Tag: Oncology

People who receive a kidney transplant are nearly four times more likely to develop melanoma, a rare but deadly form of skin cancer, according to a study in the November 1, 2005 issue of CANCER, a peer-reviewed journal of the American Cancer Society. The study indicates that risk increased with time since transplant. Furthermore, risk was highest in men — and with increasing age in men — but was significantly lower in women and blacks.

Of the various types of skin cancer, melanoma is the deadliest, with a mortality rate up to 6 percent in some regions of the world. The classic risk factors for melanoma are ultraviolet radiation, commonly caused by sunburns, a suppressed immune system, and family history of abnormal moles. Studies demonstrate that the immune system plays a critical role in monitoring the body for — and destroying — early cancerous cells, including melanoma.

Patients taking immunosuppressants after organ transplantation would be assumed to be at higher risk for cancers. Studies show that this holds true for nonmelanoma skin cancers but do not agree for melanoma risk. The baseline low incidence of melanoma in the general population may contribute to conflicting data. Low incidence of disease means that more people need to be studied to discern an association. In the largest study to date, Christopher S. Hollenbeak, Ph.D., of Penn State College of Medicine and his colleagues compared melanoma incidence rates from a registry of renal transplant patients (89,786 patients) to general population data.

They found that renal transplant recipients are 3.6 times more likely to develop melanoma than the general population. Risk increases five percent per year after the transplant. Though some melanomas will develop immediately after transplant, risk continues to increase approximately five percent per year from transplant. Melanoma risk is greatest in men and increases rapidly with age. In contrast, while women are at increased risk, too, their risk is significantly lower than men and does not increase with age. Comparison by race shows that blacks are seven-times less likely to develop melanoma than other races. “Kidney transplant patients, who are receiving long-term immunosuppression,” conclude the Dr. Hollenbeak and his colleagues, “have a 3.6-fold increase in the incidence of melanoma when compared to the general population” and should receive regular complete skin examinations.

Science Daily
October 25, 2005

Original web page at Science Daily

Scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg and the Institute of Biomedical Research of the Parc Científic de Barcelona (IRB-PCB) have now added key evidence to claims that some types of cancer originate with defects in stem cells. The study, reported in the on-line edition of Nature Genetics (September 4) shows that if key molecules aren’t placed in the right locations within stem cells before they divide, the result can be deadly tumors.

Cells in the very early embryo are interchangeable and undergo rapid division. Soon, however, they begin differentiating into more specific types, finally becoming specialized cells like neurons, blood, or muscle. As they differentiate, they should stop dividing and usually become embedded in particular tissues. Some tumor cells are more like stem cells because they are identical, they divide quickly, and in the worst case – metastasize – they wander through the body and implant themselves in new tissues. Specialized cells may die through age or injuries, so the body keeps stocks of stem cells on hand to generate replacements. Usually the stem cell divides into two types: one that is just like the parent, which is kept to maintain the stock, and another that differentiates. This is what happens with neuroblasts. Cell division creates one large neuroblast and a smaller cell that can become part of a nerve. This process is controlled by events that happen prior to division. The parent cell becomes asymmetrical: it collects a set of special molecules, including Prospero and other proteins, in the area that will bud off and become the specialized cell.

“This asymmetry provides the new cell with molecules it needs to launch new genetic programs that tell it what to become,” says Cayetano González, whose group began the project at EMBL and has continued the work as they moved to the IRBB-PCB. “The current study investigates what happens when the process of localizing these molecules is disturbed.” Whether Prospero and its partners get to the right place depends on the activity of specific genes in the stem cell. EMBL PhD student Emmanuel Caussinus from González’s group created neuroblasts in which these genes were disrupted. “We no longer had normal neuroblasts and daughter cells capable of becoming part of a nerve,” Caussinus says. “Instead, we had a tumor.”

When these altered cells were transplanted into flies, the results were swift and dramatic. The tissue containing the altered cells grew to 100 times its initial size; cells invaded other tissues, and death followed. The growing tumor became “immortal”, Caussinus says; cells could be retransplanted into new hosts for years, generation after generation, with similar effects. The study proves that specific genes in stem cells – those which control the fates of daughter cells – are crucial. If such genes are disrupted, the new cells may no longer be able to control their reproduction, and this could lead to cancer. “It puts the focus on the events that create asymmetrical collections of molecules inside stem cells,” González says. “This suggests new lines of investigation into the relationship between stem cells and tumors in other model organisms and humans.”

Science Daily
October 11, 2005

Original web page at Science Daily

A new treatment for patients with a type of bile duct cancer promises a greater chance at survival by combining radiation, chemotherapy and liver transplantation, Mayo Clinic physicians report in the September issue of the Annals of Surgery. The five-year survival rate for patients who received a liver transplant after radiation and chemotherapy was 82 percent, significantly higher than for those who had a conventional operation. “With the combined benefits of radiation, chemotherapy and liver transplantation, our patients with bile duct cancer now have a much better chance to live longer and enjoy a good quality of life,” says Charles Rosen, M.D., a Mayo Clinic transplant surgeon and co-author of the study.

Conventional therapy for hilar cholangiocarcinoma, a type of bile duct cancer, is to remove (resect) the tumor, which may require removing part of the liver. Survival for patients with this type of operation is only 25 to 35 percent, and many patients cannot be treated this way because the tumors can involve both sides of the liver. Combination therapy with liver transplantation is possible for more patients. Transplantation enables surgeons to remove the entire liver and obtain better tumor clearance. Patients treated with transplantation have enjoyed a higher likelihood of prolonged survival than those treated with the conventional operation.

To improve results of liver transplantation for unresectable hilar cholangiocarcinoma, Mayo Clinic physicians developed a treatment protocol combining radiation therapy, chemotherapy and liver transplantation. Patients receive high dose external beam radiation therapy, followed by high dose irradiation with iridium administered through a catheter passing through the bile duct and tumor. Chemotherapy starts during radiation treatment and continues until transplantation. Prior to transplantation, patients undergo a staging abdominal operation so surgeons can look for any spread of the tumor to lymph nodes or the abdomen that would prevent complete tumor removal.

