Researchers show how brain's micro-environment fuels metastatic tumor growth

August 9, 2013
researchers show how brain's micro-environment fuels metastatic tumor growth
James Driscoll, MD, PhD.

When a cancer cell breaks off from a tumor in the breast, lung or other part of the body and flows through the bloodstream to the brain, trouble erupts. Like a dandelion seed landing in the most fertile of soils, the tumor cell takes root, multiplies and rapidly grows into an often lethal metastatic brain tumor.

Why this happens with such deadly force in the brain is not completely understood. But how the process unfolds is vividly described by cancer researchers at the Brain Tumor Center at the University of Cincinnati (UC) Neuroscience Institute and UC Cancer Institute in a paper published [online today] in the Nature Publishing Group journal Scientific Reports.

The process is fueled by the interaction between and brain cells, with the cancer cell acting as the seed and the brain tumor cells acting as the soil, says James Driscoll, MD, PhD, assistant professor in the UC Department of Internal Medicine's Division of Hematology Oncology and the study's lead investigator.

"Our focus is on the brain and specifically these cell-to-cell interactions in the , where the tumor cell—the seed—usurps the surrounding beneficial effects of the normal, healthy cells in the brain tissue to actually flourish and blossom within that environment," Driscoll says.

In their paper, the researchers describe a kind of that begins when cancer cells come in physical contact with astrocytes, the most common type of brain cell. When that occurs, a small molecule known as microRNA 768-3p is reduced inside the tumor cell, and a signaling molecule known as K-ras increases. With elevated levels of K-ras acting like a kind of fertilizer, blossoms while chemotherapy drugs are stifled.

"This only happens when cancer cells and brain cells are in direct contact," Driscoll says. "MicroRNA 768 regulates K-ras. When 768 goes down, the levels of K-ras go up. K-ras is the major player that drives tumor growth."

The research carries significant clinical promise. If microRNA-768 is a tumor suppressant that is battered and diminished during its contact with invading cancer cells, a synthetic, better-armored replacement for the molecule could potentially stand up to the cancer and prevent the rise of K-ras and tumor growth.

"The ultimate focus of our studies is to try to block or overcome the growth-promoting effect of the tumor micro-environment, just as you might block the growth of dandelions in your yard," Driscoll says. "We hope to advance these studies eventually to phase-1 and 2 clinical trials, in which we evaluate the efficacy on the overall survival of patients with brain metastases."

The investigator-initiated study was funded by a pilot grant from the Brain Tumor Center Molecular Therapeutics Program and the Mayfield Education & Research Foundation. The Molecular Therapeutics Program, believed to be the first translational, metastasis-specific initiative of its kind in the United States, is a collaboration between the UC Neuroscience Institute and the UC Cancer Institute.

More than 170,000 people are diagnosed with metastatic brain tumors in the United States each year. Despite advances in surgical treatments, chemotherapy and targeted radiation treatment (radiotherapy), survival of brain metastasis remains limited.

Driscoll says researchers initially blamed the blood brain barrier and a cell membrane protein for blocking the effectiveness of on metastatic tumors in the brain. But further research indicated that other, unidentified mechanisms were promoting the stubborn survival of these tumors.

Driscoll and other researchers have recently turned their attention to MicroRNAs. "These are newly discovered, evolutionary preserved small molecules that exist in normal and tumor cells," Driscoll says. "When deregulated, they can promote tumor initiation and metastasis."

In their study, Driscoll and his colleagues first combined lung, breast and melanoma cancer cells with healthy astrocytes in the laboratory. They found that cancer cells that had been "fertilized" with nutrients from the astrocytes showed heightened resistance to chemotherapy in a petri dish.

Moving from the lab to the real world, the researchers used 20 samples of metastatic tissue from the UC Brain Tumor Center's tissue bank to test their hypothesis that that had comingled with astrocytes had a diminished level of microRNA 768 compared to normal .

"We found microRNA-768 to be 100 times lower in metastatic tissue than in normal tissue," Driscoll says. "In one case of melanoma tissue, it was 600 times lower. This supported our premise that the brain micro-environment reduces 768 in real metastatic tumors."

Taking their research a step further, the researchers compared levels of microRNA 768 in both the primary and metastatic brain tumors of 10 patients.

