The Story of PTEN
Clues from the cellular slime mold
What does a cellular slime mold have to do with the human cancer gene PTEN? The similarities between us and them suggest a way to treat several types of cancer by activating a silenced second gene that’s already in our genomes. And a cancer that develops a PTEN mutation may become resistant to some drugs and sensitive to others, affecting treatment.
The cellular slime mold Dictyostelium discoideum, which we’ll call “Dicty,” oscillates between a single-celled and a many-celled lifestyle. In times of plenty, when its bacterial food abounds under forest litter, Dicty is a single-celled amoeba, reproducing asexually. But when the environment changes and food vanishes, Dicty becomes social. Starving cells emit a biochemical signal that draws tens of thousands of them together. The resulting mass undulates upward into something shaped like a finger, then topples over to form a multicellular, mobile, gelatinous slug that seeks light, heat, and food. When the slug finds a bacteria-laden nook, perhaps underneath a rotting log, it halts. Then the center telescopes upward, elongating into a “fruiting body” of some 20,000 cells that form a base and stalk that the rest of the cells ascend, like ants crawling over each other to reach a crumb. Cells that reach the top become single-celled spores that then rain down as asexual amoebae. The cycle of life begins anew.
With a little imagination, a Dicty amoeba and the slug that it spawns resemble a human cancer. Both begin with a single cell, and in response to signals, cells divide, invade, and migrate through the landscape – a forest floor or a human body. The underlying genetic basis in both species may be the tumor suppressor gene PTEN.
The cellular slime mold has a PTEN gene, and when it is deleted, disaster ensues. The starving single cells can’t signal and as a result, they meander circuitously. Might PTEN mutations that block slime mold cells from aggregating suggest a point of intervention to block cancer in people?
“PTEN” stands for “phosphatase and tensin homolog deleted on chromosome ten,” and the gene’s product is a type of enzyme called a protein tyrosine phosphatase. PTEN is a classic tumor suppressor in that it normally provides a “brake” on cell division. When the brake is lifted, the cell loses control over division rate and number, how and where it travels, and it becomes able to attach to anything. The errant cell also coaxes the blood supply to feed it and the rest of the growing tumor, as stability of its genome shatters and mutations accumulate.
The PTEN protein is not a good drug target, because it may be absent and if present, it has such diverse activities that adverse effects would be likely. However, drugs can target the molecules that the PTEN gene affects. For example, deleting PTEN activates production of a protein called MTOR.
Two related Food and Drug Administration (FDA)-approved cancer drugs inhibit MTOR. The drug everolimus (marketed as Afinitor) treats subtypes of breast, pancreatic, brain, and kidney cancer, and temsirolimus (trade name Torisel) treats kidney cancer. Several other MTOR inhibitors are in clinical trials.
Many tumor types have missing or abnormal PTEN proteins, including small cell lung cancer, chronic myelomonocytic leukemia (CMML), glioblastoma (a brain tumor), breast cancer, prostate cancer, endometrial (uterine) cancer, melanoma, and high-grade serous ovarian cancer. PTEN is the ninth most commonly mutated cancer gene in “carcinoma of unknown primary site,” when the origin of a tumor can’t be identified.
Loss of PTEN has mostly been associated with adult cancers, but it has recently been found in Ewing sarcoma, which affects bone and soft tissue of children and young adults. Human Ewing sarcoma cell lines and cells from patients that lost PTEN are more resistant to a widely-used chemotherapy drug, vincristine. Screening for PTEN loss could save some patients from having to take the drug unnecessarily, as it has serious side effects including shortness of breath, kidney damage, decreased white blood cell count and platelets, motor difficulties, and hair loss.
PTEN mutations tend to occur in advanced cancers and may have clinical implications. For example, about 70 percent of breast cancers that have responded to the drug trastuzumab (marketed as Herceptin) eventually undergo PTEN mutations, which makes the cells resistant to the drug.
Most PTEN mutations in cancer are somatic (aka sporadic or non-inherited) – that is, they occur in the tumor cells, but not in other cells. Other disorders are associated with inheriting a “germinal” PTEN mutation via sperm or egg, so that the mutation is in all cells. “Hamartoma tumor syndrome” is a collection of conditions that cause benign growths with cell division rates similar to those of surrounding healthy tissue. Germline mutations in PTEN are also seen in autism spectrum disorders, although how loss of cell cycle control changes the brain isn’t known. And experiments in mice at St. Jude Children’s Research Hospital implicate PTEN loss in autoimmune disorders.
The cellular slime mold reveals a very different approach to restoring PTEN function. The human and slime mold genomes have additional, slightly altered versions of the gene, called pseudogenes. Biologist David Soll, at the University of Iowa, found that making too much PTEN via a turned-on pseudogene in the cellular slime mold compensates for too little PTEN in cancer. Could boosting the human pseudogene fight the cancer? A powerful precedent for this approach is a drug to treat sickle cell disease. It works by activating a silenced fetal version of the mutant beta globin gene, combating the anemia.
Nature provides many of our medications, from aspirin in willow bark to antibiotics from soil microorganisms. The tiny, pearly trail of slime coating the underside of a fallen leaf may hold the secret to a powerful approach to rescue cancer cells from a tumor suppressor mutation, PTEN.
And it’s right there in our genomes, courtesy of nature.