Bioregulators Come of Age in the Control of Tumor Growth and Metastasis

Abstract

During the last few years, there has been a resurgence of interest in the development of new approaches for the biological control of tumor growth and metastasis. This situation is due, in no small part, to our increased understanding of the roles of various growth factors and inhibitors, cytokines, interferons, and other bioregulators in controlling tumor cell proliferation and other properties important in cancer. Systemic administration of bioregulators has resulted in significant inhibition of tumor growth and, in some cases, in complete regression of tumors (7). Unfortunately, many of the most promising bioregulators, such as the interferons, possess a variety of in vivo side effects that can limit their clinical usefulness. Moreover, their pharmacokinetics are often undesirable, and other approaches, such as stimulating macrophage cytolytic function, once touted to be a panacea for controlling tumor growth and metastasis, have been generally unsuccessful in clinical settings. In a report published in this issue of the Journal, Kundu et al. (2) show that interleukin 10 (IL-10), an acid-sensitive protein of 35-40 kd originally described as an immunosuppressive cytokine, might be a useful new weapon for suppressing tumor growth and metastasis. This finding is a pleasant surprise. IL-10 has pleiotropic effects and is capable of inhibiting macrophage function and T-cell cytokine production, resulting in suppression of helper T-cell subpopulations, delayed-type hypersensitivity reactions, and other mechanisms of cellular immunity. From these properties, one would not expect much antineoplastic activity from IL-10. On the other hand, IL-10 can stimulate certain B-cell subpopulations as well as interleukin 2-regulated T-cell subpopulations, such as natural killer (NK) cells (3). These latter properties may be more important in inhibiting tumor growth and metastatic spread. That IL-10 can suppress tumor growth and macrophage infiltration in vivo was shown by Richter et al. (4) using IL-10 gene-transfected hamster CHO cells implanted in nude mice. Although these cells are not directly inhibited by IL-10, the transfected cells apparently produce and secrete enough IL-10 to cause host-mediated inhibition of tumor growth and inhibition of macrophage infiltration into tumors in a xenograft model. Similarly, Allione et al. (5) transfected various cytokine genes, including IL-10, into a murine mammary adenocarcinoma cell line and examined the growth properties of the transfected cells in syngeneic mice. They also found that IL-10 gene transfection resulted in inhibition of tumor growth. Against this background and with the observation that IL-10 administration is not associated with the systemic toxicity often found with other cytokines (6), Kundu et al. (2) evaluated the ability of IL-10 to inhibit murine mammary tumor growth and metastasis in syngeneic immunocompetent and immunocompromised mice. In their study, two transplantable, highly malignant mammary tumor cell lines that are capable of forming experimental and spontaneous metastases in mice were transfected to express and produce IL-10; one cell line was highly immunogenic, and the other was poorly immunogenic in syngeneic animals. The growth of neither of the cell lines was directly affected by IL-10. Tumor growth and metastasis were evaluated by inoculating syngeneic mice or SCID or SCID/Beige immunocompromised mice subcutaneously or intravascularly with IL-10or neo-transfected tumor cells (18 different cell clones that contained the IL-10 gene). As was found previously with other tumor cell types (4,5), the growth of the IL-10 gene-transfected highly immunogenic mammary tumor cells was completely inhibited in immunocompetent, syngeneic animals and was significantly inhibited in the immunocompromised mice. Moreover, although there was some tumor growth in immunocompromised mice, formation of experimental and spontaneous metastasis was completely inhibited, suggesting a different mechanism for inhibition of metastasis. In support of this hypothesis, Kundu et al. (2) suppressed NK activity by injecting anti-asialo-GMl ganglioside antibody into syngeneic BALB/cBy mice and found that the antimetastatic activity of IL-10 was reversed. Furthermore, IL-10 could not control metastasis in SCID/Beige mice that also lack NK function. NK activity is known to be important in suppressing bloodborne metastasis, and Kundu et al. (2) did not find any differences in the adhesion and invasion properties of the IL-10 gene-transfected cells; therefore, the suppression of metastasis formation was likely due, at least in part, to IL-10-stimulated