Submarines have periscopes. Insects have antennae. And increasingly, biologists are finding that most normal vertebrate cells have cilia, small hair-like structures that protrude like antennae into the surrounding environment to detect signals that control cell growth.
In a new study published in the June 29 issue of Cell, Fox Chase Cancer Center researchers describe the strong link between ciliary signaling and cancer and identify the rogue engineers responsible for dismantling the cell's antenna.
Cilia-based sensing has important roles in sight, smell and motion detection and in helping an embryo develop into a normal baby. Defects in cilia can produce a range of disorders, including kidney cysts, infertility, respiratory problems, reversal of organs (for example, heart on the right) and a predisposition to obesity, diabetes and high blood pressure. In each case, cells fail to appropriately detect growth-controlling signals and develop abnormally. Now, researchers are adding cancer to this list.
Many cancers arise from defects in cellular signaling systems, and we think we have just identified a really exciting signaling connection, Fox Chase Cancer Center molecular biologist Erica A. Golemis, Ph.D., points out. In the new study, Golemis and her Fox Chase colleagues found that two proteins with important roles in cancer progression and metastasis, HEF1 and Aurora A, have an unexpected role in controlling the temporary disappearance of cilia during normal cell division, by turning on a third protein, HDAC6. This action causes the antenna to be dismantled in an untimely way.
Why cilia come and go on normal cells is not entirely understood, but scientists increasingly suspect that it may play a role in timing the cell division process. Commonly, cancer cells have entirely lost their cilia, and this absence may help explain why tumors fail to respond properly to environmental cues that cause normal cells to stop growing. Hence, the discovery that too much HEF1 and Aurora A cause cilia to disassemble provides important hints into what may be happening in cancers.
Defects in cilia have already been identified in one disease that represents a significant public health burden. Polycystic kidney disease, or PKD, arises from genetic mutations that cause flawed kidney-cell ciliary signaling. PKD is the most common serious hereditary disease, affecting more than 600,000 Americans and 12.5 million people worldwide.
In this incurable syndrome, patients develop numerous, fluid-filled cysts on the kidneys. For many patients, chronic pain is a common problem. PKD leads to kidney failure in about half of cases, requiring kidney dialysis or a kidney transplant.
The proteins involved in dismantling the cilia are no strangers to Golemis and her team. Golemis has been studying HEF1 for over a decade, since she first identified the gene. She first discovered that HEF1 has a role in controlling normal cell movement and tumor cell invasion. Golemis laboratory has also shown that Aurora A and HEF1 interact to initiate mitosis (chromosome separation) during cell division.