New Signaling Pathway Linked to Breast Cancer Metastasis
Lymph nodes help to fight off infections by producing immune cells and filtering foreign materials from the body, such as bacteria or cancer cells. Thus, one of the first places that cancer cells are found when they leave the primary tumor is in the lymph nodes. The spread of cancer cells to the lymph nodes, lymphatic metastasis, is known to indicate a poor prognosis in many types of cancers; how tumor cells reach the lymph nodes, however, is not well understood. A new study by Dr. Heide Ford and colleagues at the University of Colorado School of Medicine in Aurora reveals a mechanism underlying this process in breast cancer. Using mouse models, their team found that a protein called SIX1 is a critical player in early stage metastasis, especially lymphatic metastasis. Their study showed that SIX1 induced expression of another protein called VEGF-C, which stimulated the formation of new lymphatic vessels within and near the primary tumor and lymphatic invasion. Strongly supporting a role in human breast cancer, they also showed that the expression of both proteins was correlated in human breast tumors. Their work has identified the SIX1-VEGF-C pathway as an important signaling pathway involved in breast cancer metastasis, and the targeting of this pathway could lead to new anti-cancer treatments
SIX1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer
University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA
Phone: 303-724-3509; Fax: 303-724-3512; E-mail: email@example.com
View this article at: http://www.jci.org/articles/view/59858?key=fc2b3e863de2c90952d2
Linking obesity and high cholesterol
Obese patients are at increased risk for cardiovascular disease and a hardening of blood vessel walls called atherosclerosis. One factor that drives atherosclerosis development in obesity is abnormal blood cholesterol levels. ApoB is the major lipid-binding protein that transports low density lipoprotein (LDL cholesterol) and very low density lipoprotein (VLDL cholesterol) from the liver to blood. Alan Tall of Columbia University and colleagues wanted to better understand the genes that are associated with altered levels of LDL and VLDL cholesterol in an obese mouse model system. The research team discovered that a gene call sortilin-1 was inhibited in obese mice. This inhibition caused an increase in apoB secretion and high cholesterol. Accordingly, restoring sortilin-1 levels in the obese mouse model reduced apoB levels. They went on to show that sortillin-1 levels are controlled by activity of the mTOR signaling pathway, and that rapamycin, a well-known drug that inhibits mTOR, caused an increase in liver levels of sortilin-1 and decreased apoB secretion. Their results link obesity and mTOR signaling, and demonstrate how cholesterol secretion is altered due to obesity.
Activation of ER stress and mTORC1 suppresses hepatic sortilin-1 levels in obese mice
Columbia University Medical Center, new york, NY, USA
Phone: 212-305-5789; E-mail: firstname.lastname@example.org
View this article at: http://www.jci.org/articles/view/61248?key=7c1665cd52d43320f206
Insights into the progression of colon carcinogenesis | Back to top
The WNT signaling pathway is critical for the control of cell proliferation and differentiation. Altered WNT signaling is frequently associated with colon cancer development. Activation of WNT signaling is dependent upon transcriptional activation mediated by β-catenin. Researchers at the National Taiwan University College of Medicine sought to better understand how β-catenin activates transcription and mediates aberrant cell division in colon cancer. Led by Dr. Tzuu-Shuh Jou, the team uncovered a role for a β-catenin-associated protein known as EBP50 in the initiation of uncontrolled cell growth. Dr. Jou and colleagues found that EBP50 protein is localizes to the nucleus of cells from colorectal carcinoma specimens, but not in normal cells. This nuclear EBP50 enhanced the WNT/β-catenin signaling events, which led to the transcription of downstream growth promoting genes such as c-MYC and cyclin D1. Moreover, depletion of EBP50 in colonic cancer cells significantly reduced cell divisions and tumorigenesis in mice. This demonstrates the importance of EBP50 in conferring a growth advantage to colon cancer cells through WNT signaling and presents EBP50 as an attractive target to halt the progression of colon carcinogenesis
Aberrant nuclear localization of EBP50 promotes colorectal carcinogenesis in xenotransplanted mice by modulating TCF-1 and β-catenin interactions
Department of Internal Medicine, National Taiwan University Hospital, Taipei, , TWN
Phone: 8862-23123456 ext.67625; Fax: 8862-23709820; E-mail: email@example.com
View this article at: http://www.jci.org/articles/view/45661?key=1acc81fc56e1cb0c96bb
Also in this issue
Critical Function of MyD88 in Immune Tolerance Breakdown in Murine Foxp3 Deficiency | Back to top
The breakdown of peripheral tolerance upon Regulatory T (TR) cell deficiency due to mutations in Foxp3 precipitates a multi-system autoimmune inflammatory disease. The role of the microbial signals in disease pathogenesis was examined in Foxp3 mutant mice that had concurrent deficiencies in Toll-like receptor (TLR) pathways. Deficiency of the common TLR adaptor MyD88, but not more restricted defects, dissociated the disease into a MyD88-dependent component at the environmental boundaries in the skin, lungs and gut, and a MyD88-independent systemic lymphoproliferation. This effect involved the disruption of chemokine gradients that recruit T effector and dendritic cells to target interface tissues. Thus a key role of TR cells is to maintain tolerance at host-microbial interfaces by restraining tonic MyD88-dependent pro-inflammatory signals.