Mayo Clinic’s liver transplant team has treated over 90 patients with hilar cholangiocarcinoma. Approximately one-third of the patients have findings at the staging operation that preclude subsequent transplantation, but this number may be decreasing with earlier diagnosis and referral for treatment. Sixty patients have undergone liver transplantation — many recently with living donors — and results remain superb, says Dr. Rosen.

Cholangiocarcinoma is a relatively uncommon malignant tumor that is often found in the lining of the bile duct. In the United States, the most common risk factor is sclerosing cholangitis, a chronic liver disease characterized by inflammation, destruction and fibrosis of the bile ducts, often leading to cirrhosis of the liver. The cancer also is seen in patients with congenital bile duct cysts and bile duct stones. Most frequently, these tumors are located near the liver. Cholangiocarcinomas in this location are difficult to treat because the tumor often extends deep into the liver in a way that it cannot be completely removed with a conventional operation.

The incidence of bile duct cancer is increasing in the United States, according to Gregory Gores, M.D., Mayo Clinic liver transplant specialist and co-author of the study. Mayo Clinic has ongoing research into new tests to diagnose the tumor earlier, which could lead to even better results. “The major problem is that we still don’t have enough livers for everyone who needs one,” says Dr. Rosen. “We feel that patients with cholangiocarcinoma should have equal access to donor organs, because the results are comparable to those achieved for other patients who undergo transplantation. Without a transplant, the outlook for these patients is fairly poor.”

Science Daily
September 27, 2005

Original web page at Science Daily

About 60,000 Americans will be diagnosed with melanoma this year, says the American Cancer Society, and 10,000 of those cases will be fatal. If not caught in the early stages, melanoma can be a particularly virulent form of cancer, spreading through the body with an efficiency that few tumors possess. Now, researchers at Whitehead Institute for Biomedical Research have discovered one of the reasons why this particular skin tumor is so ruthless. Unlike other cancers, melanoma is born with its metastatic engines fully revved. “Other cancers need to learn how to spread, but not melanoma,” says Whitehead Member Robert Weinberg, senior author of the paper that will be published September 4 in the early online edition of the journal Nature Genetics. “Now, for the first time, we understand the genetic mechanism responsible for this.”

Metastasis (the spread of disease to an unconnected body part) is a highly inefficient, multi-step process that requires cancer cells to jump through many hoops. The cells first must invade a nearby tissue, then make their way into the blood or lymphatic vessels. Next they must migrate through the bloodstream to a distant site, exit the bloodstream, and establish new colonies. Researchers have wondered why melanoma in particular is able to do this not only more efficiently than other cancers, but at a far earlier stage. This new study shows that as melanocytes–cells that protect the skin from sun damage by producing pigmentation–morph into cancer cells, they immediately reawaken a dormant cellular process that lets them travel swiftly throughout the body.

Central to this reawakened process is a gene called Slug (named after the bizarre embryo shape that its mutated form can cause in fruit flies). Slug is active in the neural crest, an early embryonic cluster of cells that eventually gives rise to a variety of cell types in the adult, including dermal melanocytes. In this early embryonic stage, Slug enables the neural crest cells to travel, and then settle, throughout the developing embryo. “Slug is a key component of the neural crest’s ability to migrate,” says Piyush Gupta, a MIT graduate student in Weinberg’s lab and first author on the paper. “Following its activation during embryonic development, Slug is shut off in adult tissues.” But when skin cells in, say, an individual’s mole, become malignant, they readily reactivate Slug and gain the ability to spread–something that other cancers can spend decades trying to do.

Weinberg’s team demonstrated this through a number of experiments. In the first, they created models of various cancer types by introducing cancer-causing genes into normal human cells and then injecting the tumor cells underneath the skin of mice. Mice injected with breast cancer cells or with fibroblast (connective tissue) cancer cells developed tumors, but the tumors didn’t spread. Those injected with melanoma cells immediately developed invasive tumors throughout their body, spreading everywhere from the lungs to the spleen. This strongly supported the suspicion that melanoma is so metastatic in part due to properties intrinsic to melanocytes themselves, and not simply because it is external and thus uniquely exposed to environmental stresses.

For the second experiment, the team used microarray technology (chips covered with fragments of DNA that can measure gene levels) and found that Slug was expressed in human melanoma. “Really, this isn’t that surprising,” says Gupta, “when you consider that melanocytes in the skin are direct descendants of the neural crest.” In fact, Gupta points out that occasionally physicians discover that perfectly benign melanocytes will sometimes manage to migrate through a patient’s body into, say, the lymph nodes. This phenomenon isn’t related to cancer, but rather demonstrates the latent ability of melanocytes to travel. Finally, the research team found that when Slug was knocked out in melanoma cells, the cancer was unable to metastasize when placed into a mouse. “This work is yet another demonstration of the notion that certain embryonic genes normally involved in transferring cells from one part of the body to another are also involved in enabling cancer cells to spread,” says Weinberg, who is also a professor of biology at MIT.

Science Daily
September 27, 2005

Original web page at Science Daily

Scientists at the National Institute of Dental and Craniofacial Research (NIDCR) and colleagues report in animal studies that a single, scissor-like enzyme called matriptase, when left to its own devices, can cause cancer. This finding, published in the current issue of the journal Genes and Development, marks the first report of a protein-cleaving enzyme, or protease, on the cell surface that can efficiently trigger the formation of tumor cells. The authors also note that matriptase is the first known cell-surface protease that can act as an oncogene, an umbrella term for mutated genes and their proteins that prompt cells to divide too rapidly, a hallmark of tumor cells.

“What makes matriptase potentially such a good molecular target to treat cancer is its accessibility,” said NIDCR scientist Dr. Thomas Bugge, the senior author on the paper. “We don’t have to trick the tumor cell to internalize a drug, then hope it reaches its destination in an appropriate concentration and duration. In this case, the bull’s eye is right on the cell surface.” Bugge said the exact function of matriptase in healthy human cells remains a bit of a mystery. Previous studies show that cells comprising the outer lining, or epithelium, of nearly all human organs express the protease. They also suggest that matriptase might play a role in activating other membrane-bound proteins on the cell surface that are involved in signaling basic cellular activities, such as growth and motility.

