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BROCCOLI RESTORES CANCER FIGHTING GENE

Web address:      http://www.sciencedaily.com/releases/2009/04/      090420151225.htm

Naturally Occurring Compounds Selectively Deplete Mutant P53 In Tumor Cells

ScienceDaily (Apr. 24, 2009) — Researchers at Lombardi Comprehensive Cancer Center at Georgetown University Medical Center have demonstrated that naturally-occurring compounds can selectively deplete mutant p53 and restore "wild type" function to p53 in a variety of tumor cells.

Mutations in the p53 tumor suppressor gene – which is involved in apoptosis and DNA repair – occur in about half of all human tumors. p53 often acts as a checkpoint preventing abnormal cells from continuing to grow and divide. However mutations in p53 gene are one way that pre-cancerous cells overcome normal cellular controls and replicate without restraint.

This study demonstrates for the first time that phenethyl isothiocyante (PEITC), a naturally-occurring compound, can selectively deplete mutant p53. The authors also made an intriguing observation that the depletion of mutant p53 in human cancer cells is accompanied by restoration of the wild type p53. PEITC is a member of the isothiocyanate family compounds found in cruciferous vegetables, such as watercress, broccoli and cabbage. PEITC has been shown to have cancer preventive activity.

The researchers found that PEITC not only decreases the level of mutated p53 protein in tumor cells, but also restores the "wild type" or normal activity to mutated p53. The effect of this is that tumor cell lines with mutant p53 became more sensitive to PEITC-induced cytotoxicity than tumor cells with wild type p53, suggesting that the normal p53 checkpoint control pathways have been restored in the mutant p53-expressing tumor cells. This novel finding suggests that the PEITC and other compounds in the isothiocyante family could play important role in both cancer prevention and treatment of human cancers with mutant p53.

 

CANCER TURNS OUT TO BE A CLOT OF PROTEINS

Cancer turns out to be a p53 protein aggregation disease 

http://www.vib.be/en/news/Pages/Cancer-turns-out-to-be-a-protein-aggregation-disease.aspx

Vrije Universiteit Brussel – Flanders, Belgium

Protein aggregation, generally associated with Alzheimer’s and mad cow disease, turns out to play a significant role in cancer. In a paper published in Nature Chemical Biology, Frederic Rousseau and Joost Schymkowitz of VIB, K.U.Leuven and Vrije Universiteit Brussel describe that certain mutations of p53, an important tumor suppressor, cause the protein to misfold in a way that the proteins start to aggregate. This not only disrupts the protective function of normal p53, but of other related proteins as well.

p53 plays a central role in protection against cancer

In the study, the focus was on the p53 protein which plays a key role in protecting the body against cancer. If p53 works normally, it controls cell division. If p53 control ceases - e.g. when there is a mutation in the protein - the cells start to divide in an uncontrolled manner and this may result in a tumor. Mutations in p53 are observed in about half of cancer cases, making the protein an important target in the development of new cancer therapies. 

Mutated p53 aggregates

“We have revealed a new mechanism for the action of mutant p53,” Joost Schymkowitz and Frederic Rousseau of VIB, Vrije Universiteit Brussel and K.U. Leuven say. “Mutations in p53 cause the protein to lose its protective function. The proteins change in shape, hook into each other and begin to aggregate. The active p53 disappears from the cell and can no longer carry out its control function properly." The mechanism has been encountered in about one third of p53 mutations.

Complete switch of character

Moreover, the mutations cause p53 to assume a completely different character.  From being a protective factor, the mutated p53 changes into a substance which in fact speeds up tumor growth. It seems to form aggregates with control substances (p63 and p73) in the cell, causing them to lose their function as well.

Other proteins underlying cancer and Alzheimer

Even though the underlying principle – protein aggregation - occurs similarly in particular cancers, Alzheimer and systemic amyloidosis, the diseases are otherwise totally unconnected with each other. In cancer, the clustering of p53 protein leads to uncontrolled cell growth. In Alzheimer, clustering of the beta-amyloid protein causes brain cells to die off.

Questions

As this research can give rise to patient related questions, anyone interested address them to patients@vib.be  

Financing

This research was financed by FWO, Chinese Science Council and VIB.

Scientific publication

Jie Xu et al, Gain of function of mutant p53 by coaggregation with multiple tumor suppressors, Nature Chemical Biology

Research team

This research was conducted by Jie Xu under the supervision of Frederic Rousseau en Joost Schymkowitz of VIB, Vrije Universiteit Brussel en K.U.Leuven. Also Jean-Christophe Marine and Diether Lambrechts, other VIB scientists attached to K.U.Leuven collaborated to the work.

