VonPurdy-CancerPage

NORMAL CELLS CAN SPONTANEOUSLY MORPH INTO STEM CELLS!

Scientists identify a surprising new source of cancer stem cells

April 11th, 2011 in Medicine & Health / Cancer

 

Whitehead Institute researchers have discovered that a differentiated cell type found in breast tissue can spontaneously convert to a stem-cell-like state, the first time such behavior has been observed in mammalian cells. These results refute scientific dogma, which states that differentiation is a one-way path; once cells specialize, they cannot return to the flexible stem-cell state on their own.

This surprising finding, published online this week in the Proceedings of the National Academy of Sciences (PNAS), may have implications for the development of cancer therapeutics, particularly those aimed at eradicating cancer stem cells.

"It may be that if one eliminates the cancer stem cells within a tumor through some targeted agent, some of the surviving non-stem tumor cells will generate new cancer stem cells through spontaneous de-differentiation," says Whitehead Founding Member Robert Weinberg. Cancer stem cells are uniquely capable of reseeding tumors at both primary and distant sites in the body.

During differentiation, less-specialized stem cells mature into many different cell types with defined functions. These differentiated cells work together to form tissues and organs. Inbreast tissue, for example, differentiated basal cells and luminal cells combine to form milk ducts.

While analyzing cells from human breast tissue, Christine Chaffer, who is a postdoctoral researcher in the Weinberg lab and first author of the PNAS paper, observed a small number of living basal cells floating freely in the tissue culture medium.

Intrigued by the cells' unusual behavior, Chaffer conducted further targeted investigations, including injection of the floating basal cells into mice. After 12 weeks she found that the injected basal cells gave rise to milk duct-like structures containing both basal and luminal cells—a clear indication that the floating cells had de-differentiated into stem-like cells.

Until now, no one has shown that differentiated mammalian cells, like these basal cells, have the ability to spontaneously revert to the stem-like state (a behavior described as plasticity).

To see if basal cells could become cancer stem cells, Chaffer inserted cancer-causing genes into the cells. When these transformed cells were injected into mice, the resulting tumors were found to include a cancer stem cell population that descended from the original injected basal (more differentiated) cells. These results indicate that basal cells in breast cancer tumors can serve as a previously unidentified source of cancer stem cells.

As research for new cancer therapies has recently focused on eliminating cancer stem cells, Weinberg cautions that the plasticity seen in these basal cells suggests a more complicated scenario than previously thought.

"Future drug therapies that are targeted against cancer will need to eliminate the cancer stem cells and, in addition, get rid of the non-stem cells in tumors – both populations must be removed," says Weinberg, who is also a professor of biology at MIT. "Knocking out one or the other is unlikely to suffice to generate a durable clinical response."

Chaffer is now focusing on what actually prompts these flexible cells to de-differentiate, and in the case of cancer cells, how to stop the cells from converting into cancer stem cells.

"This plasticity can occur naturally, and it seems that the trigger may be a physiological mechanism for restoring a pool of stem cells," says Chaffer. "We believe that certain cells are more susceptible to such a trigger and therefore to conversion from a differentiated to a stem-like state, and that this process occurs more frequently in cancerous cells."

In the case of normal epithelial cells, the observed behavior may also allow patient specific adult stem cells to be derived without genetic manipulation, holding promise for degenerative disease therapy.

More information: "Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state" Christine L. Chaffer et al. PNAS (2011)

Provided by Whitehead Institute for Biomedical Research

 

"Scientists identify a surprising new source of cancer stem cells." April 11th, 2011. http://www.physorg.com/news/2011-04-scientists-source-cancer-stem-cells.html

 

CHOLINE IN DIET IMPLICATED IN COLON POLYPS

Diets High In Choline May Increase Risk For Colorectal Polyps

ScienceDaily (Aug. 8, 2007) — Contrary to expectations, diets high in the nutrient choline were associated with an increased risk of some colorectal polyps, which can--but do not always--lead to colorectal cancer, according to a study published online in the August 7 Journal of the National Cancer Institute.

Major food sources of choline include red meat, eggs, poultry, and dairy products. Choline is involved in a biochemical process known as one-carbon metabolism. Studies have shown that people with increased intake of other nutrients required for one-carbon metabolism, such as folate, are at a decreased risk for colorectal polyps. This is the first study to examine the association between choline and colorectal polyps.

Eunyoung Cho, Sc.D., of Brigham and Women's Hospital in Boston and colleagues sent food-frequency questionnaires to women enrolled in the Nurses' Health Study every two to four years from 1984 to 2002. They then estimated the choline content in their diets.

