Immune System may aggravate cancer

Source: Science Daily

Researchers at the Unviverstiy of California have found out that the leukocytes which are part of the innate immune system may be triggered to boost cell growth, remodel tissues whcih are necessary for cancer growth.

The leukocytes have receptors on the surface that can detect foreign antigens. Once a foreign antigen is encountered, it is engulfed and destroyed. But now, the researchers have found out that in the presence of cancerous tissues, the receptors on the leukocytes are misdirected to do a different funcion - boost cell growth and remodel tissues thatare necessary for cancer growth.

The exact signals that make the leukocytes to take this pathway is not yet known but they feel that it may be bacause of the antibodies produced by the B cells since part of the receptor for the antibody known as immunoglobulin appears to be involved.

The good news however is that drugs for treating cancer aggravated by inflammation are already in the trials. So once the exact signals are found out, the work could be completed faster.

The research work was done using mice in which HPV was inserted. It a well known fact that HPV is tumourigenic virus causing cervical cancer. In the experiment, two batch of mice were created. One batch had the antibody receptors intact while the other mice were 'knock-out' of that receptor. The research showed that the former showed rapid growth of cancer cells while the other didn't show much progress.

A novel method to treat cancer

Source: Science Daily

Researchers have found out a novel method to treat cancer – by using the structural disorganisation of cancer cells.

Researchers used an adenoviral vector ie… a gene transfer vehicle based on adenovirus to deliver genes. The research was done in the liver since liver is an important target for metastatic cancers and they utilized the phenomenon of the adenoviral vector binding to the receptors present on the surface of the liver cells.

Both the normal and the cancerous liver cells have the adenovirus binding receptors but in the case of the normal cell, the receptor is ‘hidden’ from the blood stream. This receptor called coxsackie-adenoviral receptor is expressed openly on the surface in the case of the cancer cell. Researchers utilized this structural disorganization of the cancer cell to allow the binding of the adenoviral vector on to the cancer cell and thereby killing the cell.

This gene therapy was stopped in between following the death of a participant triggering a lot of questions regarding the safety of the therapy.

Hence the researchers started analysing the participants of the adenoviral vector therapy to find out any toxic effect on the liver due to repeated exposure to the vector. They found nothing of that sort and also they found out that the disease condition of the participants started improving after three or four shots of the vector. It was through this treatment that the researchers found out the location of the adenoviral receptor. Their experiments showed that the normal liver cells were not affected by the adenoviral vector indicating the ‘hidden’ nature of the receptor.

Experiments also showed that other cancers like breast, prostrate and pancreatic cancers were also affected by the adenoviral vector. Although this therapy is an excellent way of treating cancer patients, further clinical trials are needed to alleviate all the fears regarding this gene therapy.

New gene discovered for Brain Cancer

Source: Science Daily

Researchers have found out a new 'gateway' gene which promotes the proliferation of brain cancer cells. The protein called 'olig2' was found to be responsible for this function and knocking it out almost completely eliminated tumour formation.

Olig 2 is a transcription factor which plays a central role in stimulating neural stem cells to form the specialised brain cells during embryonic brain development. Brain tumours arise because of cell division of the mutated stem cells or the improperly differentiated progenitor cells.

Research showed that olig2 brought about cell growth in both normal stem cells and the malignant tumour cells. Specifically, they also found out that olig2 disrupts a protein P21 which is responsible for inhibiting cell growth.

Hence researchers have concluded that olig 2 is a "unifying factor" between normal cells and the malignant cells. Hence they say that olig 2 could be a target for developing drugs for brain tumour development.

But how they will inhibit olig2 without disturbing its functions on the normal neural stem cells is something that they'll have to answer...

The latest enemy for cancer - HIV

Source: Science Daily

Researchers have found out a way to make cancer cells to undergo apoptosis. They used a protein which tips the balance of the cancer cells in favour of apoptosis and this protein has been introduced into the cells using none other than the deadly HIV.

HIV has a protein called TAT which alone does not cause AIDS but which can also “drag” massive molecules along with it into the cell.

The researchers used the protein BIM which is tumour suppressive in nature and tagged it to TAT. Once inside, the TAT-BIM complex was able to activate the apoptosis mechanisms inside the cancer cells and bring about cell death.

The researchers tried the above experiment in mice and they found tremendous difference in the amount of cancer cells between the treated and the non-treated mice.

