Chronic myeloid leukemia blood cells.
Enzyme Accelerates Malignant Stem Cell Cloning in Chronic Myeloid Leukemia
An international team, headed by researchers at the University of California, San Diego School of Medicine, has identified a key enzyme in the reprogramming process that promotes malignant stem cell cloning and the growth of chronic myeloid leukemia (CML), a cancer of the blood and marrow that experts say is increasing in prevalence.
The findings are published in the Dec. 24 online early edition of the Proceedings of the National Academy of Sciences (PNAS).
Despite the emergence of new therapies, such as tyrosine kinase inhibitors, CML and other leukemias remain problematic because some cancer stem cells avoid destruction and eventually regenerate themselves, a stem cell process known as self-renewal that can result in a return and spread (metastasis) of the disease.
In the PNAS paper, principal investigator Catriona H. M. Jamieson, MD, PhD, associate professor of medicine at UC San Diego, with colleagues in the United States, Canada and Italy, report that inflammation – long associated with the development of cancer – boosts activity of an enzyme called adenosine deaminase or ADAR1.
Expressed during embryogenesis to help blood cell development, ADAR1 subsequently turns off and is triggered by viral infections where it protects normal hematopoietic stem cells from attack. In leukemia stem cells, however, overexpression of ADAR1 enhances the missplicing of RNA, which leads to greater self-renewal and therapeutic resistance of malignant stem cells.
The findings build upon previous studies by Jamieson and others that elucidate the effects of RNA missplicing and instability. “People normally think about DNA instability in cancer, but in this case, it’s how the RNA is edited by enzymes that really matters in terms of cancer stem cell generation and resistance to conventional therapy.”
The described RNA editing process, which occurs in the context of human and other primate specific sequences, also underscores the importance of addressing inflammation as “an essential driver of cancer relapse and therapeutic resistance,” Jamieson said. It also presents a new target for future therapies.
“ADAR1 is an enzyme that we may be able to specifically target with a small molecule inhibitor, an approach we have already used effectively with other inhibitors,” said Jamieson. “If we can block the capacity of leukemia stem cells to use ADAR1, if we can knock down that pathway, maybe we can put stem cells back on the right track and stop malignant cloning.”
CML is a cancer initiated by a mutant gene called BCR-ABL in blood forming stem cells that leads to an expansion of white blood cells and their precursors. It is typically slow-growing and often not diagnosed until its later stages when there can be a sudden, dramatic increase in malignant cells, known as blast crisis. Median age of diagnosis is 66 years; incidence of the disease increases with age. Despite tremendous advances in BCR-ABL tyrosine kinase inhibitor therapies, the majority of patients relapse if therapy is discontinued, in part as a result of dormant cancer stem cell resistance. This work suggests a novel mechanism for overcoming cancer stem cell resistance to therapy that may prevent relapse and progression.
The estimated prevalence of CML in the United States is 70,000 persons with the disease, projected to steadily increase to approximately 181,000 by 2050. CML is initiated by the mutant BCR-ABL gene, but scientists have not yet identified the cause of the mutation.
Blocking Tumor-Induced Inflammation Impacts Cancer Development
How tumors exploit microflora and immune cells to fuel growth
Researchers at the University of California, San Diego School of Medicine report the discovery of microbial–dependent mechanisms through which some cancers mount an inflammatory response that fuels their development and growth.
The findings are published in the October 3, 2012 Advanced Online Edition of Nature.
The association between chronic inflammation and tumor development has long been known from the early work of German pathologist Rudolph Virchow. Harvard University pathologist Harold Dvorak later compared tumors with “wounds that never heal,” noting the similarities between normal inflammation processes that characterize wound- healing and tumorigenesis or tumor-formation.
Indeed, 15 to 20 percent of all cancers are preceded by chronic inflammation – a persistent immune response that can target both diseased and healthy tissues. Chronic hepatitis, for example, may result in hepatocellular carcinoma (liver cancer) and inflammatory bowel disease can eventually cause a form of colon cancer, known as colitis-associated cancer.
