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This Month in AJP

    Open AccessPublished:April 22, 2011DOI:https://doi.org/10.1016/j.ajpath.2010.11.045

        eNOS Gene Therapy for Ischemia

        Bone marrow-derived mononuclear cells (BMMNCs) are being tested clinically to enhance postischemic neovascularization; however, cardiovascular risk factors such as diabetes and high cholesterol counteract the pro-angiogenic potential of BMMNCs. Mees et al (Am J Pathol 2011, 178:55–60) hypothesized that endothelial NO synthase (eNOS), which is pro-angiogenic, could restore the neovascularization response of BMMNCs. Overexpression of eNOS in diabetic or atherosclerotic (ApoE-knockout) BMMNCs restored their pro-angiogenic potential for treating ischemic mice, with BMMNCs differentiating into cells exhibiting an endothelial phenotype such as VEGF-A release and NO-mediated vasodilation. Moreover, eNOS-expressing ApoE-knockout BMMNCs had antiatherogenic effects. Thus, cell-based eNOS gene therapy has potential for treating ischemic cardiovascular disease.

        Bile Acids Induce Liver Inflammation

        Inflammation contributes to liver injury during bile duct blockage, or cholestasis, but the mechanism is not known. Two possible mechanisms of injury were investigated by Allen et al (Am J Pathol 2011, 178:175–186): 1) Toll-like receptor 4 (TLR4) activated by bacteria or dead hepatocytes, and 2) bile acids acting as inflammagens. Liver inflammation following bile duct ligation (BDL) was not abrogated in mice with an inactive TLR4. Bile acids, on the other hand, increased expression of proinflammatory cytokines, chemokines, and adhesion molecules in hepatocytes exposed in vitro. Up-regulation of several of these genes in hepatocytes and in BDL mouse livers required early growth response factor-1 (Egr-1). Further, the livers of patients with cholestasis displayed Egr-1 up-regulation that correlated with levels of inflammatory mediators. These data demonstrate that bile acids, not TLR4, directly promote hepatic inflammation during cholestasis.

        Do Proteasome Inhibitors Kill Cancer Cells via p53?

        Inhibitors of the cell's protein degradation complex, the proteasome, are used to treat cancer, but their mechanisms of action are not clearly understood. Pandit et al (Am J Pathol 2011, 178:355–360) examined the role of tumor suppressor p53, which is frequently mutated in cancer, in proteasome inhibitor-induced apoptosis since p53 has been implicated to play a role in several studies. Surprisingly, proteasome inhibitors induced p53-independent apoptosis in human cancer cell lines that correlated with induction of proapoptotic protein Noxa, which is p53 independent. These drugs also inhibited growth of cancer cell lines from different sources (colon, breast, and liver) independently of p53 status. These unexpected results stress the importance of performing additional experiments to explain the discrepant roles of p53 in proteasome inhibitor-induced apoptosis.

        Fibrosis IZ Key to Breast Cancer Invasion

        Dense fibrosis commonly occurs in invasive ductal breast cancer and may represent an altered tumor microenvironment (TME) that precedes tumor invasion. Kim et al (Am J Pathol 2011, 178:373–381) characterized the dense fibrotic zone of invasive ductal carcinoma, postulating the presence of an interface zone (IZ) encircling the tumor margin and overlapping the normal tissue. The extracellular matrix component laminin-332 was specifically overexpressed in the IZ, together with MMP3, MT1-MMP, Snail, and ZEB1, demonstrating alterations in TME related to fibrosis and tumor invasion. Myofibroblasts isolated from the IZ displayed laminin-332 and MT1-MMP overexpression. Thus, the fibrotic IZ may be the actual tissue site of TME and may provide a specialized microenvironment for guiding tumor invasion.

        Tregs Target Hypertension and Heart Disease

        The cellular and molecular mechanisms of hypertension-complicated coronary artery disease are not well understood, but immune cells and inflammation have been implicated. Since CD4+CD25+ regulatory T cells (Tregs) have been reported to regulate heart fibrosis in hypertension, Matrougui et al (Am J Pathol 2011, 178:434–441) examined the role of Tregs in an angiotensin II (Ang-II)-dependent hypertensive mouse model. Ang-II-mice displayed macrophage activation/infiltration into coronary arterioles and heart as well as increased local TNF-α release. Hypertensive mice injected with control Tregs, however, exhibited reduced macrophage activation and infiltration, TNF-α release, and improved coronary arteriolar endothelium-dependent relaxation. These data indicate that Tregs are involved in the development of coronary arteriolar endothelial dysfunction in hypertension.

        Linked Article

        • Bile Acids Induce Inflammatory Genes in Hepatocytes: A Novel Mechanism of Inflammation during Obstructive Cholestasis
          The American Journal of PathologyVol. 178Issue 1
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            Inflammation contributes to liver injury during cholestasis. The mechanism by which cholestasis initiates an inflammatory response in the liver, however, is not known. Two hypotheses were investigated in the present studies. First, activation of Toll-like receptor 4 (TLR4), either by bacterial lipopolysaccharide or by damage-associated molecular pattern molecules released from dead hepatocytes, triggers an inflammatory response. Second, bile acids act as inflammagens, and directly activate signaling pathways in hepatocytes that stimulate production of proinflammatory mediators.
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        • Laminin-332-Rich Tumor Microenvironment for Tumor Invasion in the Interface Zone of Breast Cancer
          The American Journal of PathologyVol. 178Issue 1
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            Dense fibrosis, which is caused by desmoplastic reaction, is usually found in invasive ductal carcinoma and may represent the alteration of the tumor microenvironment preceding tumor invasion. Thus, the dense fibrotic zone around invasive ductal carcinoma can be considered to be the actual tissue site of tumor microenvironment, where the precedent alterations for tumor invasion occur. To characterize the dense fibrotic zone, we classified invasive ductal carcinoma tissue into a tumor zone, a normal zone, and the novel interface zone (IZ), which shows dense fibrosis.
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        • Proteasome Inhibitors Induce p53-Independent Apoptosis in Human Cancer Cells
          The American Journal of PathologyVol. 178Issue 1
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            Proteasome inhibitors are used against human cancer, but their mechanisms of action are not entirely understood. For example, the role of the tumor suppressor p53 is controversial. We reevaluated the role of p53 in proteasome inhibitor-induced apoptosis by using isogenic human cancer cell lines with different p53 status. We found that well-known proteasome inhibitors such as MG132 and bortezomib, as well as the recently discovered proteasome inhibitor thiostrepton, induced p53-independent apoptosis in human cancer cell lines that correlated with p53-independent induction of proapoptotic Noxa but not Puma protein.
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