Now researchers are working on the procedure to concentrate the complex in cancer cells so that the normal cells can be spared. They are trying to link the anti cancer proteins with tracer molecules that can selectively bind to cancer cells.

New inhibitor molecule for cancer cells

Source:- Science Daily

Scientists have found out an inhibitor for a protein involved in cell division. They found the results when they tested the inhibitor in mice and tumour cell cultures.

Kinases are enzymes playing a crucial role in the cell division of normal cells. It also plays the same role in cancerous cells even though a cancer cells has a lot of modifications in its pathways as compared to a normal cell.

Scientists claim that the cell division part is handled by a set of kinases and that if they can target these, then they can arrest cell division and cease the development of cancer.

They considered a particular kinase by the name Plk1. They isolated a new molecule called BI 2536 which they found to be a potent inhibitor of Plk1. They tried the inhibitor on cancer cells grown in cell culture and also on human tumour grafts in mice and they found that BI 2536 effectively arrested the cancer cell division and therefore leading to their apoptosis.

Some of the scientists used this inhibitor on normal cells to block the function of Plk 1 inorder to learn its functions.

Research on Vitamin D

Two new vitamin D studies using a sophisticated form of analysis called meta-analysis, in which data from multiple reports is combined, have revealed new prescriptions for possibly preventing up to half of the cases of breast cancer and two-thirds of the cases of colorectal cancer in the United States. The work was conducted by a core team of cancer prevention specialists at the Moores Cancer Center at University of California, San Diego (UCSD), and colleagues from both coasts.

The breast cancer study, published online in the current issue of the Journal of Steroid Biochemistry and Molecular Biology, pooled dose-response data from two earlier studies - the Harvard Nurses Health Study and the St. George's Hospital Study - and found that individuals with the highest blood levels of 25-hydroxyvitamin D, or 25(OH)D, had the lowest risk of breast cancer.

The researchers divided the 1,760 records of individuals in the two studies into five equal groups, from the lowest blood levels of 25(OH)D (less than 13 nanograms per milliliter, or 13 ng/ml) to the highest (approximately 52 ng/ml). The data also included whether or not the individual had developed cancer.

"The data were very clear, showing that individuals in the group with the lowest blood levels had the highest rates of breast cancer, and the breast cancer rates dropped as the blood levels of 25-hydroxyvitamin D increased," said study co-author Cedric Garland, Dr.P.H. "The serum level associated with a 50 percent reduction in risk could be maintained by taking 2,000 international units of vitamin D3 daily plus, when the weather permits, spending 10 to 15 minutes a day in the sun."

The colorectal cancer study, published online February 6 in the American Journal of Preventive Medicine, is a meta-analysis of five studies that explored the association of blood levels of 25(OH)D with risk of colon cancer. All of the studies involved blood collected and tested for 25 (OH)D levels from healthy volunteer donors who were then followed for up to 25 years for development of colorectal cancer.

As with the breast cancer study, the dose-response data on a total of 1,448 individuals were put into order by serum 25(OH)D level and then divided into five equal groups, from the lowest blood levels to the highest.

"Through this meta-analysis we found that raising the serum level of 25-hydroxyvitamin D to 34 ng/ml would reduce the incidence rates of colorectal cancer by half," said co-author Edward D. Gorham, Ph.D. "We project a two-thirds reduction in incidence with serum levels of 46ng/ml, which corresponds to a daily intake of 2,000 IU of vitamin D3. This would be best achieved with a combination of diet, supplements and 10 to 15 minutes per day in the sun."

Vitamin D3 is available through diet, supplements and exposure of the skin to sunlight, or ultraviolet B (UVB). In the paper, the researchers underscored the importance of limiting sun exposure such that the skin does not change color (tan) or burn. For a typical fair-skinned Caucasian individual, adequate vitamin D could be photosynthesized safely by spending 10 to 15 minutes in the noontime sun on a clear day with 50 percent of skin area exposed to the sun. Darker skinned individuals may require more time in the sun, such as 25 minutes. For people with photosensitivity disorders, or anyone with a personal or family history of nonmelanoma skin cancer, any amount of extra sun exposure would be inadvisable.

The meta-analysis on colorectal cancer includes data from the Women's Health Initiative, which had shown in 2006 that a low dose of vitamin D did not protect against colorectal cancer within seven years of follow-up. However, the researchers wrote, the meta-analysis indicates that a higher dose may reduce its incidence.

