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joi, 15 decembrie 2011

Gene Mechanism That Stops Colorectal Cancer Modelled In Mice

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Academic Journal
Main Category: Colorectal Cancer
Also Included In: Cancer / Oncology; Genetics
Article Date: 15 Dec 2011 - 6:00 PST

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A research team in France has bred a lab mouse with a gene mutation that allows colorectal cancer tumors to grow because the protein coded by the gene is no longer able to trigger cell suicide ("apoptosis"). They hope their discovery will pave the way for developing a treatment that targets the gene so it reactivates apoptosis in cancer cells. They write about their findings in a letter published online on 11 December in the journal Nature.

The team has been working for some time in trying to understand more about cell death, and apoptosis in particular. Once activatived, the mechanism sets the cell onto a self-destruct path. The team's leader is Patrick Mehlen, Director of the DEVweCAN 'Laboratory of Excellence' at the Lyon Cancer Research Centre at the Université de Lyon, Centre Léon Bérard.

For the past 15 years, researchers in this field have been debating about the tumor-suppressing ability of a gene called DCC which in humans codes for a receptor protein known as Deleted in Colorectal Carcinoma. Receptor proteins sit on the surfaces of cells and are receptive to "ligands", special molecules that engage with them and change their behavior, such as activating or silencing signals that do things like control processes inside the cell.

We already know from previous research that DCC expression is either lost or significantly reduced in the majority of advanced colorectal cancers. We also know, that the DCC receptor triggers apoptosis, unless engaged to its ligand, netrin-1.

Mehlen and colleagues proposed that the receptors act like sentinels on the surface of the cells: these sentinels are constantly looking at what is happening in their environment, which is why they are also called "dependence receptors".

While the ligand is engaged, the DCC receptor protein sends out a signal that "all is well", and so does not activate cell death, and the cell survives. But when the ligand is not there, the receptor effectively interprets this as "all is not well", and releases the cell-death trigger.

When you apply this sentinel idea to cancer cells, then it would suggest that the absence of ligands causes the DCC receptors to signal "all is not well", and so set the cells on a path of self-destruction, thus causing the death of rogue cells that would otherwise grow into a tumor.

But, as Mehlen and colleagues point out in their Nature paper, until now, no animal tests have been able to support the idea that this side of DCC is a cause of aggressive cancer development.

So, to investigate the role that DCC-triggered apoptosis might play in the control of tumor development, they used mice already genetically predisposed to develop colon cancer (they have a particular variant of the APC gene), and further modified them so they carried a mutation of DCC whose apoptosis trigger is silent.

They found that the mice spontaneously developed colon cancer.

Mehlen and colleagues describe their findings in the Nature letter:

"Although the loss of DCC-induced apoptosis in this mouse model is not associated with a major disorganization of the intestines, it leads to spontaneous intestinal neoplasia at a relatively low frequency. Loss of DCC-induced apoptosis is also associated with an increase in the number and aggressiveness of intestinal tumours in a predisposing APC mutant context, resulting in the development of highly invasive adenocarcinomas."

They conclude that these results show that DCC behaves as a tumor suppressor in that it has the ability to trigger apoptosis in cancer cells.

Mehlen told the press:

"The organism is naturally protected from the development of cancers thanks to the presence of this tumour-suppressing gene."

But, unfortunately, there are some cancer cells that manage to escape this control by blocking the dependence receptor mechanism of DCC.

"That is how we know that the DCC gene is extinguished in most human cancers,' he explained.

The researchers hope it won't be long before this work leads to new target treatments that reactivate cell death in cancer cells. This could apply to other cancers too, such as breast and lung cancer.

"Our group has developed several candidate drugs that reactivate the cell death induced by the DCC receptor in animal models, and we hope to be able to carry out human clinical testing of these candidate drugs in three years' time," said Mehlen.

Mehlen has just been awarded Liliane Bettencourt Schueller Life Sciences Prize, which will help to fund his work.

Written by Catharine Paddock PhD
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

Visit our colorectal cancer section for the latest news on this subject. "DCC constrains tumour progression via its dependence receptor activity"; Marie Castets, Laura Broutier, Yann Molin, Marie Brevet, Guillaume Chazot, and others; Nature published online 11 December 2011; DOI:10.1038/nature10708; Link to Abstract.
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marți, 13 decembrie 2011

Vaccine Developed That Attacks Breast Cancer In Mice; Implications For Ovarian, Colorectal And Pancreatic Cancers

Main Category: Breast Cancer
Also Included In: Pancreatic Cancer; Ovarian Cancer; Immune System / Vaccines
Article Date: 13 Dec 2011 - 3:00 PST

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Researchers from the University of Georgia and the Mayo Clinic in Arizona have developed a vaccine that dramatically reduces tumors in a mouse model that mimics 90 percent of human breast and pancreatic cancer cases - including those that are resistant to common treatments.

The vaccine, described this week in the early edition of the journal Proceedings of the National Academy of Sciences, reveals a promising new strategy for treating cancers that share the same distinct carbohydrate signature, including ovarian and colorectal cancers.

