When cancer is localized to the site in which it originated, it can often be controlled, and sometimes even cured, by conventional methods; but when cancers metastasize - i.e., spread to distant locations - the situation becomes considerably more ominous. The ability of cancer to metastasize is what makes the disease potentially so deadly.

For the past several decades it has generally been assumed that metastatic spread happens relatively late in the course of the disease, and that it occurs largely as a result of increasing malignancy in the original (primary) tumor. However, several recent papers, including one published last week in the journal Science, have presented new evidence challenging this theory and raising some very interesting questions about how and when cancers begin to spread (Podsypanina, 2008).

The Science paper, authored by researchers from the Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, showed that, contrary to the late spread hypothesis, cells - even normal, non-malignant cells - can, and apparently very frequently do, break away from the organ or tissue in which they originated, and take up residence in distant organs and tissues. In other words, the phenomenon of cells breaking away and traveling via the bloodstream and lymphatic vessels to other sites is neither unusual nor is it by any means always a function of malignancy. Furthermore, the researchers showed that such breakaway cells can survive for extended periods in tissues other than those in which they originated. By contrast, in experimental models of metastasis millions of tumor cells must be injected into the bloodstream in order to establish a very small number of metastatic tumors: inducing metastasis is by no means simple.

Since clusters of cells break off primary tumors constantly, why do only such a small number develop into secondary cancers? Why not all of them? What enables a breakaway group of cells to become malignant? Why are some sites - for example, the liver, lungs, brain and bones - more commonly affected than others? While the anatomical layout of blood vessels or lymphatic drainage may to some extent dictate the likely site of development of metastases, at least 30 percent of metastases arise in locations which are not close to, or linked by direct blood supply to, the primary tumor. Neither are all tumors of the same type equally likely to give rise to metastases. While one cancer may rapidly spread far and wide another cancer of the same kind may take years to spread, or not spread at all.

The prevailing 'late metastasis' theory suggests that the breakaway cells arrive in their distant location already in a premalignant state - i.e., primed and ready to develop into a satellite tumor. However, the 'early metastasis' research described in the Science paper suggests that the migration of cells to distant tissues is not in and of itself dangerous, and that the breakaway cells arrive in their new location in a normal, not a malignant or premalignant, state. Danger only arises when those breakaway cells, now residing in distant tissues, somehow become transformed genetically and begin to proliferate.

This paradigm shift raises questions about the validity and relevance of metastasis research which is based on cell lines drawn from advanced cancer tissue. If breakaway cell colonies in distant tissues are not already premalignant and do not carry the hallmark genetic flaws that are typical of the primary tumor, does it make sense to use obviously genetically abnormal tissue in experimental metastasis research? Maybe not, say the authors of the Science paper. It may also be prudent to rethink the assumption that metastatic lesions will respond to treatment in exactly the same way as the primary tumor.

For several years now, Harvard researcher Michael Retsky and his colleagues Romano Demicheli of the Istituto Nazionale Tumori, Milano, Italy, William Hrushesky of the University of South Carolina, and Professor Michael Baum of University College, London, have been publishing papers on their work with breast cancer, showing that removal of the primary tumor may, in certain cases, actually trigger the start of malignant transformation in dormant cell clusters distant from the primary site. In a review paper published this week in Annals of Oncology, they reiterate their central hypothesis, namely that while surgical removal of a primary breast tumor may be curative (or at least beneficial) for many patients, it may also hasten development of metastatic tumors for others (Demichelli, 2008). In other words, the primary tumor may act as a brake on the growth of distant breakaway cells, and at least in some cases the excision of the primary tumor may remove that restraint on growth, spurring the malignant transformation of these distant satellites of previously dormant tissue.

Perhaps it is time to rethink the currently prevailing theory of metastasis, and to look more closely at the role of the primary tumor in controlling the behavior of breakaway cells in distant sites.

--Ralph W. Moss, Ph.D.

References:

Demicheli R, Retsky MW, Hrushesky WJM, et al. The effects of surgery on tumor growth: a century of investigations. Ann Oncol 2008 June 10.

Podyspanina K, Du YC, Jechlinger M, et al. Seeding and propagation of untransformed mouse mammary cells in the lung. Science 2008;321(5897):1841-4.

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