"Meta-analysis is an important tool for revealing trends that may not be apparent in a single study," said co-author Sharif B. Mohr, M.P.H. "Pooling of independent but similar studies increases precision, and therefore the confidence level of the findings."

The authors recommend further research to study individuals for the effect of vitamin D from sunlight, diet and supplements on the risk of cancer.

Eat Well, Get Fit, Stop Smoking -- Prevent Cancer

If you wanted to start today to reduce your chances of getting cancer, what would you have to do? Lose excess weight, get more exercise, eat a healthy diet and quit smoking.

Those basic behavior changes would have a tremendous impact on the incidence of the most prevalent types of cancer — lung, breast, prostate and colon cancer — says Graham Colditz, M.D., Dr.P.H., associate director of Prevention and Control at the Siteman Cancer Center at Washington University School of Medicine in St. Louis and Barnes-Jewish Hospital. "We estimate that more than 50 percent of cancer incidence could be prevented if we act today on what we already know," Colditz says.

Every year, more than 500,000 Americans die from cancer. The National Cancer Institute estimates that on average each person who dies from cancer loses 15 years of life, and altogether cancer deaths were responsible for nearly 8.7 million person-years of life lost in 2003, the most recent year for which the data were available.

"The loss of life and earning potential and the social impact of cancer are enormous," Colditz says. "Reducing risk by adopting lifestyle changes like quitting smoking and losing weight isn't always easy, but it may help to remember that these behavior changes can also reduce your risk of heart disease, diabetes, stroke and osteoporosis."

Colditz's recommendations for preventing cancer also include avoiding excess alcohol consumption, taking a multivitamin with folate and protecting yourself from too much sun and from sexually transmitted diseases.

Colditz recently became leader of the Siteman Center's cancer prevention program having previously headed the Harvard Center for Cancer Prevention.

Physical fitness

Estimates hold that 20 to 30 percent of the most common cancers in the United States stem from being overweight or physically inactive. Research has linked weight gain to common cancers such as breast and colon cancer, as well as uterine, esophageal and renal cancers. "Women who lose weight in their adult years reduce their risk of breast cancer significantly," Colditz notes.

Furthermore, he asserts that a clear connection exists between higher levels of physical activity and lower incidence of cancer. "For example, even after diagnosis of breast cancer, physical activity has an impact on recurrence and survival," he says.

Consumption

What people breathe in, drink or eat can influence whether they get cancer. It's well known that smoking is associated with lung cancer, but less commonly understood is that smokers also are more likely to get colorectal cancer as well as kidney, pancreatic, cervical and stomach cancers.

"The rate at which risk drops after stopping smoking varies for different cancer sites," Colditz says. "But it's very clear that within five to 10 years there will be a 50 percent reduction in cancer risk compared to people who keep smoking."

Although some recent evidence has suggested that wine and other alcoholic beverages may contain beneficial components, other data show that overconsumption of alcohol increases the possibility of getting oral, esophageal, breast and other cancers.

Eating a plant-based diet can help protect against cancer. People who eat diets rich in fruits and vegetables have a lower danger of cancers of the colon, mouth, pharynx, esophagus, stomach and lung. Diets high in red meat and animal fat increase the probability of certain cancers. "There's a strong, consistent relation between higher intake of red meat and higher risk of colon cancer," Colditz notes.

High intake of folate, a B vitamin, may protect a person from cancer, and epidemiological studies suggest that low folate status may play an important role early in cancer development. Colditz says experts recommend taking a multivitamin that contains folate every day.

Other factors

Reducing long-term exposure to the sun and to artificial light from tanning beds, booths and sun lamps can lower the danger of getting non-melanoma skin cancer. Avoiding burns and other damage from these sources — especially in children and teens — can reduce the chances of getting melanoma skin cancer.

Certain viral infections have also been strongly linked to cancer development. Some of the most important of these are human papillomavirus (HPV), a cause of cervical cancer, hepatitis B and C viruses, major causes of liver cancer, and Helicobacter pylori, which accounts for the majority of cases of stomach cancer. HPV can be spread by sexual contact, and vaccine-conferred immunity results in a marked decrease in precancerous lesions.