 

"NUTRITION AND GENETICS BREED CANCER"

Gene is linked to colon cancer when folate's low

March 29th, 2011 in Medicine & Health / Cancer

(PhysOrg.com) -- Cornell researchers report that they have identified a gene that increases the risk for colon cancer in laboratory mice when their diets lack folate.

Colorectal cancer is the second leading cause of cancer-related deaths in the United States. More than 50,000 people die each year in this country from colon cancer, many due to a lack of early detection.

The new study, published in the March 15 issue of the journal Cancer Research (71:6), provides evidence that a combination of folate deficiency and reduced expression of the SHMT1 gene, which is required for accurate DNA synthesis, boosts the risk of colon cancer in a mouse model. The study indicates that the SHMT1 gene may be a factor in itself, and also demonstrates how dietary folate, a B vitamin, may interact with an individual's genetic make-up to increase colon cancer risk. The same researchers implicated this gene as a cause of neural tube defects, a common class of birth defects (see story).

"Nutrition and genetics work together to contribute to the creation of cancer cells, and based on the similarity of folate metabolism in mice and humans; it is likely that this gene is associated with human colon cancer, "said Patrick Stover, professor in the Division of Nutritional Sciences and the senior author of the paper.

In the study, Stover and Cornell colleagues found that the interactions among nutrients and genetic factors play an important role in the development of numerous cancers, including colorectal cancer.

"Molecular antecedents that promote development of sporadic colon cancer include DNA damage. Lack of critical nutrients (such as folate) increases rates of DNA damage. Therefore, lack of folate has the potential to induce this damage that ultimately results in the progression of colon cancer risk," said Stover.

Screening for colorectal cancer is recommended to all individuals over age 50; however, close to 40 percent of the U.S. population in this age group does not take this precautionary method. Individuals who choose not to pursue colonoscopies may want to ensure that their diets contain adequate amounts of folate, Stover recommended. The U.S. recommended daily allowance for folate is 400 micrograms per day. Foods that are rich in folate include many fruits and vegetables, grains, legumes, nuts and seeds.

Provided by Cornell University

"Gene is linked to colon cancer when folate's low." March 29th, 2011. http://www.physorg.com/news/2011-03-gene-linked-colon-cancer-folate.html

 

STEM CELLS LIKELY CULPRIT IN COLON CANCER

http://www.sciencedaily.com/releases/2011/03/      110317131159.htm

Stem Cells May Be Key to Understanding the Origins of Colon Cancer and Detecting Relapse

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Intestinal epithelium with tumour stem cells marked in brown. (Credit: Image courtesy of Institute for Research in Biomedicine (IRB Barcelona))

ScienceDaily (Mar. 17, 2011) — Colorectal cancer cells trigger a set of genes similar to those found in intestinal stem cells, scientists at the Institute for Research in Biomedicine (IRB Barcelona) have found. The team of researchers, led by ICREA researcher Eduard Batlle, propose that patients with colorectal cancer undergo genetic tests of their intestinal epithelium in order to predict a higher risk of relapse. The results of the study, published online this week in Cell Stem Cell, offer new possibilities for diagnosing and treating the disease.

Colon cancer is the second cause of death by cancer worldwide. Current treatment for the disease normally involves a combination of surgery and chemotherapy. Most patients who are treated successfully go into remission, but nearly 40% relapse within months or years, when the cancer returns or metastasizes. "This shows us that there are cells within the tumour that regenerate the disease," says Batlle, "but we still know very little about the biological reasons why."

 

Cancer's "hard core"

 

The study conducted by Anna Merlos-Suárez and other researchers in Batlle's team has uncovered a close relation between intestinal stem cells (non-specialised cells that generate all cells within the intestine) and colorectal cancer. The researchers compared genes that are activated in cells from a healthy intestine -- both stem cells and specialised cells -- with the genes that are activated in tumour cells taken from patients. "Our results show that patients with colon cancer have a set of genes activated that is very similar to the set activated in stem cells. The more genes they have activated in common, the more likely it is that the patient's cancer will spread and relapse.

These stem cell genes become activated in a subset of cells in the tumour, called "tumour stem cells." When Batlle's team transplanted these cells into mice, tumours formed. Their results add to the growing hypothesis that cancer organizes itself hierarchically, in such a way that only specific cells, "tumour stem cells," are able to initiate and propagate the cancer.

