JCI early table of contents for April 9, 2012

April 9th, 2012
EDITOR'S PICK

Moving toward a better treatment for autoimmune diabetes

Insulin is required for the regulation of blood sugar levels. In type I diabetes, the cells that produce insulin are destroyed by the immune system. Chantal Mathieu and colleagues at the University of Leuven have attempted to circumvent this response by taking advantage of the fact that the immune system accepts foreign gut bacteria. The Mathieu group engineered gut bacteria so that they produce a form of insulin, and asked if these bacteria could retrain the immune system in mice with type I diabetes to accept insulin-producing cells. They found that these special bacteria increased the frequency of cured mice when compared to traditional methods alone, with seemingly no undesirable effects. Traditional methods suppress the immune system, which brings with it unfavorable consequences such as increased infections. In fact the Mathieu group confirmed that the immune system functioned in the mice following treatment. Their study provides a promising step towards the ability to reverse type I diabetes, as well as other autoimmune disorders, without incurring adverse side effects.

TITLE:
Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice

AUTHOR CONTACT:
Chantal Mathieu
Katholieke Universiteit Leuven, Leuven, , BEL
Phone: 32 (16) 346023; Fax: 32 (16) 330718; E-mail: chantal.mathieu@uzleuven.be


ONCOLOGY

Harnessing the power of angiogenesis inhibitors

The development of new blood vessels, known as angiogenesis, is critical for processes such as wound healing, but is exploited by tumors to enable more robust growth. Therapeutics targeting tumor angiogenesis have long been heralded as one of the most promising strategies for limiting a tumor's nutrient supply and eventually shrinking it. However, several recent preclinical trials have demonstrated that blocking angiogenesis in tumors can actually enhance invasion and metastasis. As tumor cells become hypoxic, signaling pathways are activated that increase malignancy. Further, the lack of blood supply can keep chemotherapeutic drugs from reaching the tumor, while a hypoxic environment decreases the effectiveness of radiotherapy.

A recent study published in the Journal of Clinical Investigation demonstrates that the normalization of tumor vasculature blocks the pro-metastatic and pro-invasive effects of angiogenesis inhibitors. Using mice that develop spontaneous pancreatic neuroendocrine tumors or cervical carcinomas, Dr. Enrico Giraudo and colleagues at the University of Torino in Torino, Italy administered the protein Semaphorin A3, an endogenous angiogenesis inhibitor, alone or in combination with the receptor tyrosine kinase inhibitor Sunitinib or the VEGF inhibitor DC101. Mice treated with Semaphorin A3 had smaller, more highly oxygenated tumors that were significantly less invasive and metastatic. Molecular analysis showed Semaphorin A3 blocked activation of the hypoxia-activated pathways that allow cancer cells to evade chemotherapy. These findings demonstrate that vascular normalization prevents the dangerous side effects of angiogenesis inhibitors and enhances their anti-tumor effects.

TITLE:
Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by anti-angiogenic treatment in mice

AUTHOR CONTACT:
Enrico Giraudo
University of Torino School of Medicine, Candiolo, UNK, ITA
Phone: +390119933505; Fax: +390119933524; E-mail: enrico.giraudo@ircc.it


ONCOLOGY

Cancer-causing genes cooperate to initiate tumors

Cancer is not caused by a single mutation, but rather is the result of multiple gene alterations that ultimately transform cells and causes malignant growth. Elevated levels of genes that promote tumor growth, known as oncogenes, have been previously shown to regulate a set of 'cooperation response genes' that synergistically contribute to the development of cancer. However, whether co-regulation of multiple cancer genes is a generalized step in the process of cancer development is unknown. Dr. Sarki Abdulkadir and his colleagues at Vanderbilt University analyzed the genome-wide binding sites for a prostate tumor suppressor protein known as Nkx3.1. They found a novel interaction between Nkx3.1 and the oncoprotein Myc. They found a significant overlap in genes directly regulated by both Nkx3.1 and Myc relevant to prostate tumorigenesis. Deletion of Nkx3.1 from mouse prostate resulted in epithelial hyperplasia while prostate-specific expression of Myc caused mild pathology. However, deletion of Nkx3.1 and Myc expression together in mouse prostate resulted in development of multi-focal micro-invasive cancer. They suggest dysregulation of multiple Nkx3.1/Myc target genes contribute to this cancer-forming phenotype and propose a model whereby an increase in the Myc/NKX3.1 ratio results in progression of malignant transformation. Their study provides new evidence for cooperation between Myc and Nkx3.1 in prostate carcinogenesis and provides a mechanistic basis for oncogene and tumor suppressor gene cooperation.