As with the new cervical cancer vaccine, advances in chemoprevention will likely add to the prevention potential that comes from healthy lifestyle choices. "In the future we'll be seeing a range of new preventative strategies," Colditz indicates. "For example, the National Cancer Institute has a trial looking at selenium as a supplement to prevent cancer. And research shows that antiestrogens may reduce the risk of breast cancer by 60 to 80 percent in women after menopause."

Machine Learning Could Speed Up Radiation Therapy For Cancer Patients

A new computer-based technique could eliminate hours of manual adjustment associated with a popular cancer treatment. In a paper published in the Feb. 7 issue of Physics in Medicine and Biology, researchers from Rensselaer Polytechnic Institute and Memorial Sloan-Kettering Cancer Center describe an approach that has the potential to automatically determine acceptable radiation plans in a matter of minutes, without compromising the quality of treatment.

"Intensity Modulated Radiation Therapy (IMRT) has exploded in popularity, but the technique can require hours of manual tuning to determine an effective radiation treatment for a given patient," said Richard Radke, assistant professor of electrical, computer, and systems engineering at Rensselaer. Radke is leading a team of engineers and medical physicists to develop a "machine learning" algorithm that could cut hours from the process.

A subfield of artificial intelligence, machine learning is based on the development of algorithms that allow computers to learn relationships in large datasets from examples. Radke and his coworkers have tested their algorithm on 10 prostate cancer patients at Memorial Sloan-Kettering. They found that for 70 percent of the cases, the algorithm automatically determined an appropriate radiation therapy plan in about 10 minutes.

"The main goal of radiation therapy is to irradiate a tumor with a very high dose, while avoiding all of the healthy organs," Radke said. He described early versions of radiation therapy as a "fire hose" approach, applying a uniform stream of particles to overwhelm cancer cells with radiation.

IMRT adds nuance and flexibility to radiation therapy, increasing the likelihood of treating a tumor without endangering surrounding healthy tissue. Each IMRT beam is composed of thousands of tiny "beamlets" that can be individually modulated to deliver the right level of radiation precisely where it is needed.

But the semi-automatic process of developing a treatment plan can be extremely time-consuming -- up to about four hours for prostate cancer and up to an entire day for more complicated cancers in the head and neck, according to Radke.

A radiation planner must perform a CT scan, analyze the image to determine the exact locations of the tumor and healthy tissues, and define the radiation levels that each area should receive. Then the planner must give weight to various constraints set by a doctor, such as allowing no more than a certain level of radiation to hit a nearby organ, while assuring that the tumor receives enough to kill the cancerous cells.

This is currently achieved by manually determining the settings of up to 20 different parameters, or "knobs," deriving the corresponding radiation plan, and then repeating the process if the plan does not meet the clinical constraints. "Our goal is to automate this knob-turning process, saving the planner's time by removing decisions that don't require their expert intuition," said Radke.

The researchers first performed a sensitivity analysis, which showed that many of the parameters could be eliminated completely because they had little effect on the outcome of the treatment. They then showed that an automatic search over the smaller set of sensitive parameters could theoretically lead to clinically acceptable plans.

The procedure was put to the test by developing radiation plans for 10 patients with prostate cancer. In all 10 cases the process took between five and 10 minutes, Radke said. Four cases would have been immediately acceptable in the clinic; three needed only minor "tweaking" by an expert to achieve an acceptable radiation plan; and three would have demanded more attention from a radiation planner.

Radke and his coworkers plan to develop a more robust prototype that can be installed on hospital computers and evaluated in a clinical setting. He hopes to see a clinical prototype in place at Memorial Sloan-Kettering in the next few years. The researchers also plan to test the approach on tumors that are more difficult to treat with radiation therapy, such as head and neck cancers.

In a related project, Radke is collaborating with colleagues at Boston's Massachusetts General Hospital to create computer vision algorithms that offer accurate estimates of the locations of tumors. This automatic modeling and segmentation process could help radiation planning at an earlier stage by automatically outlining organs of interest in each image of a CT scan, which is another time-consuming manual step.

The research is supported by the National Cancer Institute and the Center for Subsurface Sensing and Imaging Systems (CenSSIS) at Rensselaer, which is funded by the National Science Foundation. Renzhi Lu, a graduate student in electrical engineering at Rensselaer, also contributed to the research.

Prostate Cancer Patients See High Survival Rates With Seed Implants

More than ninety percent of men who receive appropriate radiation dose levels with permanent radiation seed implants to treat their prostate cancer are cured of their cancer eight years after diagnosis, according to a study released in the February 1 issue of the International Journal for Radiation Oncology*Biology*Physics, the official journal of ASTRO.

