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Recent work adds support to theory that cells may have metastatic origin.

For years, medical science has looked for clues to what makes cancer cells different from normal cells by studying the telltale changes in the DNA code. But the answer may lie in the very structure of the DNA polymer itself, according to Donald Malins, Ph.D, D.Sc., and his colleagues at Pacific Northwest Research Institute in Seattle. In back-to-back studies, Malins’ team reported that they can detect changes in the structure of DNA that can predict a cancer phenotype in cells before tumors form and furthermore can distinguish metastatic from nonmetastatic cells. Using Fourier transform–infrared spectroscopy (FTIR), a technique more familiar to forensic scientists than to molecular biologists, the scientists use the polymeric nature of DNA to study subtle changes in the stacking of base pairs and the DNA backbone that they then compare with the various stages of tumor development. The changes represent a ripple effect on the DNA polymer that results from chemical alterations to the bases, either through oxidative damage or other epigenetic changes such as methylation, said Malins. Such changes are different in metastatic and nonmetastatic cancer cells, the scientists reported in the August 4 issue of the Proceedings of the National Academy of Sciences (PNAS). But the real shocker came when Malins examined histologically normal cells surrounding prostate tumors and found the DNA identically altered in those cells as well. “We were staggered that the DNA from the normal cell was structurally indistinguishable from [that of] the tumor,” said Malins. “Initially, we didn’t have an explanation for it, but we began to realize if the metastatic cancer phenotype and the primary cancer phenotype is in fact hardwired in apparently normal progenitor cells, the current concept of metastasis is, if not wrong, as least not entirely correct.” The finding supports an emerging model that purports that metastatic progenitor cells may be fundamentally different from primary tumor cells, rather than beginning as primary tumor cells that somehow acquire the ability to become invasive and mobile. “What this paper does is it adds great weight to the idea that the metastatic phenotype evolves either in parallel to or independent of the primary tumor phenotype,” said Thomas Sutter, Ph.D., professor and Feinstone Chair of Functional Genomics at the University of Memphis. “It means metastasis isn’t just another extension of the primary tumor, that it is actually an independent process.” Malins’ study is the latest in a series that suggest the potential for metastasis is acquired in a separate or parallel process to the primary tumor. “If you assume that a metastatic cell has to jump over a set of hurdles, what the genetic background will do is raise or lower the height of the hurdles,” said Kent Hunter, Ph.D., a National Cancer Institute investigator who is studying metastasis in mouse models. “What Malins has shown is that there are at least physical structures that you can use in the DNA to distinguish high and low metastatic genotypes from normal tissue.” Beyond physical differences in structure, studies that use microarray technology to compare the genetic signatures of various tumor types have shown that metastatic cancer displays a very different gene expression pattern from nonmetastatic tumors. Todd Golub, M.D., and his colleagues at Dana Farber Cancer Institute, Boston, reported in the January 2003 issue of Nature Genetics that they identified a gene expression signature that could predict a metastatic phenotype and that it appeared in the bulk of the primary tumor cells, suggesting that tumors likely to metastasize are fundamentally different (see News, March 5, 2003, Vol. 95, No. 5, p. 350). “The [Malins] paper would appear to support the notion that primary tumors with metastatic potential are distinguishable from those without such potential,” said Golub. “The challenge is that the spectral profiles of DNA represent a bit of a ‘black box,’ so that it’s hard to really know how to follow up, and indeed validate, these findings.” However, Sutter pointed out that it is not necessary to fully understand how the FTIR process captures these fundamental changes to be able to use the technology, which is commonly used to distinguish the chemical structure of minute fiber samples and other forensic evidence. “What’s important is that here is a relatively simple procedure that is easy to perform and highly sensitive,” said Sutter. He said it should be simple to test its effectiveness in prospective studies. In fact, a second study from Malins’ group, published in the July 12 issue of PNAS, suggests that treatments that interfere with the development of the cancer phenotype can also delay the onset of cancer. In that study, the researchers injected mice with the known chemical carcinogen 3-methylcholanthrene and studied the development of tumors in the animals. Using the FTIR approach, they observed the development of a cancer phenotype in the animals’ DNA 57 days Dr. Donald Malins Dr. Kent Hunter Recent Work Adds Support to Theory That Cells May Have Metastatic Origin