GUEST COMMENTARIES Microorganisms and Cancer: Quest for a Therapy

Many microorganisms are known to cause cancer. Some examples are Helicobacter pylori, which causes gastric cancer in humans and animals (6), and Agrobacterium tumefaciens, which causes crown gall in plants (37). The use of microorganisms or their products in the treatment of cancer is, however, less widely known, particularly among the readership of the Journal of Bacteriology, as most of these papers are published in more medically oriented journals and very few relevant papers have been published in the Journal of Bacteriology. Live bacteria in the treatment of cancer. The use of bacteria or their extracts in the treatment of cancer goes back more than 100 years. The most cited case is that by the physician and surgeon William B. Coley of the then Memorial Hospital in New York City, now called Memorial Sloan-Kettering Hospital, who observed that many of his patients with various forms of cancer had their tumors regress when they were infected with bacterial pathogens. Treatment to eliminate the infections allowed the cancer to come back (5, 19). He developed a treatment modality by making extracts of some of these bacteria, later described as Coley’s toxin, which he used to help shrink the tumors in his patients (5, 19). Subsequently, many bacteria have been used in an effort to reduce the growth rate or size of tumors. The most prominent example would be the use of Mycobacterium bovis BCG, the vaccine strain, in the treatment of bladder cancer. Several well-coordinated studies have shown a clear relationship between the use of M. bovis BCG immunoprophylaxis after surgical removal of the tumor and the decreased recurrence rate or the delayed period during which recurrence could occur (15, 18). The long-term use of high titers of BCG with booster shots poses problems, such as side effects, lack of predictability of its effectiveness, and rare cases of sepsis, leading to the deaths of patients, so new ways of administering BCG have often been discussed (20). The mode of action of BCG to exert its antineoplastic effect is believed to be due to its effect on the immune system, with CD4 and CD8 T lymphocytes playing a major role (27), although the intravesical instillation of BCG is thought to result in nonspecific cystitis, which is likely accompanied by the local production of cytokines and the accumulation of inflammatory cells that are more damaging to the malignant rather than normal cells (2). The requirement of live cells of BCG for its anticancer activity is reflected in the fact that monocytes and T helper type 1 cells are often important for its effectiveness (34) and that large doses of vitamins that presumably enhance BCG survival and proliferation have a positive effect on the treatment of bladder cancer in human clinical trials (16). Similar positive effects have also been reported to be seen with immunoadjuvants such as tumor necrosis factor alpha (12). Using a human in vitro system to analyze the role of NK cells in BCGinduced cellular cytotoxicity, Brandau et al. (3) treated mononuclear cells with BCG for 7 days and demonstrated the ability of the BCG-activated killer cells to significantly destroy bladder tumor cells. Similarly, using C57BL/6 wild-type mice, NKdeficient beige mice, and mice treated with anti-NK1.1 monoclonal antibody, these authors noticed that viable BCG cells significantly prolonged survival in wild-type mice compared with control nontreated mice while BCG therapy was completely ineffective in NK-deficient beige mice or in mice treated with anti-NK1.1 monoclonal antibody (3). These studies demonstrated a key role for NK cells in BCG immunotherapy. BCG cell wall skeleton stimulation of the human innate immune system, as judged by altered levels of interleukin-12 (IL-12), IL-18, IL-10, and gamma interferon in the blood lymphocytes of patients with lung cancer, also demonstrated a role of BCG in the modulation of immune system activation (17). It should be emphasized, however, that the cancer that shows the maximal response to BCG treatment is superficial bladder cancer. Similar effects that are statistically significant have not been observed with other forms of cancer such as lung cancer (30) or melanoma (1). The reasons for such differential effects are not clear, although it is possible that certain forms of malignancies such as bladder cancer are more susceptible to BCG treatment because of cytokine network modulation or of the functional T-lymphocyte receptor repertoire expressed by surrounding tissues, recruited cells, or the malignant cells themselves. While M. bovis BCG has been used to bolster the immune system against specific cancers such as bladder cancer, attenuated bacterial vaccine vectors such as Listeria monocytogenes and Salmonella enterica serovar Typhimurium that target the antigen-presenting cells or are powerful inducers of an innate immune response and immune mediators such as IL-12 have also been recommended for use in cancer prevention and therapy (21, 22). However, facultative anaerobic bacteria such as Salmonella are also known to target tumor cells for growth and proliferation (10) and attenuated Salmonella mutants, when injected intraperitoneally in plasmacytoma-bearing mice, were reported to allow tumor regression and prolonged survival of the mice (8). Similar use of Shigella (31) and Clostridia (9) species for the delivery of therapeutic agents to target cells, * Mailing address: Dept. of Microbiology & Immunology, University of Illinois, College of Medicine, 835 S. Wolcott Ave., Chicago, IL 60612. Phone: (312) 996-4586. Fax: (312) 996-6415. E-mail: pseudomo @uic.edu.