Inflammation is a central pathway that may act as both cause and effect in a range of musculoskeletal disorders as diverse as arthritis, implant loosening, and bone tumors. For Francis Y. Lee, MD, PhD, the current chair of the AAOS Clinician Scientist Development Program, a better understanding of inflammation may open doors to innovative treatments, particularly for osteosarcomas.
“Rubor (redness), calor (heat), tumor (swelling), dolor (pain), and functio laesa (loss of function)— these classical signs of inflammation were described by Galen in the second century. But we see these same signs in diseases such as cancers and arthritis,” says Dr. Lee.
“Although the ancient Roman physicians were limited to what they could see with their two eyes, today we are beginning to understand that this recapitulation of the inflammatory profile may be the result of fundamental similarities in the underlying molecular pathways,” he explains. “Inflammatory mediators, such as phosphorylated extracelluar signal-related kinase (p-ERK) and others, are now understood to play a fundamental role in basic cellular homeostasis, apoptosis, development, tumorigenesis, metastasis, and so on.”
Inhibiting cancer cell growth
Dr. Lee believes that unraveling the inflammatory pathways in osteosarcomas will provide a new therapeutic avenue for treating osteosarcomas. Recently, his group has shown that the inflammatory mediator p-ERK is upregulated in about 70 percent to 80 percent of human osteosarcomas, as well as in several well known osteosarcoma cell lines, such as SAOS-2, and 143B.
In a nude-mouse osteosarcoma xenograft model, Dr. Lee and his colleagues have observed that a specific extracellular signal-related kinese (ERK)-pathway inhibitor, PD98059, helps slow the rate of cancer growth in the early stages, and prolongs ultimate survival.
“Targeted p-ERK inhibition using PD98059 demonstrated an anti-cancer effect comparable to that of traditional chemotherapeutics, such as doxorubicin,” says Dr. Lee, who notes that p-ERK inhibitors such as AZD6244 are already being used to treat some human cancers. His hope is that this emerging paradigm of novel adjuvant therapy will provide new treatment options for aggressive osteosarcomas (Fig. 1).
Why is p-ERK so important in promoting the growth and spread of osteosarcoma? Dr. Lee believes that this may be due to p-ERK’s role in regulating the expression of various proteins that determine a cell’s susceptibility or resistance to apoptosis.
“When healthy cells are growing out of control or disturbing homeostasis, they will naturally destroy themselves through the process of apoptosis. But cancer cells won’t do this,” he explains. “They somehow manage to resist apoptosis. We looked at the expression pattern of p-ERK in human osteosarcomas and compared it to the expression pattern of known apoptotic regulators, such as Bcl-xL, Bcl-2, and Bim. We found that p-ERK ‘co-localizes’ with anti-apoptotic proteins, such as Bcl-xL and Bcl-2, but ‘inverse-localizes’ with pro-apoptotic proteins such as Bim.”
In vitro experiments showed that p-ERK mediates doxorubicin-induced expression of Bcl-2 and Bcl-xL, which give osteosarcoma cells their chemoresistance. Inhibiting p-ERK decreases the expression of anti-apoptotic proteins and increases the expression of the propoptotic protein Bim. Overall, p-ERK inhibition results in osteosarcoma cell death.
“There are still many details to fill in,” says Dr. Lee, “but it seems that p-ERK may be the switch point that regulates the fate of cancer cells.”
Researchers need help
Dr. Lee has received a Research Grant from the Orthopaedic Research and Education Foundation (OREF), an OREF Career Development Award, two R01 grants from the National Institutes of Health, and, most recently, a Technology Development Award from the Department of Defense Congressionally Directed Medical Research Program. He credits the importance of the AAOS Clinician-Scientist Development Program in helping him achieve these awards.
“CSDP initiatives such as the Grant Writing Workshop and the Clinician Scientist Development Program were invaluable to me in honing my skills as a researcher,” he says. “I would encourage young AAOS members to make use of these resources as they work to develop their own research careers.”
However, Dr. Lee also notes that high-quality translational research also requires institutional support. “I gratefully acknowledge my colleagues at the Columbia University Department of Orthopaedic Surgery, and my Chair, Louis U. Bigliani, MD, for making high-caliber research a departmental priority. None of my work would be possible without their support.”
Dr. Lee has no conflicts to disclose.
Kumar Nair is a research technician in the department of orthopaedic surgery at Columbia University.