Since its discovery nearly 13 years ago, scientists also have suspected that matriptase might have a dark side. It is overly abundant in a variety of epithelial-derived tumors, including breast, prostate, ovarian, colon, and oral carcinomas. Then, in 2002, scientists reported women with breast and ovarian cancer have poor prognoses if their tumors contain high levels of matriptase. In fact, just two months ago, researchers reported for the first time that increased expression of matriptase is associated with more serious forms of cervical cancer.

Still unanswered, however, was the larger question of whether the protease, when deregulated and overexpressed, might actually cause cancer. To find the answer, Bugge and colleagues produced mice that expressed the human version of the matriptase gene in a stable, readily measurable manner. “After our initial round of experiments, we found that the skin of the mice was quite sensitive to fluctuations in the levels of matriptase,” said Dr. Roman Szabo, a co-lead author on the study and an NIDCR scientist. “So much so, that all 10 of the mice that produced too much matriptase developed distinctive, splotchy skin lesions within a year.” According to Szabo, that’s when things took an unexpected turn. He and his colleagues biopsied the lesions and, to their surprise, found that they were tumors that had already advanced in most cases to a type of cancer called squamous cell carcinoma, a strong indication that the excess matriptase was driving the process.

The scientists next wondered whether excess matriptase and sustained exposure to a chemical carcinogen might be a dangerous combination, a scenario with obvious real world implications. They applied various doses of the chemical DMBA, a well-characterized carcinogen present in tobacco products, to a small area of skin on each of 40 newborn matriptase overproducers. Within seven weeks, 95 percent of these mice developed tumors compared to roughly 2 percent of normal, healthy mice. The group also found that the higher the exposure to DMBA in the matriptase overproducers, the greater the chances were that the tumors would turn cancerous.

“What we found is deregulated matriptase sends a strong and versatile pro-growth signal that can travel along more than one route to the cell nucleus,” said Dr. Karin List, the other lead author and an NIDCR scientist. “But the key point is, like a classic oncogene, matriptase initiates the erroneous growth signal. As further confirmation of this, when we turned off matriptase, not only the tumors but the precancerous lesions never appeared in the mice.” “What this work really shows is the current list of about 100 known oncogenes remains very much a work in progress,” said Bugge. “It’s also clear that matriptase and the approximately 200 other distinct cell-surface proteases will have a lot more to tell us about human health and disease in the coming years.”

Science Daily
September 13, 2005

Original web page at Science Daily

In an ongoing effort to fight disease by manipulating energy regulation of cells, a collaborative study led by Dartmouth Medical School (DMS) has demonstrated that cells lacking a tumor-suppressing kinase called LKB1 can still maintain healthy energy levels when they become stressed. This energy regulation is essential for keeping cells from dying off too quickly. The study’s results could signal new advances for combating cancerous tumor growth, but also type 2 diabetes and obesity.

The study, published in the August 12 issue of the Journal of Biological Chemistry (JBC), was headed by Dr. Lee Witters, Eugene W. Leonard, Professor of Medicine and Biochemistry at DMS and of Biological Sciences at Dartmouth College, who has researched kinases for over 25 years. Kinases encompass a large family of enzyme proteins that play key roles in the workings of most animal cells. He has focused much of his research on the AMP-activated kinase (AMPK) which responsible for managing energy within cellular pathways. “A cell’s energy level is critical to its survival,” explains Witters, who likens a low-energy cell to a car with no gas in its tank. “In a previous study, we found that the cellular “gas gauge” AMPK, can turn around and alter any deficits in the cell if it is turned on by the kinase LKB1. In this JBC study, we wanted to see if AMPK could also be turned on by something besides LKB1.”

“We decided to work with cervical and lung cancer cells because LKB1 is absent from the cellular pathway,” said Rebecca Hurley, lead author of the study and a graduate student in the Molecular and Cellular Biology Program at Dartmouth. Working closely with scientists at St. Vincent’s Institute in Australia and Duke University, the DMS team concluded that two kinases in these cancer cells, CaMKKa and CaMKKß, are able to regulate AMPK independent of LBK1. “With the addition of these two kinases, we think we have all nearly the players responsible for energy regulation within the cell, which should offer new opportunities in cancer treatment,” said Hurley. “If we can stifle a cancer cell’s ability to adapt to an energy deficit, it might lose its growth advantage.” “You need to know how all these proteins interact before you can make truly significant advances,” echoes Witters “It’s like poker; not only do you need to know what each card signifies individually, but you must have an understanding of how they play off each other in order to win.”

In addition to cancer-fighting potential of AMPK regulation, the enzyme also responds to changes in insulin or glucose and mediates impaired energy metabolism, a hallmark of type 2 diabetes. “This indicates that AMPK is a very tempting target for the treatment of some forms of diabetes and even obesity,” said Witters. As Witters’ laboratory continues to zero in on the central role of kinases in the treatment of disease, he acknowledges that this research is becoming more complex and multiple approaches are needed to find solutions.

Science Daily
September 13, 2005

Original web page at Science Daily

Researchers have discovered that tumors release fatty acids that interfere with the cells that are trying to kill them. Consequently, strategies that reduce the amount of fatty acids surrounding the tumors may give a boost to anti-cancer therapeutics. The details of these findings appear in the September issue of the Journal of Lipid Research, an American Society for Biochemistry and Molecular Biology journal.

Several forms of anti-cancer therapy rely on what is known as immunotherapeutic anti-cancer strategies, therapies that encourage the body’s natural defenses, such as cytotoxic T lymphocytes, to aid in destroying tumors. However, immunotherapeutic methods are often not effective at removing established tumors for a number of reasons including a loss of the ability of the cytotoxic T lymphocytes to recognize the tumor and a physical barrier separating the lymphocytes and the tumor.