"This vaccine elicits a very strong immune response," said study co-senior author Geert-Jan Boons, Franklin Professor of Chemistry and a researcher in the UGA Cancer Center and its Complex Carbohydrate Research Center. "It activates all three components of the immune system to reduce tumor size by an average of 80 percent."

When cells become cancerous, the sugars on their surface proteins undergo distinct changes that set them apart from healthy cells. For decades, scientists have tried to enable the immune system to recognize those differences to destroy cancer cells rather than normal cells. But since cancer cells originate within the body, the immune system generally doesn't recognize them as foreign and therefore doesn't mount an attack.

The researchers used unique mice developed by Sandra Gendler, Grohne Professor of Therapeutics for Cancer Research at the Mayo Clinic in Arizona and co-senior author on the study. Like humans, the mice develop tumors that overexpress a protein known as MUC1 on the surface of their cells. The tumor-associated MUC1 protein is adorned with a distinctive, shorter, set of carbohydrates that set it apart from healthy cells.

"This is the first time that a vaccine has been developed that trains the immune system to distinguish and kill cancer cells based on their different sugar structures on proteins such as MUC1," Gendler said. "We are especially excited about the fact that MUC1 was recently recognized by the National Cancer Institute as one of the three most important tumor proteins for vaccine development."

Gendler pointed out that MUC1 is found on more than 70 percent of all cancers that kill. Many cancers, such as breast, pancreatic, ovarian and multiple myeloma, express MUC1 with the shorter carbohydrate in more than 90 percent of cases.

She explained that when cancer occurs, the architecture of the cell changes and MUC1 is produced at high levels, promoting tumor formation. A vaccine directed against MUC1 has tremendous potential, Gendler said, as a preventative for recurrence or as a prophylactic in patients at high risk for particular cancers. A vaccine also can be used together with standard therapy such as chemotherapy in cancers that cannot be cured by surgery, such as pancreatic cancer.

Boons noted that MUC1 is also overexpressed in 90 percent of the subset of patients who are not responsive to hormonal therapy, such as Tamoxifen or aromatase inhibitors, or the drug Herceptin. These so-called "triple-negative" tumors are extremely aggressive and difficult to treat, Boons said, and a new treatment option is urgently needed.

"In the U.S. alone, there are 35,000 patients diagnosed every year whose tumors are triple-negative," Boons said. "So we might have a therapy for a large group of patients for which there is currently no drug therapy aside from chemotherapy."

Therapeutic vaccines received renewed attention last year when the Food and Drug Administration approved the first cancer treatment vaccine, a drug known as Provenge that is used to treat metastatic prostate cancer. Treatment with the drug, which is manufactured in Georgia, requires clinicians to isolate immune cells from the patient and then to send the cells to a lab, where they are linked to a protein that stimulates the immune system. The cells are returned to the patient's treating physician, who then infuses the drug over three treatments, usually two weeks apart.

Boons' vaccine, on the other hand, is much simpler. It is fully synthetic, meaning that its components can be manufactured in a lab with assembly-line precision. The vaccine consists of three components - an immune system booster known as an adjuvant, a component that triggers the production of the immune system's T-helper cells, and a carbohydrate-linked peptide molecule that directs the immune response to cells bearing MUC1 proteins with truncated carbohydrates.

Biotechnology is a key industry in Georgia, and this year Boons founded an Athens-based company, known as Viamune, to help develop and commercialize the vaccine and the technologies used to create it. The company is one of nearly 30 that are affiliated with the University's BioBusiness Center, which is an incubator for life sciences start-up companies associated with UGA.

"Companies like these have the potential to create stable, high-paying jobs that have a significant social and economic impact," said Stefan Schulze, associate director of the Georgia BioBusiness Center. He noted that Viamune was a one four finalists selected from 40 companies at an investor's forum hosted this year by the non-profit organization Southeast BIO.

Boons, Gendler and their colleagues are currently testing the vaccine's effectiveness against human cancer cells in culture and are planning to assess its toxicity. If all goes well, they anticipate that phase I clinical trials to test the safety of the vaccine could begin by late 2013.

The vaccine represents nearly a decade of work on the part of Boons and his team. A 2007 study demonstrated the vaccine's effectiveness in another mouse model, and Boons is cautiously optimistic about his most recent results. Although promising results in mice often don't translate to humans, Boons said he is confident that vaccines that target the specific carbohydrate signatures of cancer cells will ultimately play an important role in the treatment of the disease.

"We are beginning to have therapies that can teach our immune system to fight what is uniquely found in cancer cells," Boons said. "When combined with early diagnosis, the hope is that one day cancer will become a manageable disease."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our breast cancer section for the latest news on this subject. In addition to co-senior authors Boons, Ph.D., and Gendler, Ph.D., the co-first authors on the paper are Vani Lakshminarayanan, Ph.D., at the Mayo Clinic in Arizona and Pamela Thompson at the University of Georgia. Additional authors include, at UGA, Margreet Wolfert, Ph.D., and Therese Buskas, Ph.D., and, at the Mayo Clinic, Judy Bradley, Latha Pathangey, Cathy Madsen and Peter Cohen, M.D.
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