Seed implants have become a widely-accepted treatment option for early stage prostate cancer because it is very effective at curing the cancer, is minimally invasive and often spares patients from side effects of other treatments, such as impotence and incontinence. The seeds, similar in size to a grain of rice, contain a radiation dose that, once implanted, delivers concentrated radiation to the prostate, sparing surrounding organs and tissue.

Doctors in this study evaluated the long-term results of permanent seed implants in men with early stage prostate cancer. Nearly 2,700 men were studied at 11 institutions in the United States over eight years. The radioactive seeds were administered with the aid of ultrasound-guided techniques to accurately place the seeds in the prostate gland. The patients received the seed implants as the sole treatment for prostate cancer with no additional chemotherapy or radiation therapy.

The results are also dependent on the quality of the seed implant according to Dr. Michael J. Zelefsky, M.D., lead author of the study and Chief of Brachytherapy Services at Memorial Sloan-Kettering Cancer Center in New York.

Medical centers participating in the study were Memorial Sloan-Kettering Cancer in New York, M.D. Anderson Cancer Center in Houston, New York Prostate Institute in Oceanside, N.Y., Arizona Oncology Services in Scottsdale, Ariz., Seattle Prostate Institute in Seattle, Chicago Prostate Institute in Chicago, Cleveland Clinic Foundation in Cleveland, Massachusetts General Hospital in Boston, Mayo Clinic in Rochester, Minn., University of Michigan Medical School in Ann Arbor, Mich., and Fox Chase Cancer Center in Philadelphia.

Brown Cancer Biologists Identify Major Player in Cell Growth

When cells go about the business of dividing, they can get sidelined. Maybe there aren't enough nutrients. Maybe there aren't the right signals to resume multiplying. Either way, cells go quiet.

What can restart cell division — the process that drives the development of embryos, the renewal of hair, skin and blood, and the creation of cancer — is a single transcription factor called GABP, according to new research from The Warren Alpert Medical School of Brown University and Rhode Island Hospital.

The work, published online in Nature Cell Biology, introduces a new pathway that can be manipulated to control cell growth. Since cell growth is a fundamental biological process, the research may shed light on everything from miscarriages to muscular dystrophy. The main application, however, is cancer. Since a key characteristic of cancer cells is unchecked growth, the research identifies potential targets for new treatments.

During the cell cycle, the four-phase process of cell division, there is a period when the biochemical brakes are put on and cells become inactive. Then the process is kick-started and cells move into the so-called S phase, when DNA is duplicated. This is a critical juncture. If genes are missing or broken, these alterations are passed on to the new cell — and could result in disability or in diseases such as cancer.

So biologists are keenly interested in identifying the accelerators that rev-up cell division. Ets
transcription factors, a family of gene-regulating proteins that are major players in embryonic and cancer development, seemed obvious culprits. Rosmarin, a hematologist-oncologist, studies one member of the Ets family called GABP. This transcription factor helps make a variety of cells, including white blood cells. If those cells develop abnormally, leukemia results.

But the exact function of GABP in the cell cycle wasn't known. Rosmarin wanted to find out. So he and members of his laboratory created mice that carried a mutation — tiny DNA sequences were inserted into their GABP-making gene. These DNA bits would serve as a time bomb of sorts, deleting a critical piece of the gene when given a chemical signal.

>From these mice, Rosmarin and his team grew fibroblasts — common connective tissue cells — in a Petri dish with nutrient-rich serum and watched them grow. When they detonated their time bomb, GABP was disrupted, and the fibroblasts' ability to divide was dramatically reduced. At the same time, other genes known to restart cell division were unchanged.

The team confirmed GABP's critical role in cell growth another way. Simply forcing dormant cells to make GABP, they found, was enough to rouse cells from their slumber and get them to grow again. 

Rosmarin said that now that they had found out a way to disrupt GABP and stop division, there is the possibility that a drug could be made to do the same thing in cancer cells.

This research has been done in Brown University.

Passive Smoke In Workplace Increases Lung Cancer Risk

Image Courtesy: Wikipedia

An analysis of nearly two dozen studies confirms the association between passive smoke in the workplace and an increased risk of lung cancer, according to a report in the American Journal of Public Health.