Still, most cancers are not preceded by chronic inflammation. On the other hand, they exploit ubiquitous, infiltrating immune cells to unduly provoke and hijack the host inflammatory reaction. Until now, the mechanism of so-called “tumor-elicited inflammation,” which is detected in most solid malignancies, was poorly explained.
“The tumor-associated inflammatory reaction is an emerging and vibrant field for biomedical studies. It may hold the keys for future preventive and therapeutic measures,” said first author Sergei Grivennikov, PhD, noting that studies of long-term users of non-steroidal anti-inflammatory drugs, such as aspirin, have revealed that general inhibition of inflammation reduces the risk of cancer death by up to 45 percent, depending on the type of cancer. “So inhibition of inflammation during cancer development may be beneficial.”
Studying early colonic tumors in humans and in animal models, the researchers, led by principal investigator Michael Karin, PhD, Distinguished Professor of Pharmacology and head of the Laboratory of Gene Regulation and Signal Transduction at UC San Diego, found that developing tumors disrupt tissue homeostasis (the normal, healthy functioning of tissues), in part because they lack a particular protective protein coating and a tight seal between their epithelial cells – a basic cell type that covers most internal surfaces and organs. Without that coating and the cellular seal, ordinarily benign, commensal bacteria present in the colon can enter the tumor to be recognized by immune cells as invaders, launching an inflammatory reaction.
In addition, said Grivennikov, who is a scientist in Karin’s lab, “cell-to-cell contacts are defective in tumors, further allowing entry of microbial products from the intestinal lumen into the tumor. These microbial products are recognized by tumor-associated macrophages and dendritic cells, which are normally isolated from commensal microflora by the intestinal barrier.”
In response, the immune cells produce signaling proteins called cytokines that further spur the inflammatory process. Chief among these is a cytokine called Interleukin-23, which regulates tumor-elicited inflammation and triggers the production of other inflammatory cytokines that promote tumor development and progression.
Grivennikov said that when researchers reduced the presence of commensal microflora through a combination of broad spectrum antibiotics, tumor-elicited inflammation and tumor growth were dampened.
“This is a very nice demonstration of how tumor-elicited inflammation in cancers that arise in the absence of underlying chronic inflammatory disease can be induced,” he said. “The next step is to look for the upregulation of Interleukin-23 and related cytokines in colon cancer patients, inhibit these cytokines and determine whether these impact cancer progression and response to therapy.”
“The Varki Five”
In the August 17, 2012 issue of the Journal of Biological Chemistry, Ajit Varki, MD, professor of medicine and cellular and molecular medicine, and colleagues publish a series of papers describing their latest work on the biology of sialic acids – sugar molecules found on the surfaces of all animal cells that serve as vital, interactive contact points with other molecules and cells, in many biological processes.
In recent years, Varki and his group have elaborated on the increasingly important roles of sialic acids in human biology and evolution. You can read about some of that earlier work here, hear, here, and here.
The latest research arose from the Varki group’s interest in a form of non-human sialic acid that finds its way into humans from eating red meats, triggers inflammation, and can increase the risk of cancers, heart attacks and other diseases.
The scientific significance of the latest papers goes far beyond the connection between red meat and cancer risk, however. While exploring this question, the researchers uncovered a completely unexpected and previously unknown set of biochemical pathways involving the impact of a single oxygen atom addition to various classes of sugar chains. Like much basic research of this kind, the work opens up new questions and opportunities for the future, ranging from immune diseases to brain plasticity.
What’s also notable is the sheer abundance of the most recent work. Varki, his co-authors at UC San Diego’s School of Medicine and collaborators at multiple institutions (notably David Vocadlo at Simon Fraser University in Canada) have published related but distinct papers back-to-back-to-back-to-back-to-back, spanning 80 pages, all in a single JBC issue. They did so, in part, to strike a contrast to a recent trend in scientific publishing: the overarching desire by most researchers to publish single short papers in a certain more popular journals.
To be sure, some of these journals are distinguished publications, and their contents frequently grab headlines around the world. But JBC is among the world’s esteemed peer-reviewed scientific journals as well. It has published countless seminal and Nobel-prize winning papers over its 107-year history.
A key for Varki and his fellow authors was the fact that JBC had no page limitations, allowing them to publish more complete and detailed studies that can more easily be reproduced by others in the future.