Now, Dr. Alan M. Kleinfeld and Clifford Okada of the Torrey Pines Institute for Molecular Studies in San Diego, CA, have added another reason to this list. They discovered that tumors secrete fatty acids which inhibit the cytotoxic T lymphocytes’ ability to kill tumor cells. “We found two things,” explains Dr. Kleinfeld. “First, the most common type of free fatty acids, which at normal levels are essential for life, at high levels prevents the cytotoxic T lymphocytes from destroying tumor cells. The second thing is that human breast cancer cells, but not normal tissue from the same breast, produce very large amounts of the type of free fatty acids that block the cytotoxic T lymphocytes. Thus the cancer may have a way of defending itself against attack by the immune system, thereby reducing the potential efficacy of novel anti-cancer therapies that rely on a functioning immune system.”

The free fatty acids act against cytotoxic T lymphocytes by blocking a number of the lymphocytes’ signaling events. For example, they keep certain proteins from being phosphorylated and they also prevent an increase in intracellular calcium that is essential for the cytotoxic T lymphocytes to kill the tumor cells. Dr. Kleinfeld suspects that these signaling events are being blocked at the cells’ membranes. These results from the Torrey Pines Institute for Molecular Studies raise the possibilities of new therapeutic targets for cancer, such as those that may transport free fatty acids out of the tumor. Alternatively, free fatty acid levels in the blood could be used to help gauge the aggressive potential of a tumor.

Science Daily
August 30, 2005

original web page at Science Daily

When cancer spreads, people often die. That’s why a lot of cancer research and drugs focus on the metabolic pathways that allow cancer to metastasize — to spread from one part of the body to another. Cornell University researchers have now furthered understanding of how these pathways work. Their insights might aid future research on drug therapies that disrupt the sequence of events that lead to metastasis. A study published in the journal Developmental Cell (Vol. 9, August 2005) reveals how connective tissue holding a cancer cell in place might degrade, unmooring the diseased cell and allowing it to spread to other parts of the body.

“We have identified a pathway that is specific for cancer,” said Jun-Lin Guan, a professor in the Department of Molecular Medicine in the College of Veterinary Medicine at Cornell and an author of the paper. “So from here, if someone identifies a drug that targets this pathway, it is possible the drug will not affect normal cell function but will affect cancer cell activity.” That, in turn, would alleviate drug side effects. Guan and his colleagues used a cultured cell line to study cancer, which are mouse cells grown in the lab for research purposes. The researchers used these cells to create a model system for cancer cells, which means its basic pathway exists in real-world systems, while the actual proteins that act on the system may vary.

In the model system, the researchers discovered critical differences between cancer cells and normal cells regarding a mechanism called endocytosis — which cells employ to let materials enter through the cell membrane. The researchers used a protein called v-Src derived from an oncogenic virus, which has the ability to transform a normal cell into one with many features resembling those found in cancer cells. While this virus has not been found in humans, it does lead to tumor growth in chickens and created cancerous cells in the cultured system. In the study, the researchers found that v-Src attaches to an enzyme, called focal adhesion kinase, inside the cell. This association jump-starts a series of cascading interactions between proteins in the cell that ultimately block some cell-surface proteins from entering through the cell’s membrane.

One of the proteins not allowed entry is called MT1-MMP. As this material accumulates on the cell surface, it degrades the connective tissue that holds the cancerous cell in place. The build-up of MT1-MMP also activates an enzyme called MMP2, which further degrades the connective tissue. In this way, the cancer cell loses its moorings and can float off to spread around the body. While no one has found v-Src in human cancer patients, a number of other cancers have been linked to viruses, including the herpes virus and its association with cervical cancer. “Critics of this work will ask why v-Src has not been found in human cancer,” said Guan. “But there are many examples of studies and ideas that come out of work like this that stimulate related research with clinical impacts. “We looked at a relatively late stage of cancer and its spread within the body,” Guan added. “The spreading part is less well understood, and it’s the spreading that is killing people.”

Science Daily
August 16, 2005

Original web page at Science Daily

Craig Thompson didn’t set out to be a spokesman for the importance of bioenergetics in determining cell fate. Now a professor of medicine and chair of cancer biology at the University of Pennsylvania School of Medicine, he trained as a physician and became interested in research when he realized that “we really didn’t understand quite as much as we needed to about basic biology to develop effective therapies for patients,” he says. To pay for medical school, Thompson accepted a scholarship from the Navy and, following his training, he turned his attention to medical procedures that were of interest to the military – for example, bone marrow transplantation. The Navy planned to be prepared should such treatments become necessary to combat radiation injury on US soil.

In the early days, physicians were using bone marrow transplantation to treat patients, mostly with leukemias, who’d done poorly on standard cancer therapies. “The side effects were horrible,” says Thompson. Before the discovery of effective immunosuppressive drugs, “people got terrible graft-versus-host disease. These were some of the sickest patients you ever saw.”

As a naval officer at Seattle’s Fred Hutchinson Cancer Research Center in 1983, Thompson helped care for the first hundred patients to receive cyclosporine, a compound that would become the crown jewel of immunosuppression. “It was nothing short of a miracle,” he says. Patients still experienced some side effects, but after the transplant they fared remarkably well – too well, says Thompson. In particular, patients on cyclosporine seemed to be able to handle infections much better than those who had received less-effective immunosuppressants. “That just didn’t make any sense to us,” he recalls. If their immune systems were truly tamped down, the patients should have been coming down with infections left and right.

This mysterious lack of toxicity led Thompson and his colleague Carl June to search for the molecular pathway that the immune system might be using to circumvent cyclosporine to fight pathogens. That led them to the discovery of the CD28 receptor and the so-called costimulatory pathway. “We now know that T cells require two integrated signals to mount an effective immune response: Signal transduction through the T-cell receptor, and signal transduction through costimulatory receptors,” says Thompson. “So we started with a very clinical question and stumbled onto a signaling pathway that hadn’t been previously described.” The ability to make that leap from bedside to bench is not necessarily common. “Craig is a physician-scientist who, until recently, still saw patients. Yet his science has been right at the cutting edge,” says Martin Raff of University College, London. “In my experience, this is quite unusual.” June has gone on to harness the power of CD28 for growing large quantities of immune cells that can be given to patients to treat cancer and AIDS (see his Vision in The Scientist, May 9, 2005 issue). Thompson, on the other hand, “became a real science nerd” and decided to track down how CD28 works. The key insight, it happens, came from chickens.