"This was a rare, highly valuable study in which we looked at matched samples of different tumors in the same patient," Driscoll says. "Only through the highly coordinated efforts of surgeons, research teams and a tissue bank could you have such a controlled analysis of such precious tissue. We were able to demonstrate that this microRNA is reduced in metastatic tissue relative to the primary tumor tissue as well.

"We are also indebted to the patients who participated in our study," he adds. "Without them, our advancement of the molecular steps in brain metastases would not have been possible."

Driscoll and his team are now working to introduce a suppressor that blocks the reduction of microRNA-768.

"Our goal is to come back with synthetically engineered microRNA's as replacement therapy, to suppress the cell growth," says Ronald Warnick, MD, medical director of the UC Brain Tumor Center and the John M. Tew, Jr., MD, Chair in Neurosurgical Oncology at UC. "The next step in our program is to evaluate microRNA replacement therapy for metastasis in a mouse model. If we can achieve that, we would then move rapidly toward our goal of human clinical trials and a phase-1 study."

Explore further: New therapy strategy could help treat cancer that has spread from breast to brain

Related Stories

New therapy strategy could help treat cancer that has spread from breast to brain

August 6, 2013
(Medical Xpress)—Researchers at UCLA's Jonsson Comprehensive Cancer Center have successfully combined cellular therapy and gene therapy in a mouse-model system to develop a viable treatment strategy for breast cancer that ...

MicroRNA molecule may serve as biomarker, target for brain metastases in breast cancer patients

February 5, 2013
Researchers have identified two molecules that could potentially serve as biomarkers in predicting brain metastases in patients with breast cancer, according to data published in Cancer Research, a publication of the American ...

Nano drug crosses blood-brain tumor barrier, targets brain tumor cells and blood vessels

July 17, 2013
( —An experimental drug in early development for aggressive brain tumors can cross the blood-brain tumor barrier and kill tumor cells and block the growth of tumor blood vessels, according to a recent study led ...

Signature of circulating breast tumor cells that spread to the brain found

April 10, 2013
Some breast tumor circulating cells in the bloodstream are marked by a constellation of biomarkers that identify them as those destined to seed the brain with a deadly spread of cancer, said researchers led by those at Baylor ...

Technique filters cancer where chemo can't reach

July 30, 2013
(Medical Xpress)—A cancer therapy that removes malignant cells from a patient's cerebrospinal fluid may soon be available to prevent metastases and decrease complications of cancers involving the brain, according to Penn ...

Key molecule suppresses growth of cancerous liver tumors, study finds

February 13, 2013
(Medical Xpress)—A molecule already implicated in a number of diverse cellular functions can suppress the growth of tumors in the liver, a Mayo Clinic Cancer Center study has found. Its name is IQGAP1, and when the molecule ...

Recommended for you

Shooting the achilles heel of nervous system cancers

July 20, 2017
Virtually all cancer treatments used today also damage normal cells, causing the toxic side effects associated with cancer treatment. A cooperative research team led by researchers at Dartmouth's Norris Cotton Cancer Center ...

Molecular changes with age in normal breast tissue are linked to cancer-related changes

July 20, 2017
Several known factors are associated with a higher risk of breast cancer including increasing age, being overweight after menopause, alcohol intake, and family history. However, the underlying biologic mechanisms through ...

Immune-cell numbers predict response to combination immunotherapy in melanoma

July 20, 2017
Whether a melanoma patient will better respond to a single immunotherapy drug or two in combination depends on the abundance of certain white blood cells within their tumors, according to a new study conducted by UC San Francisco ...

Discovery could lead to better results for patients undergoing radiation

July 19, 2017
More than half of cancer patients undergo radiotherapy, in which high doses of radiation are aimed at diseased tissue to kill cancer cells. But due to a phenomenon known as radiation-induced bystander effect (RIBE), in which ...

Definitive genomic study reveals alterations driving most medulloblastoma brain tumors

July 19, 2017
The most comprehensive analysis yet of medulloblastoma has identified genomic changes responsible for more than 75 percent of the brain tumors, including two new suspected cancer genes that were found exclusively in the least ...

Novel CRISPR-Cas9 screening enables discovery of new targets to aid cancer immunotherapy

July 19, 2017
A novel screening method developed by a team at Dana-Farber/Boston Children's Cancer and Blood Disorders Center—using CRISPR-Cas9 genome editing technology to test the function of thousands of tumor genes in mice—has ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.