The researchers had hypothesized that choline intake would decrease the risk of colorectal polyps like folate does. But the results suggest the opposite--greater amounts of choline in the diet were associated with an elevated risk of colorectal polyps.

"Although our results were contrary to expectation based on choline's role [in one-carbon metabolism], there is a potential biologic basis for the positive association that we observed...Once a tumor is initiated, growth into a detectable [polyp] depends in part on choline availability because choline is needed to make membranes in all rapidly growing cells," the authors write. However, because this was the first study of choline and colorectal polyps, and other components of diets high in choline may be responsible for the association, the finding needs to be replicated in other studies.

In an accompanying editorial, Regina Ziegler, Ph.D., and Unhee Lim, Ph.D., of the National Cancer Institute in Bethesda, Md., describe the complexity of the relationship between one-carbon metabolism and the development of cancer.

"Clearly, one-carbon metabolism and its role in [cancer development] is more complicated than originally anticipated, and our understanding of the underlying mechanisms is probably incomplete. More research, and caution in developing public health policy and guidance, is warranted," the authors write.

Article: Cho E, Willett WC, Colditz GA, Fuchs CS, Wu K, Chan AT, Zeisel SH, Giovannucci EL. Dietary Choline and Betaine and the Risk of Distal Colorectal Adenoma in Women.

Editorial: Ziegler RG, Lim U. One-carbon Metabolism, Colorectal Carcinogenesis, Chemoprevention -- with Caution. J Natl Cancer Inst 2007; 99:1214-1215

 

IT'S NOT GENES BUT MICROBES IN YOUR GUT

Colon cancer and the microbes in your gut

March 31st, 2009 in Biology / Cell & Microbiology

A typical Western diet, rich in meat and fats and low in complex carbohydrates, is a recipe for colon cancer, Professor Stephen O'Keefe from the University of Pittsburgh, USA, told the Society for General Microbiology meeting at Harrogate today (Tuesday 31 March). He described an expanding body of evidence to show that the composition of the diet directly influences the diversity of the microbes in the gut, providing the link between diet, colonic disease and colon cancer.

People eating a healthy diet containing high levels of complex carbohydrate had significant populations of micro-organisms in their gut called Firmicutes. These bacteria use the undigested residues of starch and proteins in the colon to manufacture short-chain fatty acids and vitamins such as folate and biotin that maintain colonic health. One of these fatty acids, butyrate, not only provides most of the energy to maintain a healthy gut wall, but it also regulates cell growth and differentiation. Both experimental and human studies support its role in reducing colon cancer risk.

However, gut microbes may also make toxic products from food residues. Diets high in meat will produce sulphur - this decreases the activity of 'good' bacteria that use methane and increases the production of hydrogen sulphide and other possible carcinogens by sulphur-reducing bacteria.

"Colon cancer is the second leading cause of cancer-related deaths in adults in Westernized communities." said Professor O'Keefe, "Our results suggest that a diet that maintains the health of the colon wall is also one that maintains general body health and reduces heart disease".

"A diet rich in fibre and resistant starch encourages the growth of good bacteria and increases production of short chain fatty acids which lessen the risk of cancer, while a high meat and fat diet reduces the numbers of these good bacteria." Professor O'Keefe went on. "Our investigations to date have focused on a small number of bacterial species and have therefore revealed but the tip of the iceberg, our colons harbour over 800 bacterial species and 7,000 different strains. The characterization of their properties and metabolism can be expected to provide the key to colonic health and disease".

Source: Society for General Microbiology

 

"Colon cancer and the microbes in your gut." March 31st, 2009. http://www.physorg.com/news157705943.html

 

PROGNOSIS FORMULA FOR COLON CANCER

New Formula Gauges Disease-Free Colorectal Survival

Elsevier Global Medical News. 2011 Apr 1, P Wendling

 

DETROIT (EGMN) - A simple formula that incorporates tumor area and percentage of positive lymph nodes helps predict 5-year disease-free survival in colorectal cancer, and may be used to guide treatment, a new study suggests.

"The formula is simple and inexpensive to apply," lead author Dr. Lisa Poritz said at the annual meeting of the Central Surgical Association. All the data are in the pathology report. "It does not require genetic or biologic tests that are expensive and not available throughout the country."

Although tumor size is not part of the widely used TNM (tumor, node, metastasis) staging system, Dr. Poritz and her colleagues hypothesized that it would be important in determining disease-free survival. To test that hypothesis, they used data from pathology reports to calculate the tumor area-to-node ratio (T:N) for 63 patients with stage III colorectal cancer (CRC) who underwent resection at the Hershey (Pa.) Medical Center from January 2000 to June 2008.