While at the Fred Hutchinson Cancer Research Center, Thompson had become interested in studying cancer and immunity in chickens. Working with Paul Neiman, Thompson found that the oncogene myc promotes proliferation of chicken lymphocytes, but only when the cells are safely ensconced in the bursa of Fabricius, the organ in which the bird’s B cells mature. When he removed the cells from the bursa, “they died like stones,” says Thompson. “We thought, gee, if that’s true, there must be something in the bursal environment that keeps cells from undergoing apoptosis as long as they’re there,” he explains. “So we went looking for genes that would keep bursal cells alive.” And they found bcl-X, a relative of the bcl-2 gene that keeps programmed cell death in check. The discovery of this cell-death inhibitor “rocketed him to fame,” says Raff. “It made an especially big splash because cell death was just in the beginning of its exponential rise. So that made him one of the heroes in the field.”

Thompson then connected these two major discoveries, showing that CD28 stimulates production of bcl-X in mouse and human T cells, suggesting that the costimulatory pathway works by regulating cell survival during an immune response. Linking an extracellular signaling pathway with cell survival was not a major leap of imagination; most biologists now believe that animal cells are programmed to kill themselves if they don’t receive the proper signals from their neighbors, says Raff. These survival signals, acting through proteins such as bcl-2, keep the cell death program shut down. But Thompson then tossed metabolism into the mix.

“Craig argues that the bcl-2 family mainly regulates metabolism. So that what survival signals are doing is not regulating cell death directly, but regulating death indirectly by regulating metabolism – for example, the transport of glucose and amino acids across the plasma membrane,” says Raff. “That’s where he’s unique.” Indeed, Thompson hypothesizes that the function of extracellular signaling molecules is to give cells permission to take up sufficient nutrients to grow, maintain themselves, or reproduce. “We believe that in mammals, there’s a constant supply of nutrients – glucose and amino acids – but that cells need specific transporters and specific metabolic enzymes to utilize those resources,” says Thompson. “And those genes are under absolutely exquisite control by extracellular signal transduction.” In other words, cells need permission from other cells in the organism to be able to access the nutrients they need to live.

Derailment of the cell’s system, Thompson finds, can lead to cancer. The oncogene akt, for example, boosts glucose uptake in transformed cells by driving the recruitment of glucose transporters to the cell surface. The added fuel could power the cancer cell’s penchant for proliferation, and might explain something called the “Warburg effect.” In 1930, German biochemist Otto Warburg observed that most cancer cells undergo a shift in metabolism: they tend to scarf up and burn through loads of glucose because they rely more heavily than do normal cells on glycolysis to produce their ATP. Warburg believed that this reliance on glucose came about because cancer cells somehow lost the ability to carry out the more efficient ATP-generating process of oxidative phosphorylation, which coupled with glycolysis produces on the order of 30 ATP molecules per molecule of glucose, compared to the two ATPs produced by glycolysis alone.

But Thompson and others think that the shift occurs not because tumor cells can’t carry out oxidative phosphorylation, but because they gain the ability to take up and process as much glucose as they can – allowing them to make all the energy and the components they need to survive and proliferate. Although glycolysis alone produces less energy than oxidative phosphorylation, cancer cells crank up the activity of the pathway enough to more than compensate for the loss of efficiency. The theory makes sense according to oncologist Chi Dang of the Johns Hopkins University School of Medicine, who finds that myc also boosts the activity of enzymes involved in glycolysis. “In the paradigm we have now, oncogenes are like the accelerator and tumor suppressors are like the brakes. But basically what people forget about is the fuel source for the car.” And like any cells, tumor cells need fuel to grow. What’s more, by favoring glycolysis over oxidative phosphorylation, cancer cells can spare their pyruvate – the glycolytic product that gets carried into the mitochondria to produce ATP. Instead of burning its pyruvate, a cancer cell can save it to make the fatty acids needed to build new membranes, “which you have to do in order to make another cell,” says Lewis Cantley of Harvard Medical School.

Although the idea that this metabolic derangement is a necessary step in cancer formation is still somewhat controversial, more researchers are warming up to the idea. “We arrived at similar conclusions that the regulation of metabolism is going to be a major mechanism by which the PI3 kinase/Akt pathway is transforming cells,” says Cantley. Whether the conversion will be strictly required for all cancers remains to be seen. “But, yes, I think that it’s going to be very frequent in tumors and that one way or another something has to happen to turn on this pathway in order to get a tumor,” he adds. “One by one, all of our favorite oncogenes are going to tie into this story,” Cantley predicts. “I think it’s going to turn out to be incredibly important.” Thompson and Dang hope to take advantage of cancer’s metabolic Achilles’ heel to design novel therapeutics.

The Scientist
August 2, 2005

Original web page at The Scientist

Tumor cells can trigger angiogenesis by a process involving physical contact with neighboring endothelial cells, scientists report in this month’s issue of Cancer Cell. This is the first time, according to the paper, that such a mechanism has been described involving the Notch pathway, which is known to play key roles in embryonic vascular development and angiogenesis, but whose participation in tumor angiogenesis has been unclear. There are several ways by which a tumor might stimulate angiogenesis, said coauthor Jan Kitajewski, from Columbia University in New York, including the well-documented paracrine mechanism and some emerging contact-dependent mechanisms. “Here Notch seems to act as a proangiogenic factor in head and neck tumors,” he told The Scientist, “and it probably does so in other tumors.”

The team, led by Cun-Yu Wang from the University of Michigan, Ann Arbor, conducted a microarray analysis of head and neck squamous cell carcinoma cells. “We discovered that in the presence of common tumor stimulating growth factors, the Notch ligand Jagged1 is overexpressed,” Wang told The Scientist. “This expression depends on the mitogen-activating protein kinase (MAPK) pathway, which is already implicated in other angiogenic routes.” Because endothelial cells possess Notch receptors on their surface, the researchers hypothesized that a cell-to-cell mechanism involving Notch might participate in angiogenesis, as it does during embryogenesis.