MyD88 is critically involved in immune tolerance breakdown at environmental interfaces of Foxp3-deficient mice
Children's Hospital Boston, Harvard Medical School, Boston, MA, USA
Phone: 617-9192483; Fax: 617-7300528; E-mail: firstname.lastname@example.org
View this article at: http://www.jci.org/articles/view/40591?key=047b407fa466953ed373
Mechanism of lipopolysaccharide-induced skin edema formation in the mouse | Back to top
Prostaglandin E2 (PGE2) regulates many proinflammatory processes, including swelling and pain. Here we show that tissue resident dendritic cells (DCs) are the main source of PGE2 and the main controllers of tissue edema formation in a model of lipopolysaccharide (LPS)-induced inflammation. Mechanistically, PGE2 production by DCs following LPS exposure is controlled by CD14/NFAT pathway, which regulates the expression of the microsomal PGE synthase-1 (mPGES-1), a key enzyme in the PGE2 biosynthesis. Therefore, tissue edema formation induced by LPS is DCs- and CD14/NFAT-dependent. Moreover, by controlling the transudate formation in the presence of LPS, DCs can regulate free antigen arrival to draining lymph nodes.
CD14 and NFAT mediate lipopolysaccharide-induced skin edema formation in mice
University of Milano-Bicocca, Milan, , ITA
Phone: 390264483553; E-mail: email@example.com
View this article at: http://www.jci.org/articles/view/60688?key=690bae7dd09d029af162
Anti-ceramide Antibody Prevents The Radiation GI Syndrome in Mice | Back to top
The Radiation Gastrointestinal (GI) Syndrome is a major lethal toxicity that might occur after a radiation/nuclear incident. There are no prophylactic countermeasures against Radiation GI Syndrome lethality for first responders, military personnel or remediation workers entering a contaminated area. Pathophysiology of this syndrome requires depletion of stem cell clonogens (SCCs) within the Crypts of Lieberkühn, necessary for post-injury regeneration of gut epithelium. Recent evidence indicates SCC reproductive death is not exclusively a result of DNA damage, but is critically coupled to ceramide-induced endothelial cell apoptosis within the mucosal microvascular network. Here we show that ceramide generated on the surface of endothelium coalesces to form ceramide-rich platforms that transmit an apoptotic signal. We report generation of 2A2 anti-ceramide monoclonal Ab, a countermeasure that binds ceramide to prevent platform formation on the surface of irradiated endothelial cells of the murine GI tract. Consequently, 2A2 protects against endothelial apoptosis in the small intestinal lamina propria and facilitates recovery of crypt SCCs, preventing death of mice from the GI Syndrome at high radiation doses, up to 17 Gy. As such, 2A2 represents a prototype of a new class of anti-ceramide therapeutics and an effective countermeasure against Radiation GI Syndrome mortality.
Anti-ceramide Antibody Prevents The Radiation GI Syndrome in Mice
Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Phone: 646-888-2174; Fax: 646-422-0281; E-mail: firstname.lastname@example.org
View this article at: http://www.jci.org/articles/view/59920?key=1372fbfe9f90f79d09c5
Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination | Back to top
Spontaneous gene repair, also called revertant mosaicism, has been documented in several genetic disorders involving organs that undergo self-regeneration, including the skin. Genetic reversion may occur through different mechanisms, and in one individual the mutation can be repaired in various ways. Here we describe a disseminated pattern of revertant mosaicism observed in six patients with Kindler syndrome (KS), a genodermatosis caused by loss of kindlin-1 and clinically characterized by patchy skin pigmentation and atrophy. All patients presented duplication mutations (c.456dupA and c.676dupC) in the FERMT1 gene encoding kindlin-1, and slipped mispairing in direct nucleotide repeats was identified as the reversion mechanism in all investigated revertant skin spots. The sequence around the mutations demonstrated high propensity to mutations, favoring both microinsertions and –deletions. Additionally, in some revertant patches mitotic recombination generated areas with homozygous normal keratinocytes. Restoration of kindlin-1 expression led to clinically and structurally normal skin. Since loss of kindlin-1 severely impairs keratinocyte proliferation, we predict that revertant cells have a selective advantage that allows their clonal expansion and, consequently, the improvement of the skin condition.
Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination
University Medical Center Freiburg, Freiburg, , DEU
Phone: 0049-076127067100; E-mail: email@example.com
View this article at: http://www.jci.org/articles/view/61976?key=3b0f274fc1938461dd73
Hepatocyte-specific mutation of both NF-κB RelA and STAT3 abrogates the acute phase response in mice | Back to top
The acute phase response is an evolutionarily conserved reaction in which physiological stress triggers the liver to remodel the blood proteome. It is stimulated by diverse cytokines that activate either NF-κB or STAT3, leading us to hypothesize that the acute phase response could be eliminated by interrupting both transcription factors selectively in hepatocytes. The combined mutation of NF-κB p65 (RelA) and STAT3 together, but neither alone, abrogated all acute phase responses measured. This failure to respond was consistent across multiple different infectious, inflammatory, and noxious stimuli. Pneumococcal pneumonia altered the expression of >1100 transcripts in the liver, and this outcome was >96% inhibited by the combined mutation of RelA and STAT3. This interruption of liver responses increased mortality and exacerbated bacterial dissemination during pneumonia, possibly due to an acute humoral enhancement of opsonophagocytosis that was impaired in hepatocyte-mutant mice. Thus, a critical role of the acute phase response is to compartmentalize local infection. We conclude that RelA and STAT3 are essential for stress-induced transcriptional remodeling in the liver, and their hepatocyte-specific mutation reveals functional roles of the acute phase response.
Hepatocyte-specific mutation of both NF-κB RelA and STAT3 abrogates the acute phase response in mice
Boston University School of Medicine, Boston, , USA
Phone: 617-638-6125; E-mail: firstname.lastname@example.org
View this article at: http://www.jci.org/articles/view/59408?key=d1f1b014af15f850b079
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