The research, led by University of Illinois at Chicago epidemiologist Leslie Stayner, is posted online and will appear in the March print issue of the journal.

Stayner and colleagues conducted a statistical analysis combining data from 22 studies evaluating workplace smoking exposure and lung cancer risk. They also analyzed workers' level and duration of exposure to passive smoke and their risk of lung cancer.

The researchers found a 24 percent increase in lung cancer risk among people exposed to passive smoke in the workplace. Workers who were highly exposed had a 100 percent increased (or doubled) risk of lung cancer, and workers with a long history, or duration, of exposure to
passive smoke had a 50 percent increased risk.

"We believe this provides the strongest evidence to date of the relationship between workplace environmental tobacco smoke and lung cancer," said Stayner, professor and director of epidemiology and biostatistics at the UIC School of Public Health, and lead author of
the study.

The research, Stayner said, has important policy implications for cities and states that have not yet legislated smoking bans in bars and restaurants where there are high levels of environmental smoke.

Co-authors include James Bena of the Cleveland Clinic Foundation; Annie Sasco of the Victor Segalen Bordeaux 2 University in France; Randall Smith of the National Institute for Occupational Safety and Health, Cincinnati; Kyle Steenland of Emory University; Michaela Kreuzer of the GSF-National Research Centre for Environment and Health in Neuherberg,
Germany; and Kurt Straif, of the International Agency for Research on Cancer, Lyons, France.

New Test Predicts Blood Cancer's Sensitivity To Experimental Cancer Drug

BCL 2
Image courtesy: Wikipedia

A test developed by Dana-Farber Cancer Institute scientists is the first to identify which malignant blood cells are highly vulnerable to a promising type of experimental drugs that unleash pent-up "cell suicide" factors to destroy the cancer.

The researchers demonstrated that chronic lymphocytic leukemia, CLL, which is diagnosed in 10,000 Americans each year, is an easy mark for the new drug because the cancerous cells are strongly dependent on a particular survival molecule, Bcl-2, that keeps the self-destruct signals at bay. They showed that the investigational drug neutralizes the Bcl-2 action, unleashing molecules that trigger suicide in the cancer cells, a process known as programmed cell death or apoptosis.

The research in the laboratory of Anthony Letai, MD, PhD, of Dana-Farber, is described in the January issue of The Journal of Clinical Investigation. The lead author is Victoria Del Gaizo Moore, PhD, a member of the Letai group.

Letai was a colleague of the late Stanley J. Korsmeyer, MD, of Dana-Farber, who discovered the key role in cancer played by anti-apoptosis molecules such as Bcl-2, which promote the survival of cells that are damaged or abnormal despite the body's efforts to eliminate them through apoptosis.

Inspired by this pioneering research, drug companies have begun testing novel Bcl-2 inhibiting drugs designed to restart the natural death processes thwarted by the survival molecule.

Letai said that his group has tested Abbott's investigational compound ABT-737 against cultured CLL cells with striking results. "We've treated CLL samples from several dozen patients, and each has responded to a very low concentration of the drug," said Letai. "We find it particularly interesting that the cells died within four hours."

Cells from CLL, a currently incurable disease, are vulnerable to this dramatic reversal of fortune because they are "primed for death;" they are surviving only because Bcl-2 proteins are blocking powerful cell-death molecular signals by holding them hostage. Primed cells, Letai explained, are like a car with a revved-up engine on the edge of a cliff, restrained only by its emergency brake; if the brake was released, the car would plunge over the cliff.

Drugs such as ABT-737, in effect, release the brake. The drug molecules liberate the pro-death signaling molecules from their Bcl-2 captors. These pro-apoptosis molecules -- a key one is called BIM -- then trigger a chain of events that cause the cell's power plants, or mitochondria, to rupture and spill out chemicals that cause the cell to die and be tagged for disposal. This class of drugs is expected to be relatively non-toxic to most normal cells, which are much less dependent on Bcl-2 function than are cancer cells to stay alive.

"It's essential to figure out which cancers are going to respond to the drug by identifying the cells that are dependent on Bcl-2 for survival," said Letai, who is also an assistant professor of medicine at Harvard Medical School. "Up to now there hasn't been a way to do this."

In developing the test, the Letai team first isolated mitochondria from cancer cells; then they exposed them to protein fragments -- peptides -- that were known to interact with survival molecules like Bcl-2. "If they interact, then the cell is primed to die, and the test will identify which of the survival molecules is keeping the cells alive," he added. "Then you know that to kill the cell, you have to target Bcl-2."

