CORRESPONDENCE

Re: Medroxyprogesterone Acetate and Metastases: Of Mice and (Wo)Men

Ann F. Chambers

Correspondence to: Ann F. Chambers, PhD, London Regional Cancer Program, 790 Commissioners Road East, London, Ontario N6A 4L6, Canada (e-mail: ann.chambers{at}Lrcc.on.ca).

I read with interest the article by Palmieri et al. (1), which demonstrated a novel use for the compound medroxyprogesterone acetate. This compound led to reduced metastatic outgrowth of breast cancer cells, apparently via induction of expression of the metastasis suppressor gene Nm23-H1. Because metastases are responsible for most breast cancer deaths, I applaud this work, which may lead to novel approaches to prevent metastatic progression. However, I was concerned by the statement in the accompanying editorial by Jordan (2) that "[t]he received wisdom for breast cancer is that metastatic spread has often occurred by the time of diagnosis of the primary tumor." This is indeed true, but it is important to avoid confusing "metastatic spread" with the development of clinically relevant, lethal metastases ("metastatic outgrowth"). Metastasis is a process, and the fact that early steps in the process (i.e., metastatic seeding) may have already occurred before diagnosis does not mean that the outgrowth of these cells is inevitable. It is not necessary to, as Jordan suggests, "prevent the initial colonization of organs with metastatic cells" (2), because this is not the only therapeutic window for preventing the formation of lethal metastases. The strategy proposed by Palmieri et al. would not need to be used in a "chemoprevention" setting, as suggested by Jordan (2)—it could also, as proposed by Palmieri et al. (1), have great utility in preventing progression of cells already seeded to distant organs.

As my colleagues and I noted in a review article (3), "The metastatic growth phase fortunately is a clinically broad target, and any treatment that limits growth of metastases prior to their causing irreversible harm to the patient has the potential to be clinically useful. A variety of therapeutic approaches to target this phase are under active development, including inhibition of angiogenesis or signal transduction pathways needed to support the growth of metastatic cells." Outgrowth of metastases is responsible for much of cancer mortality and morbidity, and this phase of the metastatic process is therefore an important clinical target for therapeutic development (46). For example, my group recently demonstrated the utility of targeting metastatic outgrowth in a murine model of postsurgical dietary intervention (7). In that study, outgrowth of metastatic tumor cells that had been seeded before surgery was inhibited by a dietary intervention that was initiated after surgical resection of the primary tumor.

The elegance of the study by Palmieri et al. (1) is that it shows that growth suppression of cells seeded in metastatic sites can be achieved by reactivating metastasis suppressor gene function. This study demonstrates that it is not too late to treat metastases at the time of cancer diagnosis. A clinical therapeutic window exists, so long as metastatic cells have not grown to the point of causing irreversible damage to the patient. Inhibition of outgrowth of cells that have started the metastatic process by being seeded to distant organs is therefore an important goal for antimetastatic therapy development.

REFERENCES

(1) Palmieri D, Halverson DO, Ouatas T, Horak CE, Salerno M, Johnson J, et al. Medroxyprogesterone acetate elevation of Nm23-H1 metastasis suppressor expression in hormone receptor-negative breast cancer. J Natl Cancer Inst 2005;97:632–42.[Abstract/Free Full Text]

(2) Jordan VC. Medroxyprogesterone acetate and metastases: of mice and (wo)men. J Natl Cancer Inst 2005;97:619–21.[Free Full Text]

(3) Chambers AF, MacDonald IC, Schmidt EE, Morris VL, Groom AC. Clinical targets for anti-metastasis therapy. Adv Cancer Res 2000;79:91–121.[ISI][Medline]

(4) Hedley BD, Winquist E, Chambers AF. Therapeutic targets for antimetastatic therapy. Expert Opin Ther Targets 2004;8:527–36.[CrossRef][ISI][Medline]

(5) Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002;2: 563–72.[CrossRef][ISI][Medline]

(6) Chambers AF, MacDonald IC, Schmidt EE, Koop S, Morris VL, Khokha R, et al. Steps in tumor metastasis: new concepts from intravital videomicroscopy. Cancer Metastasis Rev 1995;14:279–301.[CrossRef][ISI][Medline]

(7) Vantyghem SA, Wilson SM, Postenka CO, Al-Katib W, Tuck AB, Chambers AF. Dietary genistein reduces metastasis in a postsurgical orthotopic breast cancer model. Cancer Res 2005;65:3396–403.[Abstract/Free Full Text]



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