Specifically, tumor area is based on the two largest tumor measures multiplied together. The percentage of positive nodes is based on the number of nodes that are positive divided by the total number of nodes harvested, then multiplied by 100. The T:N ratio is based on the tumor area divided by the percentage of positive nodes.

In all, 35 patients remained disease free at 5 years and 28 developed metastatic disease at a mean of 16.4 months, said Dr. Poritz, a colorectal surgeon at Penn State Hershey.

The mean T:N ratio was significantly higher (2.76) in the disease-free group, compared with 0.50 in the metastatic group (P = .0009), meaning that a higher ratio is a better prognostic sign, she said.

In a receiver operating characteristic analysis, T:N ratio demonstrated the highest correlation with 5-year disease-free survival at an area under the curve of 0.86 vs. 0.79 for percentage of positive nodes, 0.75 for number of positive nodes, and just 0.61 for tumor volume.

When the data were applied to a logistic regression curve, the beta0 was 1.682 and beta1 was 2.274. From these values, the risk of distant metastasis can be calculated for a specific T:N ratio. For example, a patient with a T:N ratio of 1.22 would have a 25% risk of developing metastatic disease in 5 years, compared with a 50% risk for a patient with a T:N ratio of 0.77 and a 75% risk for a patient with a T:N ratio of 0.26, Dr. Poritz said.

Notably, even after controlling for the critical factor of nodal stage, researchers found that the T:N ratio remained significant in logistic regression analysis at a P value of .008.

Dr. Poritz also presented two hypothetical patients to illustrate how the formula could be used to influence clinical decision making. Patient A had a small tumor with an area of 1.52 and 2 of 17 positive nodes. This resulted in a T:N ratio of 0.25 and a 75% risk of developing metastatic disease in 5 years. Patient B had a large tumor with an area of 28.3 and also 2 of 17 positive nodes. The T:N ratio would be 2.4, and the patient would have only a 2% chance of developing metastatic disease within 5 years.

"If you only looked at the number of nodes or [percentage of positive nodes], you might consider treating these patients in exactly the same manner, or at least consider their risk of developing metastatic cancer to be exactly the same," she said. "However, when you use our calculations, you can see that tumor volume is very important, and it changes the risk of developing metastatic disease dramatically in these patients. In this context, you might want to treat patient A more aggressively than patient B."

Invited discussant Dr. Anthony Senagore of the University of Southern California in Los Angeles asked whether data were available on the relationship between T stage and the size of the tumor, because "you seem to imply that what we historically believe about depth of penetration seems to be less important, and that it's the mass of the tumor that matters."

Dr. Poritz replied that depth of penetration - which is included in the TNM staging system - remains important, especially in stage II and node-negative disease when clinicians are trying to determine who should receive chemotherapy. However, the data would suggest that at least within stage III disease, tumor area may be more important than T stage, which has not been shown to correlate well with prognosis either in their study or others.

An audience member remarked that the researchers may be making too big a leap in suggesting that the formula could be used to guide therapy, and asked whether they have considered taking the findings to SWOG (formerly the Southwest Oncology Group) for further validation. Dr. Poritz said that they are in the process of applying the formula to a larger database, similar to that of SWOG.

Colon cancer was present in 21 patients in the disease-free group and in 19 patients in the metastatic group, with 14 cases of rectal cancer in each group. There were no differences between the two groups with regard to sex, age, tumor location, vascular or lymphatic invasion, or T stage. Perineural invasion was significantly more common in the metastatic group than in the disease-free group (11 cases vs. 2 cases), but Dr. Poritz urged caution in interpreting this because data on perineural invasion were not mentioned in 30 cases.

As expected, significantly more patients in the metastatic group than in the disease-free group had an N stage of 2 (18 cases vs. 6 cases) or N stage of 3 (1 case vs. 0). Similarly, the mean number of positive nodes was higher in the metastatic group than in the disease-free group at 6.1 vs. 2.3 (P = .0049), as was the percentage of positive nodes at 39.6% vs. 13% (P = .0006).

The study excluded patients who had inflammatory bowel disease, associated CRC, recurrent cancer, or perforated cancer, or who had received any neoadjuvant therapy or had died of unknown causes or causes other than cancer.

The authors reported no study support or conflicts of interest.

 

WORMWOOD AND OXYGEN KILL CANCER NATURALLY

April 4, 2011

High dose of oxygen enhances natural cancer treatment

By Hannah Hickey

News and Information http://www.washington.edu/news/articles/high-dose-of-oxygen-enhances-natural-cancer-treatment

A technique Michael Jackson reportedly used to prolong his youth is showing promise as a way to boost the effectiveness of a natural cancer remedy.

An environment of pure oxygen at three-and-a-half times normal air pressure adds significantly to the effectiveness of a natural compound already shown to kill cancerous cells, researchers at the University of Washington and Washington State University recently reported in the journal Anticancer Research.