The researchers have dubbed the test "BH3 profiling" because the array of protein fragments are known as "BH3 domains." Letai said work is under way to make the laboratory profiling operation more automated, looking toward a time when it could be used on a routine basis to assess the vulnerability of patients' cancers to compounds that antagonize BCL-2 or related anti-death proteins.

"This is a totally new class of drugs and has the potential to be a major addition to how we treat cancer," he said.

The paper's co-authors are Jennifer R. Brown, MD, PhD, Michael Certo, Tara M. Love, PhD, and Carl D. Novina, MD, PhD, all of Dana-Farber.

The research was funded by the National Institutes of Health, the Dunkin' Donuts Rising Stars Program, the Richard and Susan Smith Family Foundation, and the Sidney Kimmel Foundation for Cancer Research.

Toward Development Of An 'Eggshell-and-yolk' Anticancer Nanomedicine

Scientists in Hong Kong are reporting synthesis and early laboratory tests of a new nanostructure that they believe may lead to the design of an anticancer nanomedicine.

In a study scheduled for publication in the Feb. 21 issue of the weekly Journal of the American Chemical Society, Bing Xu and colleagues describe the structure as an eggshell nanocrystal.

Like a chicken's egg, the structure has an outer shell that encloses a "yolk" that can be released from the shell.

In their experiments, the researchers used a yolk consisting of iron and platinum, the metal responsible for the activity of the widely used chemotherapeutic drug, cisplatin. Cultures of human cancer cells took up the nanostructures and the nanostructures released their yolks, which proved to have "exceptionally high toxicity" for the cancer cells.

"This type of yolk-shell nanostructures may lead to novel nanomedicine for treating cancers," the researchers state, describing nanostructures that may be coated with antibodies that specifically target cancer cells and thus reduce body-wide side effects that occur with traditional chemotherapeutic drugs.

Scientists Uncover Enzyme's Dual Role In Cancer Metastasis

Before cancer cells can migrate, or metastasize, to other parts of the body, they first have to disconnect from their neighbors in the tumor. A team of University of Wisconsin-Madison and Canadian scientists has made a surprising discovery: The same enzyme that controls the ability of cancer cells to move also governs a process that binds them tightly in place.

"It's kind of a schizophrenic enzyme in a sense, because it can control both pathways," says Richard Anderson, a pharmacology professor in the UW-Madison School of Medicine and Public Health and lead author of the study published in the Jan. 29 issue of the Journal of Cell Biology. "But it is also so fundamental, because this enzyme is at the forefront of regulating two key aspects of cancer metastases."

Anderson and his colleagues reported earlier how the enzyme, known scientifically as PIP kinase, dictates the growth of protein clusters that metastasizing cancer cells use to crawl through tissue. The researchers now describe PIP kinase's role as a "master switch" in the assembly of another protein, called E-cadherin, on the outermost membrane of cells. There, E-cadherin prevents cell migration by holding cells together so tightly even the tiniest ions can't pass between them.

"One of the hallmarks of cancer, especially metastatic cancer, is a loss of E-cadherin at the outer membrane of cells," says Anderson. "If we could decipher how to enhance PIP kinase's control of E-cadherin, we could block metastasis."

The team studies a specific cell type, the epithelial cell, which is known to give rise to roughly 70 percent of all human cancers. A single layer of epithelial cells grows as a protective lining, like a row of bricks, around all the organs and compartments in the body, such as the intestines, the lungs, and the ducts in breast tissue. E-cadherin contributes to these barriers by maintaining extremely tight contacts between adjacent epithelial cells that keep materials from leaking from one compartment into another.

When epithelial cells begin growing out of their neat rows and into disorganized, cancerous masses, E-cadherin can suppress metastasis by holding the cells together. The trick is for cells to continue assembling E-cadherin at the outer membrane, says Anderson, rather than taking the protein into the cell interior. That's where regulation by PIP kinase comes in.

Based on their data, the scientists have proposed a model in which PIP kinase first binds to E-cadherin and then links it to a specific protein complex. This event marks E-cadherin's entry into the protein transport system of the cell. At the same time, PIP kinase produces a signaling molecule that directs E-cadherin - now in the form of a carrier known as a vesicle - to the outer membrane, where it creates the tight cell-cell connections.