To test this hypothesis, they induced Jagged1 expression by retrovirus-mediated transduction of human SCC9 squamous cell carcinoma cell lines in which Jagged1 is endogenously undetectable. In cocultures with human endothelial cells, the comparison of wild SCC9 cell lines with the mutated strain revealed that Jagged1 is necessary to activate the Notch-dependent luciferase reporter in endothelial cells and to induce capillary sprout formation. The team then implanted wild SCC9 cell lines, the mutated strains, and endothelial cells into mice. After histology and immunostaining testing, they reported similar results in vivo. Warren Pear from the University of Pennsylvania, Philadelphia, told The Scientist that the group’s hypothesis was intriguing. “But I think they still have a long way to go to show whether this process is relevant in naturally arising tumors,” said Pear, who did not participate in the study.

In the future, it will also be important to understand the different ways in which Notch might be implicated in cancer cell growth, the authors said. “If we hypothesize from what occurs during embryogenesis, Notch could have antiangiogenic effects in other settings,” said Kitajewski. “Studies have shown that Notch is also commonly overexpressed in cancer cells themselves, where it could play a role in dedifferentiating cells or in the tumor cell’s survival.” Meanwhile, this new discovery represents a potential additional target for antiangiogenic therapy. “Notch could be an alternative pathway that tumors use to escape control by angiogenesis inhibitors that target paracrine factors such as [vascular endothelial growth factor],” Judah Folkman, from Harvard Medical School, who did not participate in the study, told The Scientist. “If you need to completely shut down Notch signaling in the body to inhibit tumor angiogenesis, then it’s not a viable treatment,” added Pear. “If you can lower the dosage to maintain Notch in the gut for instance, and still act upon the tumor, then there may be a therapeutic window in which toxicity is minimal.”

E-mail address The Scientist Daily
August 2, 2005

Original web page at The Scientist

A team of researchers led by scientists at Dana-Farber Cancer Institute have discovered a genetic abnormality in the cells of some advanced melanoma patients that worsens their chances of survival, but also might be a target of future drug attack against the dangerous skin cancer. Dana-Farber’s Levi Garraway, MD, PhD, and William Sellers, MD, the paper’s first and senior authors, and their colleagues will report their findings in the July 7 issue of the journal Nature.

“By pinpointing the abnormally multiplied MITF oncogene, we may be able to develop better diagnostic and prognostic tools as well as provide a target for highly specific therapies for metastatic melanoma patients who have this overcopied gene,” explains Sellers, who also holds an appointment with the Broad Institute of Harvard and MIT and with Harvard Medical School. Melanoma accounts for just six percent of diagnosed skin cancer cases in the United States, but it is the deadliest, causing three quarters of all skin cancer related deaths. The American Cancer Society estimates that 7,700 melanoma patients will die this year.

Caused mainly by sun exposure, melanoma has been increasing rapidly over the past several decades. Nearly 60,000 new cases are expected in 2005. Most cases caught early can be cured, but if melanoma cells penetrate the skin deeply, the cancer is highly prone to spread with life-threatening consequences despite treatment with surgery, chemotherapy and radiation. The researchers used single nucleotide polymorphism (SNP) array technology, which focuses on the building blocks of individual genes, to identify regions of chromosomes where genes were either left out or multiplied over and over – mistakes that are often associated with cancer.

In studying cells from primary and metastatic melanoma tumors, the scientists observed as many as 13 extra copies of the MITF gene in 10 percent of primary melanomas and 21 percent of metastatic tumors. When they checked the treatment outcomes of the patients from whom the tumor samples were taken, researchers found poorer 5-year survival rates among patients whose metasases contained the overcopied or “amplified” MITF gene. Abnormal amplification of the MITF gene was found to be associated with other genetic changes as well. They included mutations in a gene, BRAF, previously found in melanoma cells, and silencing of p16, a “tumor-suppressor” gene that normally keeps cells from dividing too rapidly and causing cancer.

Aside from its clinical potential, the scientists say the finding advances the understanding of cancer: It highlights a previously unknown mechanism by which a tumor can become “addicted” to an oncogene that, in its normal form, plays a role in developing and maintaining tissues. That is, the tumor cannot survive without a high level of production of the oncogene’s protein. Dana-Farber’s David E. Fisher, MD, PhD, an author on the paper, has previously shown that the MITF gene normally regulates the development of the skin’s pigment-producing cells, or melanocytes. It appears the extra dosage of MITF protein spurs the melanocytes into malignant growth and maintains the tumor’s survival.

“We might be able to treat these metastatic melanomas by targeting the MITF gene or protein, alone or in combination with drugs that block BRAF,” says Sellers. “We know that when MITF activity is reduced, melanoma cells become more vulnerable to chemotherapy drugs.” However, he said, MITF is a “transcription factor” that controls the expression of other genes, and these factors have proven difficult to manipulate with drugs.

Source: Dana-Farber Cancer Institute

Bio.com
July 19, 2005

Original web page at Bio.com

Epidemiological evidence strongly links fish oil, which is rich in docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), with low incidences of several types of cancer. The inhibitory effects of omega-3 polyunsaturated fatty acids on cancer development and progression are supported by studies with cultured cells and animal models. Propofol (2,6-diisopropylphenol) is the most extensively used general anesthetic–sedative agent employed today and is nontoxic to humans at high levels (50 µg/ml). Clinically relevant concentrations of propofol (3 to 8 µg/ml; 20 to 50 µM) have also been reported to have anticancer activities. The present study describes the synthesis, purification, characterization and evaluation of two novel anticancer conjugates, propofol-docosahexaenoate (propofol-DHA) and propofol-eicosapentaenoate (propofol-EPA). The conjugates linking an omega-3 fatty acid, either DHA or EPA, with propofol were synthesized and tested for their effects on migration, adhesion and apoptosis on MDA-MB-231 breast cancer cells. At low concentrations (25 µM), DHA, EPA or propofol alone or in combination had minimal effect on cell adhesion to vitronectin, cell migration against serum and the induction of apoptosis (only 5 to 15% of the cells became apoptotic). In contrast, the propofol-DHA or propofol-EPA conjugates significantly inhibited cell adhesion (15 to 30%) and migration (about 50%) and induced apoptosis (about 40%) in breast cancer cells.

