Cancer is commonly described as a genetic disease, a proliferation of cells caused by genes gone wrong. That conceptualization has motivated decades of successful cancer research, from Janet Rowley’s landmark studies of chromosomal abnormalities in leukemia to Kevin White’s new project to sequence 1000 tumor genomes. But what if there’s another way to describe what natural process goes awry to create stubborn, fast-growing tumors that can spread throughout the body? What if those cells were like slacker adults – unwilling to grow up and causing trouble through their immaturity?
This idea, cancer as a differentiating disease, was proposed by Tong-Chuan He, associate professor of surgery at the University of Chicago Medical Center, in his lecture to the Committee on Cell Physiology this week. He, the director of the Molecular Oncology Laboratory, came to that theory through his study of osteosarcomas, bone cancers that predominantly arise in growing teenagers. Unlike many other cancer types, osteosarcoma doesn’t appear to run in families, and researchers have failed to find common genetic factors that might offer some clue to its cause.
To He and his laboratory, those characteristics suggested a different culprit: stem cells. Usually publicized for their therapeutic potential, stem cells naturally perform an important role in the growing human body, maturing or differentiating into tissues such as bone, muscle and cartilage. When bones are growing, mesenchymal stem cell replicate rapidly before maturing – or differentiating – into cells called osteoblasts. Osteoblasts then differentiate into osteocytes, the cells that make up bones. When the osteocyte stage is reached, the cells settle into their new life, declining to replicate further.
“Proliferation and differentiation are two opposite fates,” He wrote to me after his talk. “Once a cell is committed to proliferation, it will shut down differentiation, or vice versa.”
The cells that make up osteosarcoma tumors resemble these osteoblasts in some ways, but instead of settling, they continue to replicate and grow. So He’s group hypothesized that osteosarcoma could result from the derailment of this process, trapping these stem cells in the proliferation stage and producing tumors instead of mature osteocytes. Drawing upon simultaneous studies in the laboratory examining the factors that instruct stem cells to follow their path of destiny to bone formation, He looked at the response of osteosarcoma cells to those factors. Sure enough, those cells were resistant to a “differentiating signal” called BMP-9, refusing to mature into osteocytes. Furthermore, treating a mouse model of osteosarcoma with BMP-9 increased the tumor size, suggesting that the stem cells were stuck in a proliferative state.
“What we have seen is that cancer is actually a differentiation disease, not just a genetic disease,” He said. And rather than replacing the genetic theory of cancer, this idea may “upgrade” the earlier concept, making it more specific. “Many of the genetic and epigenetic changes in cancer are changes that lead to disruption of terminal differentiation.”
What may seem like a mere quibble over how to define cancer could actually have a profound effect on how cancer is treated. Currently, He pointed out, most cancer therapies are designed to kill tumor cells while sparing the surrounding normal cells, the strategy behind treatments such as radiation therapy or chemotherapy. But perhaps a smarter strategy would be “differentiation therapies,” forcing the tumor cells out of their immature, proliferating state into the dormant, mature state. One such treatment, overexpressing a class of nuclear receptors for retinoids, was successful in slowing the growth of bone tumors in mouse models.
It’s a strategy that could be expanded beyond osteosarcomas to other cancers as well, He told me in an e-mail conversation after his lecture. Examples of arrested differentiation leading to tumors have also been seen in a certain type of leukemia, where retinoids are already used as therapy.
“Differentiation therapy alone may not be able to cure cancer,” He wrote. “The key is to combine both chemo/radiation therapy and differentiation. By doing so, it may reduce the adverse effect associated with chemo/radiation therapy and may also reduce possible drug-resistance.”