Illuminating the 'Dark Matter' of the Genome: Vast hidden network regulates gene expression in cancer

Researchers have uncovered a vast new gene regulatory network in mammalian cells that could explain genetic variability in cancer and other diseases.

(Credit: Image courtesy of Columbia University Medical Center)

Researchers at Columbia University Medical Center (CUMC) and two other institutions have uncovered a vast new gene regulatory network in mammalian cells that could explain genetic variability in cancer and other diseases.

The studies appear in the online edition of Cell.

"The discovery of this regulatory network fills in a missing piece in the puzzle of cell regulation and allows us to identify genes never before associated with a particular type of tumour or disease," said Andrea Califano, PhD, professor of systems biology, director of the Columbia Initiative in Systems Biology, and senior author of the CUMC research team.

For decades, scientists have thought that the primary role of messenger RNA (mRNA) is to shuttle information from the DNA to the ribosomes, the sites of protein synthesis.

However, these new studies suggest that the mRNA of one gene can control, and be controlled by, the mRNA of other genes via a large pool of microRNA molecules, with dozens to hundreds of genes working together in complex self-regulating sub-networks.

The findings have the potential to broaden investigations into how tumors develop and grow, who is at risk for cancer, and how to identify and inactivate key molecules that encourage the growth and spread of cancer.

For example, in the case of the phosphatase and tensin homolog gene (PTEN), a major tumour suppressor, deletions of its mRNA network regulators in patients appear to be as damaging as mutations of the gene itself in several types of cancer, the studies show.

The newly identified regulatory network (called the mPR network by the CUMC investigators) allows mRNAs to communicate through small bits of RNA called microRNAs.

Researchers first realized about a decade ago that microRNAs, by binding to complementary genetic sequences on mRNAs, can prevent those mRNAs from making proteins.

Turning this concept on end, the new studies reveal that mRNAs actually use microRNAs to influence the expression of other genes.

When two genes share a set of microRNA regulators, changes in expression of one gene affects the other. If, for instance, one of those genes is highly expressed, the increase in its mRNA molecules will "sponge up" more of the available microRNAs.

As a result, fewer microRNA molecules will be available to bind and repress the other gene's mRNAs, leading to a corresponding increase in expression. Although such an effect had been previously elucidated, the range and relevance of this kind of interaction had not been characterised.

"It turns out that this type of microRNA-mediated regulation is commonplace in the cell, and thousands of genes are regulating one another through hundreds of thousands of microRNA-mediated interactions," says Pavel Sumazin, PhD, research scientist in systems biology and a first author of the CUMC paper.

"This is similar in size and effect to other regulatory networks, such as transcriptional regulatory networks, where target genes are regulated by transcription factors."

In the CUMC study, Dr. Sumazin and his colleagues analyzed glioblastoma mRNA and microRNA expression data from the Cancer Genome Atlas, a public database, uncovering a regulatory layer comprising more than 248,000 microRNA-mediated interactions.

Looking specifically at the tumour suppressor gene PTEN, the researchers found that it is part of a sub-network of more than 500 genes.

Of these genes, 13 are frequently deleted in glioblastoma and seem to work together through microRNAs to stop PTEN activity -- achieving the same result as if the tumors had inactivating mutations or deletions of PTEN itself.

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Vaccine to kill Tumour Cells

This study examines patients with colorectal cancer. Dr. Richard Barth, a Dartmouth surgeon and the author of the study, operated on 26 patients whose colorectal cancer had metastasised to the liver.

In such a situation, patients are expected to die from tiny undetectable metastases that escape the surgeon's scalpel.

But here's where Dr Barth and his colleagues tried something different. They took proteins from the patient's tumor and mixed them with a certain kind of cell grown from the patient's blood.

The personalised vaccines were injected into each patient a month after surgery. Barth was able to determine that about 60% of the patients developed an immune response from the vaccine.

About five years later, he was able to compare the clinical outcomes between those who had had an immune response, and those who had not. Of the group who did not have an immune response from the vaccine, only 18% were alive and tumor-free.

