Volume 18 Issue 1, January 2012

In September, Ronald DePinho became the new president of the MD Anderson Cancer Center at the University of Texas in Houston. He arrived there after 14 years at the Dana-Farber Cancer Institute in Boston. Rebecca Hersher spoke with him about his decision to go to the Lone Star State and the current status of the cancer field.

Each year, around 100,000 people worldwide receive solid organ transplants, and from the day of their surgery to the day they die almost all of them have to take daily immunosuppressant drugs to prevent the body from attacking the new organ. But an experimental procedure in which patients receive some of the donor's bone marrow in addition to the organ hopes to eliminate the need for lifelong drug therapy. Elie Dolgin talks to the scientists who are rejecting the idea of transplantation as usual.

In the US, science has increasingly taken a backstage to politics in policy decisions. But as the country enters the presidential primary season this month, one of the most counterintuitive but effective ways for researchers to make a difference may be to join the GOP.

The beneficial cytoprotective effects of heme oxygenase-1 (HO-1) in malaria infection are counterpoised by higher susceptibility to nontyphoidal Salmonella (NTS) bacteremia. A new study in mice co-infected with malaria and Salmonella provides a mechanism for the long-recognized association between malaria and NTS infection in African children.

A new study in mice shows that platelet-derived growth factor-B (PDGF-B) boosts tumor growth by exerting a double function after induction of erythropoietin (EPO) expression from stromal components—a proangiogeneic response in the endothelium and hematopoietic stimulation (pages 100–110).

The search for compounds to treat neurodegenerative disorders is especially pressing given the rapidly growing elderly human population and has led to the consideration of sirtuin proteins as potential therapeutic candidates. Two studies now report that modulating the expression of the sirtuin Sirt1 has therapeutic benefit in Huntington's disease mouse models and identify putative downstream targets of Sirt1 involved in improved disease outcomes (pages 159–165 and 153–158).

Collapsing glomerulopathy, the classic kidney lesion in HIV-associated nephropathy, is characterized by the closure of glomerular capillary loops and epithelial cell proliferation. A new study shows that upregulation of TERT, the reverse transcriptase component of telomerase, in podocytes, the key filtration cells in the kidney, plays a major part in the development of this condition by activating Wnt signaling (pages 111–119).

Cancer cells thrive owing to different means of survival and proliferation. But despite growing understanding of the biology of cancer and the mechanism of tumorigenesis, complete knowledge of what causes cancer is still lacking. There are multiple hypotheses as to what drives cells to become malignant. One of them is the Warburg effect, which supports that an increase in glycolysis over oxidative respiration, even in the presence of oxygen, may be the cause of cancer. But this premise has not yet been confirmed. In 'Bench to Bedside', Michael Ohh peruses a recent study showing a common mutation in people with renal cell carcinoma and melanoma that may rekindle the debate as to whether a metabolic switch is a major driver in cancer and whether it has potential as a therapeutic target. Every so often, an 'old' drug seems to work for a condition that was not previously known. Two recent human studies show that aspirin can prevent colorectal cancer in people genetically predisposed to this disease after several years after treatment. In 'Bedside to Bench', Patrick Maxwell discusses the possible mechanisms of action of aspirin in decreasing the risk of developing colorectal cancer.

Autoimmune diseases have a complex etiology and despite great progress having been made in our comprehension of these disorders, there has been limited success in the development of approved medications based on these insights. Development of drugs and strategies for application in translational research and medicine are hampered by an inadequate molecular definition of the human autoimmune phenotype and the organizational models that are necessary to clarify this definition.

Great strides have been made in our understanding of the pathogenesis of autoimmune diseases. Research has identified genetic associations, new functional subsets of effector and regulatory T cells and the gut microbiota as crucial environmental factors in regulating immune function. This commentary discusses recent advances in our understanding of genetic and environmental factors as well as the role of innate and adaptive immune responses in driving immune-mediated tissue injury.

Translational research in autoimmunity is hampered by a number of hurdles, including a lack of knowledge regarding initiating and pathologically relevant autoantigens, the low frequency of autoreactive pathogenic B and T cells, difficulty in accessing the affected tissue, differences between self-reactive and pathogen-specific lymphocytes, a lack of etiologically relevant preclinical animal models and the heterogeneity of disease presentation. Given the need for biomarkers and new therapeutics, it is imperative that these hurdles be surmounted.

Recent progress has revealed the molecular basis of how self-reactive T cells are normally generated in the immune system and differentiate into autoimmune effector T cells and how they are controlled by central and peripheral mechanisms of self-tolerance. There is also evidence that target tissues and cells in autoimmune disease have different sensitivities to immune mediators. Here we describe how these basic findings can be clinically translated to re-establish self-tolerance in individuals with autoimmune disease.

There are multiple immune-based therapeutics available for some of the most prevalent autoimmune diseases, but for others, there are few or no approved immune therapies. This dichotomy poses discrete challenges. First, for diseases in which multiple therapy choices exist, a rational decision tree is required to select the best therapy. Second, we must devise new strategies for the autoimmune diseases that have the highest unmet clinical need. This commentary outlines new strategies for designing more efficient and selective approaches for immune therapy of autoimmune diseases.

Animal models are indispensable for studying disease pathogenesis and discovering new treatments for human organ-specific autoimmune diseases. However, there is a need of more refined paradigms for these models. Ideally, a small-animal model should represent the clinical features of human disease in their entirety. Disease in the animals should develop spontaneously, should be followed over an extended period of time and should involve the genetic, molecular and cellular elements that contribute to human pathogenesis.