TITLE:
Nkx3.1 and Myc crossregulate shared target genes in mouse and human prostate tumorigenesis

AUTHOR CONTACT:
Sarki Abdulkadir
Vanderbilt University Medical Center, Nashville, TN, USA
Phone: 615-322-9668; E-mail: sarki.abdulkadir@vanderbilt.edu


Also in this issue...

NEPHROLOGY

Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model

A common renal complication of multiple myeloma is "myeloma kidney," or cast nephropathy. This lesion is directly related to the production of monoclonal immunoglobulin free light chains (FLC), which co-precipitate with Tamm-Horsfall glycoprotein (THP) in the lumen of the distal nephron. In the present series of studies, analysis of the binding interaction between FLC and THP demonstrated that the secondary structure and key amino acid residues on the Complementarity-Determining Region 3 (CDR3) of FLC were critically important determinants of the molecular interaction with THP. The findings permitted development of a cyclized competitor peptide (AHX-CLSADSSGSYLYVCKK), which demonstrated strong inhibitory capability in the binding of FLC to THP in vitro. When used in a rodent model of cast nephropathy, this cyclized peptide construct served as an effective inhibitor of intraluminal cast formation and prevented the functional manifestations of acute kidney injury in vivo. These experiments provided proof of concept that intraluminal cast formation was integrally involved in the pathogenesis of acute kidney injury from cast nephropathy. Further, the data supported a clinically relevant and novel approach to the management of renal failure in the setting of multiple myeloma.

TITLE:
Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model

AUTHOR CONTACT:
Paul W. Sanders
University of Alabama at Birmingham, Birmingham, AL, USA
Phone: 205 934-3589; Fax: 205 975-6288; E-mail: psanders@uab.edu

ACCOMPANYING COMMENTARY

TITLE:
Treating myeloma cast nephropathy without treating myeloma

AUTHOR CONTACT:
Nelson Leung
Mayo Clinic, Rochester, MN, USA
Phone: 507-266-7083; Fax: ; E-mail: Leung.nelson@mayo.edu


NEPHROLOGY

Development and prevention of acute kidney injury

It took a long time for physicians to realize Bence Jones protein was nephrotoxic. One of the first patients described with multiple myeloma had massive proteinuria without renal damage. It was not until Tamm Horsfall protein (THP) was discovered in the casts that this enigma was fully answered. Using the knowledge, a cyclized competitor protein was synthesized capable of preventing the coprecipitation of free light chains and THP. The discovery represents a novel strategy for the treatment of cast nephropathy.

COMMENTARY TITLE:
Treating myeloma cast nephropathy without treating the myeloma

COMMENTARY AUTHOR CONTACT:
Nelson Leung
Mayo Clinic, Rochester, MN, USA
Phone: 507-266-7083; Fax: ; E-mail: Leung.nelson@mayo.edu

ACCOMPANYING RESEARCH ARTICLE

TITLE:
Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model

RESEARCH AUTHOR CONTACT:
Paul W. Sanders
University of Alabama at Birmingham, Birmingham, AL, USA
Phone: 205 934-3589; Fax: 205 975-6288; E-mail: psanders@uab.edu


HEPATOLOGY

Liver LXRalpha expression is crucial for whole body cholesterol homeostasis and reverse cholesterol transport in mice

