerbation of Allergic DiseaseThe American Journal of PathologyVol. 179Issue 1
- PreviewSevere respiratory syncytial virus (RSV) infections are characterized by airway epithelial cell damage, mucus hypersecretion, and Th2 cytokine production. Less is known about the role of IL-17. We observed increased IL-6 and IL-17 levels in tracheal aspirate samples from severely ill infants with RSV infection. In a mouse model of RSV infection, time-dependent increases in pulmonary IL-6, IL-23, and IL-17 expression were observed. Neutralization of IL-17 during infection and observations from IL-17−/− knockout mice resulted in significant inhibition of mucus production during RSV infection.
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