Congenital disorder of glycosylation-Ia in humans is a multisystemic disease marked by severe neurological deficits and results from deficient glycoprotein processing during development. Christian Körner and his colleagues now show that orally supplying mannose to pregnant dams in a mouse model of the disease is sufficient to ameliorate disease symptoms and early lethality, suggesting a possible therapy to treat this devastating condition.

The authors identify a set of microRNAs regulated by EGFR and MET that are involved in the oncogenic signaling exerted by these receptors and also modulate the response of tumors to targeted EGFR inhibition. These results shed light on the known contribution of MET to therapy resistance and suggest that MET-regulated microRNAs can be key mediators of its effects and potential markers of clinical utility.

This report uncovers a role for the mRNA binding factor CPEB4 in cancer. CEPB4 is upregulated in human pancreatic adenocarcinomas and glioblastomas, where it supports tumor growth by providing translational activation of normally silent mRNAs, including tPA, an important contributor to malignancy. The findings illustrate that altered post-transcriptional regulation of gene expression may be an important contributing factor to cancer.

The authors find a reciprocal negative regulation loop between TCTP and P53. TCTP modulates P53 by competing with NUMB for MDM2 binding and increasing MDM2-mediated degradation of P53. This is reciprocated by p53's direct transcriptional repression of TCTP. Some human breast tumors have increased amounts of TCTP, which only in some cases correlateswith decreased P53 activity, and elevated TCTP is associated with poor prognosis and may influence P53-regulated stemness of tumor cells.

The cytokine PDGF has multiple effects on the vasculature and influences tumor growth and progression. Yuan Xue et al. uncover a new role for PDGF as a regulator of hematopoiesis and provide a unifying mechanism by which PDGF induction of the cytokine erythropoietin in stromal cells underlies PDGF's effects on both hematopoiesis and the tumor vasculature.

Steven Artandi and his colleagues have found that dedifferentiation and proliferation of kidney podocytes as a result of TERT or Wnt signaling leads to a collapsing glomerulopathy phenotype in mice, similar to that seen in HIV-associated nephropathy (HIVAN) in humans, and that inhibiting these pathways corrected disease progression. They also found that TERT expression and Wnt activity is elevated in a mouse model of HIVAN and in human HIVAN renal samples, suggesting possible targets to treat this disease.

Salmonella infection is a common complication in people with malaria. Here the authors show that induction of heme oxygenase-1, a mechanism of tolerance to malaria, impairs resistance to Salmonella infection by limiting production of bactericidal reactive oxygen species.

Sepsis is associated with a hyperinduction of proinflammatory cytokines. ATF3, a transcription factor, is induced in macrophages under conditions of endotoxic shock and downregulates expression of cytokines, including interleukin-6 (IL-6). Although ATF3 may thereby mitigate the severity of sepsis, Hoetzenecker et al. now show that endotoxin-induced ATF3 increases the susceptibility of mice to secondary pathogenic infections due to suppression of IL-6. Their findings suggest that temporal modulation of ATF3 may be important for the successful resolution of sepsis and the ensuing sepsis-associated immunosuppression.

Graft-versus-host disease (GVHD) can be a life-threatening complication of bone marrow transplantation (BMT). Understanding the mechanisms causing GVHD is important to developing treatments or preventive therapies. In this issue, Koyama et al. report the surprising finding that recipient nonhematopoietic antigen-presenting cells, rather than dendritic cells, are the crucial factor in inducing CD4⁺ T cell–dependent GVHD and death in mice.

By immunizing mice with a small synthetic metal-baring complex mimicking the active site of matrix metalloproteinases (MMPs), the authors have generated antibodies that bind and inhibit activated MMP2 and MMP9 in a manner analogous to the mechanism of action of tissue inhibitors of metalloproteinases. Targeting the active conformation of these MMPs is therapeutically effective in mouse models of inflammatory bowel disease.

A major issue in the clinic is excessive, or hypertrophic, scarring of the skin after injury. Geoffrey Gurtner and his colleagues have now shown that mechanical forces during such injury upregulates focal adhesion kinase (FAK), which in turn leads to the release of a cytokine that promotes inflammation and fibrosis. They also show that genetic deletion of FAK or its pharmacological inhibition results in minimal scarring in a mouse model.

Huntington's disease is a neurodegenerative disease caused by the accumulation of mutant htt protein. Now, two groups led by Dimitri Krainc and Wenzhen Duan report that mutant htt binds and inactivates the deacetylase enzyme SIRT1 and that SIRT1 overexpression is protective in Huntington's disease mouse models.

Huntington's disease is a neurodegenerative disease caused by the accumulation of mutant HTT protein. Now, two groups led by Dimitri Krainc and Wenzhen Duan report that mutant HTT binds and inactivates the deacetylase enzyme SIRT1 and that SIRT1 overexpression is protective in Huntington's disease mouse models.

Ali Ertürk and colleagues present a novel tetrahydrofuran-based histological tissue clearing procedure that renders fixed and unsectioned adult CNS tissue (spinal cord and brainstem) transparent and, as such, fully amenable to a range of different optical imaging techniques. This three-dimensional imaging method can be used for studying axon regeneration and glial reactions.

New methods for analyzing ligand-receptor binding under physiologic conditions in cell-based assays and living animals are much needed for the testing and validation of candidate therapeutic agents targeting ligand-receptor binding. Here, Kathryn Luker and her colleagues developed a molecular imaging assay for ligand-receptor binding based on Gaussia luciferase complementation, focusing on chemokine CXCL12 and its chemokine receptors CXCR4 and CXCR7, although the assay could be applied more broadly to any receptor with a protein ligand.