Liver X receptors (LXRalpha and LXRbeta) are important regulators of cholesterol and lipid metabolism and their activation has been shown to inhibit cardiovascular disease and reduce atherosclerosis in animal models. These previous studies have stimulated interest in the therapeutic potential of small molecules targeting LXRs; however, the finding that agonists also promote hepatic lipogenesis has led to the idea that hepatic LXR activity is undesirable from a therapeutic perspective. In this report we utilized gene targeting to create the first conditional LXR knockout by selectively deleting LXRalpha in hepatocytes. Liver-specific deletion of LXRalpha substantially decreased reverse cholesterol transport, cholesterol catabolism and excretion, revealing the essential importance of hepatic LXRalpha for whole body cholesterol homeostasis. Additionally, in a pro-atherogenic background liver-specific deletion of LXRalpha significantly increased atherosclerosis, uncovering an important function for hepatic LXR activity in limiting cardiovascular disease. Nevertheless, synthetic LXR agonists still elicited anti-atherogenic activity in the absence of hepatic LXRalpha indicating that the ability of agonists to reduce cardiovascular disease does not require an increase in cholesterol excretion. Furthermore these observations suggest that therapeutic strategies which bypass the liver or limit the activation of hepatic LXRs should still be beneficial for the treatment of cardiovascular disease.

TITLE:
Liver LXRalpha expression is crucial for whole body cholesterol homeostasis and reverse cholesterol transport in mice

AUTHOR CONTACT:
Ira Schulman
University of Virginia, Charlottesville, VA, USA
Phone: 434-924-5682; Fax: 434-982-3878; E-mail: igs4c@virginia.edu


ONCOLOGY

Cooperation between the Rb pathway and Arf in murine retinoblastoma suppression

The pediatric cancer retinoblastoma has served a paradigm for tumor suppressor gene function. Retinoblastoma is initiated by RB gene mutations, but the subsequent cooperating mutational events leading to tumorigenesis are poorly characterized. We explored genomic alterations beyond RB mutation in retinoblastoma using human samples and mouse models. Array-CGH studies revealed Cdkn2a deletions (including Arf and p16Ink4a) in both human and murine retinoblastoma. Through mouse genetic analyses we found that Arf was the critical tumor suppressor gene in the region of deletion. Inactivation of one allele of Arf cooperated with Rb and p107 loss to rapidly accelerate retinoblastoma, with frequent loss of heterozygosity (LOH) at the Arf locus. Arf has been reported to exhibit p53-independent tumor suppressor roles in other systems. However, our results showed no additive effect of p53 and Arf co-inactivation in promoting retinoblastoma. Moreover, p53 inactivation completely eliminated any selection for Arf LOH. Our data reveal important insights into the p53 pathway in retinoblastoma and show that Arf is a key collaborator with Rb in retinoblastoma suppression.

TITLE:
Cooperation between Rb and Arf in suppressing mouse retinoblastoma

AUTHOR CONTACT:
David MacPherson
Carnegie Institution, Baltimore, MD, USA
Phone: 410-246-3084; E-mail: macpherson@ciwemb.edu


ONCOLOGY

Comparing human pancreatic cell secretomes by in vitro aptamer selection identifies cyclophilin B as a candidate pancreatic cancer biomarker

To distinguish between the secretomes of pancreatic cancer and non-cancerous cells, we devised an in vitro positive/negative selection strategy to identify RNA ligands (aptamers) that can detect structural differences between these proteomes. Using this molecular recognition approach, we identified an aptamer (M9-5) that discriminates between the sera of pancreatic cancer patients and healthy volunteers with higher sensitivity and specificity than the best existing serum biomarker for pancreatic cancer. We utilized biochemical purification methods and mass spectrometric analysis to identify the M9-5 target as Cyclophilin B (CypB). As opposed to pure bioinformatics-based approaches, this molecular recognition-based strategy simultaneously identified CypB as a serum biomarker and generated a new reagent to recognize it in body fluids. This aptamer has potential to serve as a tool for the early detection of pancreatic cancer. Moreover, this approach should be generalizable and complementary to traditional approaches that focus on expression levels rather than structural differences between samples.

TITLE:
Comparing human pancreatic cell secretomes by in vitro aptamer selection identifies cyclophilin B as a candidate pancreatic cancer biomarker

AUTHOR CONTACT:
Partha Ray
Duke Univeristy Medical Center, Durham, NC, USA
Phone: 919-684-4864; E-mail: partha.ray@duke.edu

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