The entire process is closely regulated, but the initial bond between PIP kinase and E-cadherin seems to be a critical step. As evidence, Anderson points to a particular genetic mutation in E-cadherin that prevents it from binding to PIP kinase. This mutation is sufficient to induce an inherited and highly metastatic type of gastric cancer, says Anderson, which often strikes people in their early thirties.

In response to other regulatory cues and in association with another protein, called talin, PIP kinase also controls a nearly opposite process in cancer cells - the one in which they develop an ability to crawl away from a tumor.

"I think what we're seeing now is that this enzyme is one of the molecules that defines the fate of cells: whether cancer cells will stay together or metastasize," says Anderson.

Anderson's research is funded by the National Institutes of Health.

Molecular Link between Inflammation and Cancer Discovered

A team led by biochemists at the University of California, San Diego has found what could be a long-elusive mechanism through which inflammation can promote cancer. The findings may provide a new approach for developing cancer therapies.

The study, published in the January 26 issue of the journal Cell, shows that what scientists thought were two distinct processes in cells--the cells' normal development and the cells' response to dangers such as invading organisms--are actually linked. The researchers, who were also from the Salk Institute for Biological Studies and the La Jolla Institute for Allergy and Immunology, say that the linkage of these two processes may explain why cancer, which is normal growth and development gone awry, can result from chronic inflammation, which is an out-of-control response to danger.

"Although there is plenty of evidence that chronic inflammation can promote cancer, the cause of this relationship is not understood," said Alexander Hoffmann, an assistant professor of chemistry and biochemistry at U.C. San Diego, who led the study. "We have identified a basic cellular mechanism that we think may be linking chronic inflammation and cancer."

Cellular defense is a rapid process compared to cellular development, just as a state's response to terrorist threats is swifter than the construction of new infrastructure. However, in both settings, safeguarding against threats and building structures have certain steps in common and require similar types of workers, or molecules.

Hoffmann referred to the parallel sets of steps in cellular defense and development as "mirror image pathways." His team showed that these pathways are not distinct from one another because they are linked by a protein called p100. They found that inflammation leads to an increase in p100, but that p100 is also used in certain steps in development. Therefore p100 allows communication between inflammation and development.

A small amount of dialogue between inflammation and development is beneficial, say the researchers, akin to how information from anti-terrorism efforts could be useful to crews building the state's infrastructure. On the other hand, the constant influence of defense processes on development is detrimental.

"Studies with animals have shown that a little inflammation is necessary for the normal development of the immune system and other organ systems," explained Hoffmann. "We discovered that the protein p100 provides the cell with a way in which inflammation can influence development. But there can be too much of a good thing. In the case of chronic inflammation, the presence of too much p100 may overactivate the developmental pathway, resulting in cancer."

In the paper, the researchers propose that thinking of the processes of defense and development as part of a single large system "represents an opportunity for therapeutic intervention." For example, it might be easier to break the link between inflammation and cancer by targeting the developmental pathway, rather than the inflammation pathway.

"Many of the developmental signals that cells use are sent outside the cell, so they should be easier to block with drugs than inflammation signals, which tend to be confined within cells," said Hoffmann. "It's more challenging to design drugs that will enter cells."

Because the molecules that play a role in the inflammation and development pathways have been extensively studied for many years, the researchers say that it is surprising to find a new molecule that significantly revises scientists' understanding about the interactions between inflammation and development. They credit their discovery to an approach that combines biochemical techniques and computation.

"Our mathematical model of inflammation and development includes 98 biochemical reactions," said Soumen Basak, a postdoctoral fellow working with Hoffmann. "When we ran the model, it predicted that p100 levels would be elevated for a significant period of time when the inflammation pathway was stimulated. We confirmed the prediction using biochemical techniques with cells in the laboratory."

"The finding is exciting because it means that p100 provides cells with a memory to inflammatory exposure," added Basak, who was the first author on the paper.

Also contributing to the study were Hana Kim, Jeffrey D. Kearns, Ellen O'Dea, Shannon L. Werner and Gourisankar Ghosh from U.C. San Diego, Vinay Tergaonkar and Inder M. Verma from the Salk Institute for Biological Studies, and Chris A. Benedict and Carl F. Ware from the La Jolla Institute for Allergy and Immunology.

The study was supported by the National Institutes of Health, the Leukemia and Lymphoma Society of America and the American Heart Association.