For Metastases—All Sarcomas are Not Created Equal
An ESUN Article
As an oncologist who specializes in the treatment of sarcomas in children and young adults, all too often I observe a familiar scenario in newly diagnosed patients. Typically, the child or young adult has had recurring pain over the course of several months prior to diagnosis. The pain comes and goes, and may limit sports or other strenuous activity, but usually the patient manages to get by with over-the-counter pain medications for some time. The patient often visits numerous primary care doctors or surgeons who provide many and varied explanations for the pain but do not make the correct diagnosis. Understandably, the patient, and the patient’s parents and/or extended family conclude that the pain “is not serious” and comply with the variety of remedies which are recommended. Finally, the correct diagnosis of sarcoma is ultimately made, and the emotional reaction varies from anger at the medical system for not making the diagnosis sooner to guilt, especially for parents and family members, who feel as though they are somehow responsible for the delay in diagnosis. To make matters worse, it is not uncommon for sarcomas to be metastatic at the time of diagnosis, making the ultimate chance for cure of the tumor less. Especially for patients with metastatic disease at the time of diagnosis, the guilt and anger related to the delay in diagnosis continues to plague the patient and their families throughout the period of treatment and beyond.
But how much does the delay in diagnosis ultimately impact the outcome of treatment? Did the delay in diagnosis give the tumor time to metastasize? Would the tumor have been localized if the diagnosis were made sooner? These questions are asked silently and out loud, over and over again, by both patients and their families. Common sense would suggest that if a tumor is allowed to grow for a longer period of time that it is more likely to spread and therefore more difficult to cure. However, recent scientific evidence shows that this is not always true and confirms, as oncologists have long appreciated, that the time from symptoms to diagnosis does not necessarily correlate with the presence of metastases. Two papers published last month provide evidence that some tumors inherently metastasize early and efficiently, making the likelihood of metastatic disease high even with a quick diagnosis. Other tumors appear to lack what it takes, and therefore are likely to remain localized even if they are allowed to grow for a long period of time prior to diagnosis.
Investigators at the National Cancer Institute in Bethesda, Maryland studied metastasis in both osteosarcoma and rhabdomyosarcoma (Nature Medicine, February 04). In the osteosarcoma study, Khanna et al., derived tumor cell lines from an osteosarcoma which had spontaneously developed in a mouse. The investigators noticed that although all of the cell lines studied readily developed into primary tumors, some lines efficiently metastasized to the lungs while other cell lines did not. The investigators undertook genetic studies to compare these two types of cell lines and found that one particularly interesting molecule, ezrin, was highly expressed only in the highly metastatic lines. Ezrin makes sense as a potential culprit to aid in metastasis since it links the tumor cell’s structural architecture (e.g. the cytoskeleton) to the cell membrane and it may help tumor cells to survive in the harsh environment of the lung which differs substantially from bone where it originated. The investigators then inhibited ezrin and showed that without ezrin expression or function, the highly metastatic lines were converted to low metastasis lines, while maintaining their capacity to develop primary tumors. Adding more credence to the notion that ezrin is important in the spread of osteosarcoma, was data provided from studies of pet dogs with osteosarcoma. Here, although >90% of dogs have metastases at the time of diagnosis, the dogs whose tumors expressed high levels of ezrin did not live as long as those who had tumors with low ezrin. Finally, in children who were diagnosed with localized (non-metastatic) osteosarcoma, those with high ezrin levels in their tumors had faster rates of tumor recurrence compared to those with low ezrin levels.
In the same issue of Nature Medicine, Yu et al. examined a mouse model of embryonal rhabdomyosarcoma, which is another common sarcoma of childhood. Like osteosarcoma, investigators observed that among cell lines derived from animals which were genetically predisposed to rhabdomyosarcoma, there were remarkable differences in their ability to metastasize. Although all of the cell lines were ultimately derived from genetically identical mice, highly metastatic cell lines had evolved a different “genetic signature” than those with low metastatic potential. Ezrin was among a handful of genes that were overexpressed in the highly metastatic cell lines compared to those with low metastatic potential. Forcing high levels of ezrin expression in low metastatic lines again rendered them able to metastasize efficiently. Further, in studies of human rhabdomyosarcoma, higher levels of ezrin expression were found in tumors taken from children with metastatic disease at the time of diagnosis than in those without metastatic disease.
The implications of these studies are several fold. First, by identifying specific molecules that are critical for metastasis, these investigators have provided new potential therapeutic targets. One could imagine for instance, that drugs which inhibit ezrin expression or function could potentially diminish the ability for pediatric sarcomas to metastasize. Since patients are more likely to die from metastasis than primary tumors, the identification of therapies that can specifically target metastatic tumor cells is critically important. Beyond the potential for new therapies however, these studies also illustrate what most practicing oncologists come to appreciate over time but which may not be apparent to patients and their families. That is that some tumors are highly aggressive and metastasize early even in the face of a quick diagnosis. Others tend to be less aggressive, and may not metastasize, even when there has been a long delay in the time to diagnosis. This is not to suggest that primary care physicians should not become more adept at rendering a diagnosis of sarcoma earlier in young patients with recurring and unexplained pain. However, the emerging science would suggest that the genetic signature of the tumor may be a more important factor than the time from symptom onset to diagnosis in determining whether or not metastases are present at the time of clinical presentation.
References
The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis, by Chand Khanna, Xiaolin Wan, Seuli Bose, Ryan Cassaday, Osarenoma Olomu, Arnulfo Mendoza, Choh Yeung, Richard Gorlick, Stephen M Hewitt and Lee J Helman, Nature Medicine, February 2004 Volume 10 Number 2 pp 182-186.
Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators, by Merlino, February 2004 Volume 10 Number 2 pp 175-181.
V1N2 ESUN Copyright © 2004 Liddy Shriver Sarcoma Initiative.