Plus, putting all five papers in a single journal issue gives the research a certain critical mass, Varki said, and draws even more attention to the findings. Indeed, since the papers were first posted online in June, they’ve become known in some quarters as the “Varki Five.”
A photomicrograph of superficial keratinocytes or skin cells. Image courtesy of Thomas Deerinck, National Center for Microscopy and Imaging Research, UC San Diego.
What Happens When We Sunburn
Researchers describe inflammatory mechanism for first time
The biological mechanism of sunburn – the reddish, painful, protective immune response from ultraviolet (UV) radiation – is a consequence of RNA damage to skin cells, report researchers at the University of California, San Diego School of Medicine and elsewhere in the July 8, 2012 Advance Online Publication of Nature Medicine.
The findings open the way to perhaps eventually blocking the inflammatory process, the scientists said, and have implications for a range of medical conditions and treatments.
“For example, diseases like psoriasis are treated by UV light, but a big side effect is that this treatment increases the risk of skin cancer,” said principal investigator Richard L. Gallo, MD, PhD, professor of medicine at UC San Diego School of Medicine and Veterans Affairs San Diego Healthcare System. “Our discovery suggests a way to get the beneficial effects of UV therapy without actually exposing our patients to the harmful UV light. Also, some people have excess sensitivity to UV light, patients with lupus, for example. We are exploring if we can help them by blocking the pathway we discovered.”
Using both human skin cells and a mouse model, Gallo, first author Jamie J. Bernard, a post-doctoral researcher, and colleagues found that UVB radiation fractures and tangles elements of non-coding micro-RNA – a special type of RNA inside the cell that does not directly make proteins. Irradiated cells release this altered RNA, provoking healthy, neighboring cells to start a process that results in an inflammatory response intended to remove sun-damaged cells.
We see and feel the process as sunburn.
Age-related macular degeneration (AMD) gradually destroys sharp, central vision. It is the most common cause of blindness among the elderly. There are two forms: dry AMD and the typically more severe and faster-acting wet AMD. In dry AMD, light-sensitive cells in the center of the retina slowly break down, obscuring central vision. In wet AMD, abnormal blood vessels grow under the retina, leak and disrupt vision. In this image, drusen – yellowish deposits of cellular debris – accumulate in a case of dry AMD.
Immune Mechanism Blocks Inflammation Generated by Oxidative Stress
Potential therapeutic target for treating disorders like age-related macular degeneration
Conditions like atherosclerosis and age-related macular degeneration (AMD) – the most common cause of blindness among the elderly in western societies – are strongly linked to increased oxidative stress, the process in which proteins, lipids and DNA damaged by oxygen free radicals and related cellular waste accumulate, prompting an inflammatory response from the body’s innate immune system that results in chronic disease.
In the October 6, 2011 issue of Nature, researchers at the University of California, San Diego School of Medicine, as part of an international collaborative effort, identify a key protein that binds to a molecule generated by oxidative stress, blocking any subsequent inflammatory immune response. The scientists, led by senior author Christoph J. Binder, assistant adjunct professor of medicine at UC San Diego, principal investigator at the Center for Molecular Medicine of the Austrian Academy of Sciences and professor at the Medical University of Vienna, say their findings reveal important insights into how the innate immune system responds to oxidative stress and might be exploited to prevent and treat AMD and other chronic inflammatory diseases.
Tumors are characterized by extensive inflammatory infiltrates, which can comprise up to 25 percent of the tumor’s mass. Myeloid cells invade tumors in response to diverse inflammatory stimuli produced by the tumor. Invading myeloid cells differentiate into a type of macrophage that promotes tumor angiogenesis, growth and metastasis and inhibits anti-tumor immunity. In the June 14 issue of Cancer Cell, Schmid et al. demonstrate that tumor inflammation (myeloid cell invasion of tumors) requires PI3kinase gamma, a gatekeeper enzyme that is primarily expressed by myeloid cells. Inhibitors of PI3kinase gamma strongly inhibit tumor inflammation, growth and metastasis for a wide variety of cancers. PI3kinase gamma inhibitors hold promise as a new class of general cancer therapeutic agents.