Discovery sheds light on mechanisms that allow cells to steer directly toward chemical cues

May 30, 2002

Biologists at the University of California, San Diego have found that two genes associated with the development of human cancer play a central role in orienting a cell's "internal compass," guiding white blood cells with missile-like precision to the sites of infections and leading other types of cells directly to nutrients and a myriad of other important chemical cues.

Their discovery, detailed in a paper in the May 31 issue of the journal Cell, sheds light on the long-standing mystery of how cells are able to steer directly toward the source of chemical attractants, a process biologists call "chemotaxis."

"Many cells within our body are able to sense chemical signals over long distances and move to the source of these signals," says Richard A. Firtel, a professor of biology and director of the Center for Molecular Genetics at UCSD. "For example, when a wound becomes infected, white blood cells rush to the site of the wound in the body's first major response to fighting the infection. The white blood cells are able to sense the bacteria because the bacteria release small molecules that are recognized by proteins on the surface of the white blood cell. Similarly, breast cancer cells can migrate out of the tumor in the direction of blood vessels, leading to metastasis and secondary sites of tumor formation."

Scientists have learned much about the chemical cues that elicit these responses in cells. But until now, the mechanisms cells use to steer themselves to these attractants had been poorly understood.

Firtel and his colleagues-UCSD postdoctoral researchers Satoru Funamoto and Reudi Meili; Susan Lee, a research associate; and Lisa Parry, an undergraduate student-elucidated how this internal directional compass in cells works by studying Dictyostelium discoideum, a simple social amoeba and model genetic system that exhibits many of the properties of white blood cells. The scientists first determined that chemotaxis in Dictyostelium is controlled by two genes responsible for the production of a pair of proteins-phosphatidylinositol-3 kinase, or PI3K, and phosphatidylinositol-3 phosphatase, or PTEN, the latter of which is associated with half of all human tumors. Mutations in the two genes that control the production of these proteins result in cells that have little chemotaxis ability.

"Instead of moving toward the source of the signal, these cells wander about, having lost their internal sense of direction," says Firtel, who is also chair of the Section of Cell and Developmental Biology of UCSD's Division of Biological Sciences.

Using a fluorescent tag attached to the PI3K molecules to visualize the movement of this protein in living cells, the scientists then determined how the steering mechanism worked. They found that normal cells steered toward chemical attractants by first accumulating PI3K within the part of the cell closest to the direction of the chemical gradient. Once localized there, the protein acts as both an internal compass and steering mechanism.

"At rest, PI3K is uniform in the cell," explains Firtel. "So PI3K functions as a compass by going to the side of the cell closest to the direction it wants to move. That side of the cell is the direction in which the level of the chemical attractant is the highest. This is how a cell senses direction."

The researchers also discovered that when cells lacked PI3K, they were unable to effectively organize the cellular motors to make the cell move. In addition, when PI3K is attached to uniformly to the entire inside of the cell's membrane, the scientists found that the cells no longer put out a new front only in the direction of the chemical attractants.

"The result is that instead of a single front, the cell acts as if it has many fronts moving in many directions at the same time," says Firtel. "It's as if the cell has many drivers, all wanting to lead the cell in a different direction."

Perhaps the most unexpected aspect of the discovery is that the two proteins that control the cell's directional ability, as well as the genes responsible for producing them, also control the development of human cancer.

"PTEN is a regulator of PI3K and, loss of it from cells within our body leads to human cancer," explains Firtel. "PTEN basically works in normal cells to put the brakes on PI3K. When PI3K becomes overactive, you have unregulated cell growth and the cell becomes cancerous."

The researchers demonstrated in their experiments that PTEN controls cell movement in a manner similar to the way it controls the normal growth of cells by inhibiting the activity of PI3K. During chemotaxis, PTEN inhibits the PI3K function in specific sites within the cell, keeping the cell "focused" on going in the right direction. The scientists also discovered that when PI3K is concentrated at the front end of a chemotaxing cell, PTEN is concentrated on the sides and back part of the cell. In this way, the compass, or PI3K, can only work at the front, in the direction the cell wants to move.

"This suggests that PTEN works much like the blinders on a racehorse, restricting its field of vision, so that the cells move efficiently in the direction the compass is pointing," says Firtel. "Cells in which PTEN activity is decreased lose their sense of direction because they have lost these blinders and they make incorrect turns."