These results suggest that the novel propofol-DHA and propofol-EPA conjugates reported here may be useful for the treatment of breast cancer.

BioMed Central
July 5, 2005

Original web page at BioMed Central

Scientists have uncovered a surprising role for non-coding genetic material in the development of cancer. The realization should help with both the diagnosis and treatment of tumours. Cancer biologists have known for decades that some genes cause cancer by creating proteins that disrupt normal cellular growth. Now researchers have found that chunks of genetic material known as microRNAs can trigger tumours by regulating such proteins. “Everybody has been focused on understanding how proteins fit into cancer-causing pathways, but there is another regulatory pathway that controls not the protein product but its utilization,” says Greg Hannon of the Cold Spring Harbor Laboratory in New York.

Scientists have long thought of RNA as the intermediate ‘messenger’ between genes and proteins, because DNA is transcribed into RNA before being translated into protein. But during the past few years, scientists have discovered that many genes are transcribed into RNA and never made into proteins. These ‘non-coding’ RNAs seem to act as regulators rather than messengers. They influence the expression of genes, for instance, by destroying coding RNA molecules so they cannot be translated into proteins.
This process was known to be important in normal human growth and development, but research that appears in Nature this week shows that a type of non-coding RNAs called micro-RNAs can cause disease as well. Hannon’s work, for example, shows that some microRNAs can accelerate the development of cancer when transplanted into mice.

The discovery should also help researchers to identify the type of cancer that an individual has, a step that is crucial in assigning treatment. Todd Golub’s lab at the Dana-Farber Cancer Institute in Boston, Massachusetts, has found that different types of tumour express different levels of microRNAs. By measuring the levels of expression of 217 genes in different types of cancers, Golub and colleagues made microRNA ‘profiles’ of many cancers. The researchers showed they could use these profiles to diagnose the origin of tumours that are difficult to classify by the traditional method of looking at cell shape and character under a microscope.

MicroRNA profiling also worked better than existing genetic profiling methods, correctly diagnosing 12 of 17 tricky tumours. The existing method diagnosed only one of these tumours correctly. Others note that the discovery could have knock-on effects for treatment strategies. “These papers show that microRNAs are potentially therapeutic. You could deliver them to tumours, maybe in combination, or even along with chemotherapeutic drugs,” says John Rossi, a molecular biologist at the Beckman Research Institute in Duarte, California. “A lot of people are going to want to follow up on this work.”

Nature
June 21, 2005

Original web page at Nature

Previous epidemiological studies of the relation between alcohol consumption and risk of non-Hodgkin lymphoma (NHL) have been inconsistent, probably because of small sample sizes of individual studies that result from stratification by NHL subtype and type of alcoholic beverage. We aimed to assess the role of alcohol consumption in NHL with sufficient sample size to analyse by both type of alcoholic beverage and disease subtype.

We obtained original data from nine case-control studies from the USA, UK, Sweden, and Italy in the International Lymphoma Epidemiology Consortium (InterLymph), yielding a pooled study population of 15175 individuals (6492 cases and 8683 controls). We derived odds ratios (OR) and 95% CI from unconditional logistic regression models, controlling for study centre and other confounding factors.
Heterogeneity between studies was assessed by comparison of results from joint fixed-effects logistic regression and two-stage random-effects logistic regression, and by calculation of Wald Χ2 statistics.

People who drank alcohol had a lower risk of NHL than did non-drinkers (OR 0•83 [95% CI 0•76–0•89]). Compared with non-drinkers, risk estimates were lower for current drinkers than for former drinkers (0•73 [0•64–0•84] vs 0•95 [0•80–1•14]), but risk did not decrease with increasing alcohol consumption. The protective effect of alcohol did not vary by beverage type, but did change with NHL subtype.
The lowest risk estimates were recorded for Burkitt’s lymphoma (0•51 [0•33–0•77]).

People who drink alcoholic beverages might have a lower risk of NHL than those who do not, and this risk might vary by NHL subtype. Further study designs are needed to determine whether confounding lifestyle factors or immunomodulatory effects of alcohol explain this association.

The Lancet
June 21, 2005

Original web page at The Lancet

A decade-long investigation of childhood leukaemia has come to the conclusion that the disease is probably often triggered by common infections in toddlers, scientists announced today in London. By identifying the exact types of infections involved, one might be able to prevent some cases of leukaemia, the researchers say. They add that exposure to infections very early in life may help to develop children’s immune systems and protect them against developing tumours in later years. The cause of leukaemia has been the subject of much debate. Some have suggested that it is influenced by exposure to radiation and chemicals, and others have controversially proposed that electromagnetic waves from power lines might also contribute to cases. But the United Kingdom Childhood Cancer Study, which compiled information from studies of more than 10,000 children, including 1,737 with leukaemia, concludes that infection is a far more important factor. The group says their work agrees with previous studies that have shown no connection between power lines and leukaemia.

Leukaemia accounts for a third of all cancers in children under the age of 15, mostly affecting industrialized countries. The disease commonly strikes infants in the first two to four years of life, and is treated with aggressive chemotherapy. About 80% of those affected survive the first 5 years following diagnosis. Researchers first proposed a link between childhood leukaemia and viruses such as measles in the 1920s. Five decades later, researchers discovered that viruses were to blame for the onset of leukaemia in cats and cattle. And one particular virus has been found to be a trigger for a rare form of leukemia that occurs primarily amongst adults in Japan. But it took the UK assessment to convince researchers of a credible link between infection and most types of leukaemia. Infections induce a proliferation of white blood cells in bone marrow as part of the normal immune response.
In those genetically predisposed to leukaemia, the infection could cause an uncontrolled proliferation of cells, leading to cancer, says Mel Greaves of the Institute of Cancer Research, London.