What is it about stem cells that allows them to promote cancer? By definition, stem cells renew tissues, including in this case the intestinal epithelium, and can produce up to 5 grams of intestinal epithelial cells each day. Scientists believe that tumours may exploit the capacity of these cells to renew indefinitely in order to grow and spread. Furthermore, while the majority of cells have an average lifespan of days, as in the case of intestinal epithelial cells, or even months, stem cells survive for many years, increasing the probability that their DNA will accumulate damage and that they will turn cancerous.

One of the biggest hurdles that oncologists face is a lack of tools to identify which patients have a higher risk of relapse. Discovering a close relation between intestinal stem cells and the propagation of cancer is a clear breakthrough in this respect. The hypothesis that colorectal cancer requires a specific type of cell to develop and thrive has also been demonstrated in other types of cancer, including gliomas, some types of lymphoma or breast cancer. This finding opens the door for the development of treaments aimed at these new targets in the fight against cancer: tumour stem cells.

 

HEATED CHEMO HELPS PATIENT

Surgeons Combine Heat, Chemistry to Bolster Anti-Cancer Drugs

http://www.sciencedaily.com/videos/2005/1205-heated_chemo.htm

December 1, 2005 — In efforts to boost the effectiveness of anti-cancer drugs, a new method called intra-peritoneal hyperthermic chemotherapy works by flushing a heated chemotherapy drug through tissue surrounding a tumor. Immediately after the tumor is removed, heat boosts the drug's potency and weakens the tumor's ability to repair itself. The targeted delivery means a higher concentration of the anti-cancer drug reaches the tumor.

 

WINSTON-SALEM, N.C.--There are some cancers against which chemotherapy is virtually useless, but a new technique is making a major difference for some patients.

Day-by-day cancer patient Fred Blum is regaining his strength. Just five months ago, he was battling intestinal cancer -- and the prognosis was bleak. "You just think of this tumor growing and enlarging and getting worse and spreading. And psychologically, it's very hard."

Standard chemo does little to fight advanced abdominal cancers like Blum's. But now, surgical oncologists are using a new twist to make chemo effective and extend survival for patients who often have no other options.

It's called intraperitoneal hyperthermic chemotherapy. It works by flushing a heated chemotherapy drug through tissue surrounding a tumor immediately after the tumor's removed. Perry Shen, an assistant professor of surgery at Wake Forest University Baptist Medical Center in Winston-Salem, N.C., says "That hopefully provides kind of a mop-up or cleanup of any residual cancer cells left behind."

Heat boosts the drug's potency and weakens the tumor's ability to repair itself. The targeted delivery means a higher concentration of the chemo reaches the cancer. "This procedure can provide them a longer-term survival than regular chemotherapy alone," Dr. Shen says.

Before the treatment, Blum's prognosis was about six months. Now, he's planning on staying healthy and strong for a long time.

Some patients are undergoing treatment in an effort to prevent cancer from spreading to the abdomen from nearby organs like the appendix. There's potential the heated chemo could be applied to some non-intestinal, hard-to-treat cancers, like pancreatic cancer.

BACKGROUND: Researchers at Wake Forest University Baptist Medical Center have shown that surgery plus inserting heated chemotherapy drugs directly into the abdomen can improve survival rates, as well as the quality of life, in patients who suffer from several types of cancer. These cancers include tumors of the abdominal cavity (peritoneal cancer, which affects the lining of the abdominal wall) that have spread to multiple organs, and advanced ovarian cancer. Patients with these types of cancer usually fare poorly with conventional cancer treatments.

HOW IT WORKS: There are two stages to the new procedure. First, as much as possible of the cancer is removed with surgery. This often involves multiple organs. Next, while the patient is still on the operating table, the surgeon injects a heated saline solution combined with the chemotherapy drug directly into the abdominal cavity. Scientists have found that tumor tissue is more sensitive to heat than normal tissue. So raising the temperature of the drug makes the tumor less resistant to chemotherapy.

THE RESULTS: The results from four separate studies conducted on animals indicate that the new procedure could kill cancer cells that have spread to other parts of the body. And delivering the drug immediately after the surgery means that more of the drug remains near the tumor instead of spreading throughout the entire body. This means less of the usual unpleasant side effects of chemotherapy.

Editor's Note: This article is not intended to provide medical advice, diagnosis or treatment.