Firtel notes that the primary function of these two proteins evolutionarily is to provide the steering mechanisms for normal cellular functions, but that many cancer cells have co-opted this mechanism to metastasize or spread cancerous cells throughout the body.

"There is growing evidence that many cancer cells metastasize using the same process of chemotaxis," he adds. "So, understanding how a white blood cell or Dictyostelium cell moves will provide insights into how cancer cells metastasize. Cancer cells also need to move and they need to move directionally. Chemicals called chemokines within the blood or tissues outside the tumor are what attract the metastasizing cancer cells."

Information about the steering mechanisms that control the accumulation of white blood cells within the body could also provide medical researchers with new tools to control the pain and swelling associated with arthritis and injuries that take longer to heal because of excessive inflammation.

"When we have a site of inflammation or an arthritic attack, white blood cells rush to these sites just as they would to the site of an infection," explains Firtel. "But in this instance, instead of fighting a bacterial infection, the white blood cells trigger other responses, resulting in swelling and pain."

Financial support for the studies that led to these discoveries was provided by grants from the U.S. Public Health Service.
Richard A. Firtel, 858-534-2788,, Cell phone: 619-300-3366

Media Contact:
Kim McDonald, 858-534-7572,

Movies and photographs of Dictyostelium cells orienting and moving toward a chemical attractant released from a micropipette. Credit: Susan Lee and Rick Firtel, UCSD Available at:

University of California - San Diego

Related Cancer Cells Articles from Brightsurf:

Cancer researchers train white blood cells to attacks tumor cells
Scientists at the National Center for Tumor Diseases Dresden (NCT/UCC) and Dresden University Medicine, together with an international team of researchers, were able to demonstrate that certain white blood cells, so-called neutrophil granulocytes, can potentially - after completing a special training program -- be utilized for the treatment of tumors.

New way to target some rapidly dividing cancer cells, leaving healthy cells unharmed
Scientists at Johns Hopkins Medicine and the University of Oxford say they have found a new way to kill some multiplying human breast cancer cells by selectively attacking the core of their cell division machinery.

Breast cancer cells use message-carrying vesicles to send oncogenic stimuli to normal cells
According to a Wistar study, breast cancer cells starved for oxygen send out messages that induce oncogenic changes in surrounding normal epithelial cells.

Breast cancer cells turn killer immune cells into allies
Researchers at Johns Hopkins University School of Medicine have discovered that breast cancer cells can alter the function of immune cells known as Natural killer (NK) cells so that instead of killing the cancer cells, they facilitate their spread to other parts of the body.

Breast cancer cells can reprogram immune cells to assist in metastasis
Johns Hopkins Kimmel Cancer Center investigators report they have uncovered a new mechanism by which invasive breast cancer cells evade the immune system to metastasize, or spread, to other areas of the body.

Engineered immune cells recognize, attack human and mouse solid-tumor cancer cells
CAR-T therapy has been used successfully in patients with blood cancers such as lymphoma and leukemia.

Drug that keeps surface receptors on cancer cells makes them more visible to immune cells
A drug that is already clinically available for the treatment of nausea and psychosis, called prochlorperazine (PCZ), inhibits the internalization of receptors on the surface of tumor cells, thereby increasing the ability of anticancer antibodies to bind to the receptors and mount more effective immune responses.

Engineered bone marrow cells slow growth of prostate and pancreatic cancer cells
In experiments with mice, researchers at the Johns Hopkins Kimmel Cancer Center say they have slowed the growth of transplanted human prostate and pancreatic cancer cells by introducing bone marrow cells with a specific gene deletion to induce a novel immune response.

First phase i clinical trial of CRISPR-edited cells for cancer shows cells safe and durable
Following the first US test of CRISPR gene editing in patients with advanced cancer, researchers report these patients experienced no negative side effects and that the engineered T cells persisted in their bodies -- for months.

Zika virus' key into brain cells ID'd, leveraged to block infection and kill cancer cells
Two different UC San Diego research teams identified the same molecule -- αvβ5 integrin -- as Zika virus' key to brain cell entry.

Read More: Cancer Cells News and Cancer Cells Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to