Researchers block common colon cancer tumor type in mice

July 20, 2016
Electron microscopic image of a single human lymphocyte. Credit: Dr. Triche National Cancer Institute

A new scientific study has identified why colorectal cancer cells depend on a specific nutrient, and a way to starve them of it. Over one million men and women are living with colorectal cancer in the United States. The National Cancer Institute estimates 4.5% of all men and women will be diagnosed with the cancer during their lifetime, making it the third most common non-skin cancer.

In the study published online in Nature Communications, researchers showed how certain colorectal reprogram their metabolism using glutamine, a non-essential amino acid. Many cancer cells rely on glutamine to survive. How they become so dependent on the molecule is hotly debated in the field.

Researchers studied a subset of colorectal cancer cells containing a genetic mutation called PIK3CA. This mutation is located in a gene critical for cell division and movement, and is found in approximately one third of all colorectal cancers. The mutation is also the most commonly identified genetic mutation across all cancers, making the results of the study universally appealing.

Researchers were interested in determining whether or not the common PIK3CA mutation contributes to changes in cancer cell metabolism, such as how nutrients like glutamine are processed. Normally, glutamine is broken down by cancer cells into several other molecules with the help of specific enzymes. This complicated system helps produce adenosine triphosphate, the energy currency of all cells, and other molecules critical for colorectal cancer cell growth.

The researchers found that colorectal cells with the PIK3CA mutation broke down significantly more glutamine than cells without the mutation. The researchers identified several enzymes involved in the process that are more active in the mutant cancer cells than in other cell types, explaining the increased need for glutamine. These enzymes become overactive in the mutant cancer cells due to a cascade of signals led by the protein encoded by mutant PIK3CA gene. This finding represents a novel and important link between the common PIK3CA mutation and altered glutamine metabolism in cancer cells.

Zhenghe John Wang, PhD, professor of genetics and genome sciences and co-leader of the Cancer Genetics Program at Case Western Reserve University School of Medicine helped lead the study. "In layman's terms, we discovered that colon cancers with PIK3CA oncogenic are addicted to glutamine, a particular nutrient for cancer cells. We also demonstrated that these cancers can be starved to death by depriving glutamine with drugs."

When the researchers lowered the amount of glutamine available to mutant cancer cells growing in laboratory dishes, the cancer cells died. This discovery led the team to investigate the effects of blocking glutamine availability in mice with colorectal cancer tumors containing the common PIK3CA mutation. Wang and colleagues found that exposing these mice to a compound that blocks glutamine metabolism consistently suppressed tumor growth. They did not observe the same effect on tumors without the mutation. Together, these results provide a promising new therapeutic avenue to suppress growth of colorectal tumors with the PIK3CA mutation. The researchers have filed a patent application based on the unique mechanism of tumor suppression they have identified and the work is available for licensing.

"This study provides the basis for a colon cancer treatment clinical trial that will be started in the summer at the University Hospitals Seidman Cancer Center," according to Neal Meropol, MD, Dr. Lester E. Coleman, Jr. Professor of Cancer Research and Therapeutics, chief of the division of hematology and oncology, and principal investigator for the trial. The phase I/II study will test the effects of a glutamine metabolism inhibitor in patients with advanced colorectal tumors.

Explore further: Starving cancer cells by blocking their metabolism

More information: Yujun Hao et al, Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer, Nature Communications (2016). DOI: 10.1038/ncomms11971

Related Stories

Starving cancer cells by blocking their metabolism

June 14, 2016
Scientists at EPFL have found a way to starve liver cancer cells by blocking a protein that is required for glutamine breakdown—while leaving normal cells intact. The discovery opens new ways to treat liver cancer.

Starving cancer the key to new treatments

May 5, 2016
Researchers have identified a vital supply route that cancer cells use to obtain their nutrients, in a discovery that could lead to new treatments to stop the growth of tumours.

Targeting downstream proteins in cancer-causing pathway shows promise in cell, animal model

November 13, 2012
The cancer-causing form of the gene Myc alters the metabolism of mitochondria, the cell's powerhouse, making it dependent on the amino acid glutamine for survival. In fact, 40 percent of all "hard-to-treat" cancers have a ...

Scientists find potential loophole in pancreatic cancer defenses

March 27, 2013
Dana-Farber Cancer Institute scientists and colleagues have discovered that pancreatic cancer cells' growth and spread are fueled by an unusual metabolic pathway that someday might be blocked with targeted drugs to control ...

Genes may determine aspirin's effect on advanced colon cancer

October 24, 2012
(HealthDay)—For patients suffering from advanced colorectal cancer, aspirin may prolong their lives if their tumor has a certain gene mutation, a new study finds.

Genetic mutations found linked to rare cases of multiple bowel tumors

July 5, 2016
Researchers have identified genetic mutations affecting the immune system which may lead to the development of more than one bowel tumour at the same time. Understanding how these cancers develop could improve targeting of ...

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 ...

0 comments

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.