 

 

Note: This story and accompanying video were originally produced for the American Institute of Physics series Discoveries and Breakthroughs in Science by Ivanhoe Broadcast News and are protected by copyright law. All rights reserved.

 

 

BROCCOLI IS GENE THERAPY CANCER FIGHTER

Discovery of a Biochemical Basis for Broccoli's Cancer-Fighting Ability

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Broccoli. Scientists are reporting discovery of a potential biochemical basis for the apparent cancer-fighting ability of broccoli and its veggie cousins. They found for the first time that certain substances in the vegetables appear to target and block a defective gene associated with cancer. (Credit: iStockphoto)

ScienceDaily (Jan. 26, 2011) — Scientists are reporting discovery of a potential biochemical basis for the apparent cancer-fighting ability of broccoli and its veggie cousins. They found for the first time that certain substances in the vegetables appear to target and block a defective gene associated with cancer.

Their report, which could lead to new strategies for preventing and treating cancer, appears in ACS' Journal of Medicinal Chemistry.

Fung-Lung Chung and colleagues showed in previous experiments that substances called isothiocyanates (or ITCs) -- found in broccoli, cauliflower, watercress, and other cruciferous vegetables -- appear to stop the growth of cancer. But nobody knew exactly how these substances work, a key to developing improved strategies for fighting cancer in humans. The tumor suppressor gene p53 appears to play a key role in keeping cells healthy and preventing them from starting the abnormal growth that is a hallmark of cancer. When mutated, p53 does not offer that protection, and those mutations occur in half of all human cancers. ITCs might work by targeting this gene, the report suggests.

The scientists studied the effects of certain naturally-occurring ITCs on a variety of cancer cells, including lung, breast and colon cancer, with and without the defective tumor suppressor gene. They found that ITCs are capable of removing the defective p53 protein but apparently leave the normal one alone. Drugs based on natural or custom-engineered ITCs could improve the effectiveness of current cancer treatments or lead to new strategies for treating and preventing cancer.

The authors acknowledged funding from the Ruth L. Kirschstein National Research Service Award and a grant from the National Cancer Institute of the National Institutes of Health.

 

VITAMIN D CAN STOP CANCER IF ENZYME HELD IN CHECK

Study links vitamin D to lung cancer survival

March 1st, 2011 in Medicine & Health / Cancer

 Recent research suggests vitamin D may be able to stop or prevent cancer. Now, a new study finds an enzyme that plays a role in metabolizing vitamin D can predict lung cancer survival.

The study, from researchers at the University of Michigan Comprehensive Cancer Center, suggests that this enzyme stops the anti-cancer effects of vitamin D.

Levels of the enzyme, called CYP24A1, were elevated as much as 50 times in lung adenocarcinoma compared with normal lung tissue. The higher the level of CYP24A1, the more likely tumors were to be aggressive. About a third of lung cancer patients had high levels of the enzyme. After five years, those patients had nearly half the survival rate as patients with low levels of the enzyme.

Researchers then linked this to how CYP24A1 interacts with calcitriol, the active form of vitamin D. CYP24A1 breaks down calcitriol, which has a normal and crucial role when kept in check. But when levels of CYP24A1 climb, the enzyme begins to hinder the positive anti-cancer effects of vitamin D.

Results of the study appear in Clinical Cancer Research.

Previous studies have linked low levels of vitamin D to a higher incidence of cancer and worse survival. Researchers are looking at using vitamin D to help prevent lung cancer from returning and spreading after surgery. This new study suggests the possibility of using CYP24A1 levels to personalize this approach to those likely to benefit most.

"Half of lung cancers will recur after surgery, so it's important to find a way to prevent or delay this recurrence. A natural compound like vitamin D is attractive because it has few side effects, but it's even better if we can determine exactly who would benefit from receiving vitamin D," says study author Nithya Ramnath, M.D., associate professor of internal medicine at the U-M Medical School.

Researchers also are working to identify drugs that block CYP24A1. Blocking the enzyme would reinstate the positive anti-cancer effects of vitamin D, suggesting that this inhibitor could potentially be combined with vitamin D treatments.

More information: Reference: Clinical Cancer Research, Vol. 17, No. 4, pp. 817-826

Provided by University of Michigan Health System

 

"Study links vitamin D to lung cancer survival." March 1st, 2011. http://www.physorg.com/news/2011-03-links-vitamin-d-lung-cancer.html