Exposure to pathogens in the first year of life may help to train a child’s immune system to somehow prevent this, says Greaves. He points out that the incidence of childhood leukaemia in East Germany before reunification was a third less than its Western counterpart. This may be in part because every three-month-old infant in East Germany was sent to playgroups, he says, exposing them to a healthy dose of disease.

A paper published online in the BMJ this week reaches a similar conclusion. From a survey of more than 9,000 UK children, it concludes that infants who attend group day care twice a week in the first few months of life are half as likely to develop childhood leukaemia. Greaves notes that US and Finnish studies have suggested that the Hib vaccine against acute respiratory infection helps to protect against childhood leukaemia. But he cautions that many details about the biological mechanisms remain unknown.

Nature
May 24, 2005

Original web page at Nature

Exitement about the potential of stem cells for curing all manner of ills is being tempered by two new studies that highlight the potential dangers. They show that even stem cells taken from adults can turn cancerous if they are allowed to multiply for too long outside the body. Researchers have long known that there is a cancer risk with stem cells extracted from very early embryos. Until they change into more specialised tissue, they can form aggressive cancers called teratomas when injected into animals. Until now, it has been widely assumed that adult stem cells, such as those taken from bone marrow, do not form cancers. But the latest studies suggest that adult stem cells are safe only if the number of times they are allowed to divide outside the body is limited.

A team at the Autonomous University of Madrid in Spain grew human mesenchymal stem cells extracted from fat tissue for up to eight months. During this time the cells divided between 90 and 140 times. When transplanted into animals, the oldest cells formed cancers (Cancer Research, vol 65, p 3035). The pioneering treatments with bone-marrow stem cells that are already being tested in people, for instance for treating damaged hearts, should be safe because the cells are only briefly grown outside the body. “In normal conditions in clinical applications we think the cells are pretty safe, but we must be careful,” says Antonio Bernad, head of the Madrid team. “The key is not to grow them for too long.” However, treatments that rely on multiplying a small number of stem cells through many generations, or on cell lines maintained for years in the stem cell banks currently being established around the world, may not be safe.

Stem cells grown in culture for a long time probably become cancerous because they start making telomerase, an enzyme that immortalises cells by rejuvenating the “fuse” on chromosomes that normally limits the number of times cells can divide. A Danish team whose results appear in the same issue found that permanently switching on the telomerase gene in mesenchymal stem cells eventually turns them cancerous.

“Cell lines maintained for years in the stem cell banks being established around the world may not be safe. ”Although it’s an artificial situation, it’s clearly sufficient for them to acquire the ability to become tumorigenic,” says Jorge Burns, head of the team at the University Hospital of Odense. Until the cells start making telomerase, they should be safe. The Madrid team suggests around 60 generations as a provisional cut-off point, but more research needs to be done to establish a safe limit. “We need to know where to draw the line between safe and unsafe expansion of cells even in non-telomerase-producing cells,” Burns says. “Both these papers reinforce the potential danger of using stem cells,” says Robert Lanza of Advanced Cell Technology, a stem cell company in Worcester, Massachusetts. “They underscore the need for extensive safety testing before any type of stem cell is used for medical therapy.”

New Scientist
May 10, 2005

Original web page at New Scientist

Progress toward development of a breast cancer vaccine has been reported by researchers at Washington University School of Medicine and the Siteman Cancer Center in St. Louis.

Cancer-fighting vaccines stimulate immune cells to recognize tumor cells as foreign and destroy them. Physicians believe a vaccine-induced immune response could be used to supplement other cancer therapies or to immunize high-risk people against cancer. “We’ve been studying a protein called mammaglobin-A found in 80 percent of breast tumors,” says Thalachallour Mohanakumar, Ph.D., the Jacqueline G. and William E. Maritz Professor of Immunology and Oncology in the Department of Surgery and at the Siteman Cancer Center. “The protein is especially interesting for cancer immunotherapy because of its frequent occurrence and because breast tumors express it at high levels.”

In articles in the Journal of the National Cancer Institute and Breast Cancer Research and Treatment, the researchers report that they constructed a vaccine consisting of copies of the DNA sequence that makes mammaglobin-A in humans. The researchers theorized the DNA vaccine would rev up special immune cells called T cells to recognize mammaglobin-A as a foreign molecule when it is displayed on the surface of cells as an antigen (a small protein that the immune system may recognize). The primed T-cells then would proliferate and attack when they met with mammaglobin-A antigens.

“Mammaglobin-A is involved in breast development and secreted in breast milk,” Mohanakumar says. “So we had to prove first that we could elicit an immune response to a protein that is in the body normally.” They injected the DNA vaccine under the skin of test mice that had been engineered so that their immune systems would react to the human mammaglobin-A like a human immune system. The researchers loaded specific cells in the mice with mammaglobin-A antigens and found that the vaccine-primed T-cells attacked those loaded cells.

The research team also transferred vaccine-primed T cells into mice with growing tumors that had or didn’t have mammaglobin-A antigens. Tumors with mammaglobin-A antigens stopped growing and shrunk in volume, while those without the antigens continued to grow at the usual pace. “The results demonstrated that the vaccine-primed immune response is specific to mammaglobin-A antigens,” Mohanakumar says.

Breast tumors with mammaglobin-A antigens on their surface also may display antigens that come from multiple parts of the mammaglobin-A molecule. Further experiments confirmed the importance of generating T cells that can react to a variety of different mammaglobin-A antigens. When the research team tested a DNA vaccine containing the DNA code for just one part of the mammaglobin-A molecule, they found T cells reacting to only that antigen, indicating that the method can generate immune cells that target specific parts of the mammaglobin-A protein.

“Now that we’ve found how effectively an immune response can be generated to mammaglobin-A, we plan to conduct clinical trials in patients who are at very high risk for breast cancer and in patients who have had a relapse after initial treatment,” Mohanakumar says. “We want to see if giving patients the DNA vaccine can prevent or eliminate breast cancer or at least slow its growth.”

Source: Washington University in St. Louis

Bio.com
March 15, 2005

Original web page at Bio.com