Annual wormwood, Artemisia annua L., yields the important antimalarial drug artemisinin. Researchers at UW and WSU are exploring its ability to treat cancer.

The compound artemisinin – isolated from Artemisia annua L, commonly known as wormwood – is a natural remedy widely used to treat malaria. In the mid-1990s UW researchers were the first to explore its ability to treat cancer.

In the new study, using artemisinin or high-pressure oxygen alone on a culture of human leukemia cells reduced the cancer cells’ growth by 15 percent. Using them in combination reduced the cells’ growth by 38 percent, a 50 percent increase in artemisinin’s effectiveness.

“If you combine high-pressure oxygen with artemisinin you can get a much better curing effect,” said author Henry Lai, a UW research professor of bioengineering. “We only measured up to 48 hours. Over longer time periods we expect the synergistic effects to be even more dramatic.”

The history of artemisinin brings to mind an Indiana Jones story. In the early 1970s, Lai says, Chinese leader Mao Zedong issued an order to develop an anti-malarial treatment. At the same time, a farmer in central China discovered a 2,000-year-old tomb that contained three coffins. One coffin contained a silk scroll describing various prescriptions, including artemisinin to treat malaria. The Chinese followed the directions and thus rediscovered an ancient remedy.

Today, artemisinin is widely used in Asia and Africa for malaria treatment.

In the decades since, scientists have discovered artemisinin reacts with iron within a cell to form a free radical, a highly reactive charged particle that destroys the cell. Because the malaria parasite is high in iron, artemisinin targets malaria-infected cells.

Since rapidly dividing cancer cells also need iron to form new DNA, Lai theorized they would also make targets for artemisinin. Subsequent research showed this to be the case.

Lai and colleagues at the UW developed a variant several thousand times more potent than natural artemisinin, which was licensed in 2004 to a Chinese company.

“Artemisinin is a promising low-cost cancer treatment because it’s specific, it’s cheap and you don’t have to inject it,” Lai said. “It’s 100 times more specific than traditional chemotherapy,” he added. “In breast cancer, it’s even better.”

Lai says he’s long hypothesized that high oxygen levels would enhance artemisinin’s effects, because oxygen promotes the formation of free radicals. In 2010, he put the theory to the test in a hyperbaric chamber that co-author Raymond Quock, WSU professor and chair of pharmaceutical sciences, has been using to study highly pressurized oxygen’s ability to relieve pain.

Reimers Systems, Inc.

A Petri dish with human cancer cells was placed in this high-pressure oxygen chamber for 48 hours.

Hyperbaric chambers, filled with oxygen at high pressure, help scuba divers who surface too quickly gradually readjust to normal oxygen levels. A photo of pop singer Jackson in the mid-80s sleeping in a portable hyperbaric chamber sparked rumors that he was trying to heal scars from plastic surgery, retain his youthful appearance or extend his lifespan. The photo turned out to be a publicity stunt, but the U.S. Food and Drug Administration has approved hyperbaric oxygen therapy for several ailments, including decompression sickness, carbon-monoxide poisoning, severe burns and slow-to-heal wounds.

In clinical practice, the artemisinin-hyperbaric study could lead to people or animals spending time in a hyperbaric chamber to enhance the artemisinin’s effectiveness.

Other co-authors are Yusuke Ohgami, Catherine Elstad and Eunhee Chung of WSU and Donald Shirachi of the Chico Hyperbaric Center. The research was funded by the Washington State University College of Pharmacy and the Chico Hyperbaric Center.

In related artemisinin work, funded through a $1.5 million grant from the state’s Life Sciences Discovery Fund to a team led by UW chemistry professor Tomikazu Sasaki:

                  UW researchers are developing synthetic artemisinin compounds with enhanced potency and anti-cancer selectivity, and WSU researchers are conducting a clinical trial evaluating these compounds’ ability to treat cancer in dogs. The molecular-engineered artemisinin compounds, which are stronger and more targeted than natural artemisinin but can still be taken by mouth, are licensed to Artemisia Biomedical of Newcastle, Wash.

                  WSU crop scientists are planting Artemisia annua in eastern Washington to test whether the region could plant artemisinin as a commercial crop.

                  Researchers are working with Northwest Organic Foods, a Washington chicken-feed company, to try adding artemisinin, instead of small amounts of arsenic, to chicken feed. Artemisinin acts as a natural preventative for avian coccidia infection, one of the poultry industry’s most costly parasitic diseases.

###

For more information, contact Lai at 206-543-1071 or hlai@uw.edu and Quock at 509-335-5956 or quockr@wsu.edu.