Of the group who did have an immune response from the vaccine, 63% were alive and tumor-free--a remarkable result indeed. (The vaccine approach has the added benefit of being non-toxic, in contrast to chemo.)

The results were published this week in the journal Clinical Cancer Research. This is not the first time doctors have tried to fight fire with fire (or rather, tumor with tumor).

Dr Barth has been trying it on mice and humans for over a decade. And other clinical researchers had tried it as well--but without much success. Researchers were hoping that tumor-derived vaccines could actually attack and kill fully-grown tumors, rather than the microscopic metastases.

Paired drugs kill precancerous colon polyps, spare normal tissue

Paired drugs kill precancerous colon polyps, spare normal tissue

A two-drug combination destroys precancerous colon polyps with no effect on normal tissue, opening a new potential avenue for chemoprevention of colon cancer, a team of scientists at The University of Texas M. D. Anderson Cancer Center reports in the advance online edition of the journal Nature.

The regimen, tested so far in mouse models and on human colon cancer tissue in the lab, appears to address a problem with chemopreventive drugs - they must be taken continuously long term to be effective, exposing patients to possible side effects, said senior author Xiangwei Wu, Ph.D., associate professor in M. D. Anderson's Department of Head and Neck Surgery.

"This combination can be given short term and periodically to provide a long-term effect, which would be a new approach to chemoprevention," Wu said.

The team found that a combination of Vitamin A acetate (RAc) and TRAIL, short for tumour necrosis factor-related apoptosis-inducing ligand, kills precancerous polyps and inhibits tumour growth in mice that have deficiencies in a tumour-suppressor gene.

That gene, adenomatous polyposis coli (APC) and its downstream signaling molecules, are mutated or deficient in 80 percent of all human colon cancers, Wu said.

Ineffective separately, powerful together
Early experiments with APC-deficient mice showed that the two drugs combined or separately did not harm normal colon epithelial cells. Separately, they showed no effect on premalignant polyps called adenomas.

RAc and TRAIL together killed adenoma cells, causing programmed cell suicide know as apoptosis. RAc, researchers found, sensitizes polyp cells to TRAIL.

The scientists painstakingly tracked the molecular cascade caused by APC deficiencies, and found that insufficient APC sensitizes cells to TRAIL and RAc by suppressing a protein that blocks TRAIL.

Drug-trial cancer patients recover: Magic Bullet found! Ipilimumab

Two men with advanced and inoperable prostate cancer have staged dramatic recoveries after being treated with an experimental antibody drug.

Both are now cancer-free and have returned to normal life after they took part in a trial of a drug called ipilimumab that boosts the immune system.

Before treatment at the Mayo Clinic in Rochester, Minnesota, US, each of them had aggressive tumours that had grown well beyond the prostate gland into abdominal areas.

Trial leader Dr Eugene Kwon said: "The goal of the study was to see if we could modestly improve upon current treatments for advanced prostate cancer.

"The candidates for this study were people who didn't have a lot of other options. However, we were startled to see responses that far exceeded any of our expectations."

First, the patients received traditional hormone therapy to remove testosterone, which fuels prostate cancer. Researchers then introduced a single dose of ipilimumab. The drug is an antibody which builds on the hormone therapy and boosts the immune system's response to the cancer.

Both patients saw their prostate specific antigen (PSA) levels drop to the point where they became eligible for surgery. PSA is a protein in the blood that allows doctors to monitor prostate cancer.

When the surgeons made their incisions, they had a surprise. Mayo clinic urologist Dr Michael Blute said: "The tumours had shrunk dramatically. I had never seen anything like this before. I had a hard time finding the cancer. At one point the pathologist asked if we were sending him samples from the same patient."

Further research is now planned to understand more about the mechanisms of the antibody and how best to use it on patients, but Dr Kwon added: "This is one of the holy grails of prostate cancer research. We've been looking for this for years."