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Microbial-based Cancer Therapies
Microbial-based cancer therapy is the usage of live, attenuated bacteria or their purified products to treat tumors. The potential to treat cancer by microbial-based methods has long been recognized, however limitations due to toxicity and deleterious effects originally halted the advancements of this technology [3]. Recently, new genetically engineered attenuated strains and anti-cancerous microbial compounds have shown considerable potential for future cancer therapies with nonsignificant side effects. Microbial-based cancer therapies include inducing the cytotoxicity in nontoxic prodrugs by the expression of foreign genes in attenuated bacterial strains. Bacterial products may also be used to target cells and inhibit growth, induce apoptosis or arrest the cell cycle, such as enzymes and immunotoxins [1].
Emersion of Microbial-based Cancer Therapies
Cancer is responsible for one fifth of all deaths in the western world and conventional cancer treatments generally do not cause complete cancer remission and often have severe side effects [1]. This desperate need promoted the exploration of alternative cancer treatments, including those microbial-based. Beginning in 1890, William Coley first identified bacteria as anticancer agents by demonstrating a tumor reduction in those infected with a pathogenic bacteria [7]. In 1935, Connell observed enzymes produced from pathogenic bacteria caused tumor regression. Since then, it has been noticed that many live and engineered pathogens can selectively target cancer cells. How this functions physiologically has been more recently understood and for this reason, usage of live bacteria in treatments has greatly been since pursued. As demonstrated by Figure 1, there are many methods by which bacteria and their products can be used in cancer treatments.
Live, attenuated & engineered bacterial strains to treat cancer & their limitations
Many anaerobic bacteria are promising vectors for delivering therapeutic genes for anticancer therapies as they have an inexhaustible metabolic potential and preferentially grow in tumor micro-environments [6]. By growing in the oxygen deprived regions of tumor cores, they are selective for the particular regions where radiation and chemotherapy is unsuccessful [7]. In recent years, many strains of facultative and obligate anaerobic bacteria have been shown to not only localize but also cause lysis in transplanted tumors of test animals [6] The specificity of many bacteria to a hypoxic environment has incredible potential for the expression and engineering of anticancer agents, however many limitations are presented by the use of live bacteria namely, toxicity and tumor size. In fact, as shown in Clostridia [1]. Bacteria require a minimum threshold tumor size to survive in their specific microenvironment and spore production can also be a limiting factor. Bacteria have been transfected with varieties of anti-tumor genes including TNFa and IL2, prodrug converting enzymes, angiogenesis inhibitors and cytokines [6] Certain strains pose many benefits and limitations to this method, including colonizing tumors, spore formation and difficulty in manipulation as well as administration of these bacteria. The ideal bacterial strain would be non toxic to the host, specific to the tumor but dispersed evenly through out it, cause lysis and be nonimmunogenic [6]. Some pathogenic species for example, Salmonella , preferentially colonize tumor cells however still can cause disease so an attenuated strain is necessary. The salmonella strain can then be engineered to produce several anti-tumor proteins and toxins, and will also naturally increase the anti-tumor immune response by causing increasing amounts of neutrophils and CD8+ T cell. In this sense, the use of a single microbial species has multiple negative effects on the tumor. Similarly, BCG, the tuberculosis vaccine, can boost the hosts immunes response to fight the cancer by inducing NK cell activation and Interferon gamma production [6]. While the use of live and engineered anaerobic or facultatively anaerobic pathogens have significant obstacles to overcome in their development, they possess the incredible potential to inhibit cancer growth, enhance the immune system response and carry anticancer genes [1].
Purified Microbial Products as Anticancer Agents
Many bacterially derived products can be applicable to cancer therapies via cytotoxic factors, enzymes, antibiotics and secondary metabolites specifically targeted to cancer cells. An incredibly important part of cancer pathogenicity, cancer metastasis, the spread from one organ to another, is very specific and dependent on the origin tumors histotype and many chemokine factors [3]. Naturally, bacteria produce many inhibitors for these chemokine molecules and receptors and can be used as an inhibitor of cancer metastasis [5]. Other bacterial enzymes are candidate agents for cancer treatments including tumor growth inhibitors, example ADI, and antibiotics and pigments. Pseudomonas aeruginosa produces at least two cytotoxic proteins to cancer cells [1]. One of these proteins of great interest, azurin, involved in the electron transport chain, has been shown to induce apoptosis in cancer cell lines and transfected nude mice by forming a complex with tumor suppressor protein p53 [4]. A copper-containing oxido-reductase naturally involved in electron transport of denitrification, the microbial product azurin has been found to stabilize to a normally unstable human apoptosis causing protein p53. Known as a tumor suppressor protein due to its antigrowth, apoptosis causing activities, in regular healthy cells p53 has a short half life and is usually degraded by binding to Mdm2 [6]. Azurin enters the cells and binds p53, alowing it to carry out the cell arrest signalling pathway via transcriptional factors. Unlike many other therapies, azurin intervenes in multiple cancerous pathways, most likely due to its homology with many cell proteins.
Future of microbial-based cancer therapies
The ability of cancer to mutate rapidly greatly decreases the therapeutic efficacy of many treatments, so alternative approaches are desperately explored. The potential for both live attenuated engineered microbes and microbial products in cancer therapies is enormous and diverse, however there are many obstacles to overcome before this is clinically possible. Toxicity is present at levels necessary for therapeutic efficacy and there exists the risk of systemic infections as well as harmful DNA mutations of the bacteria used. In recent years, important advances have been made in the studies of live, transfected bacteria with encoded toxins targeting cancer cells and isolated natural anti-tumorous bacterial products. Many types of obligate or facultative anaerobic bacteria are selective to cancerous micro-environments, and will only grow in hypoxic regions within the core of the tumor. Even when lacking the transfection of numerous anti tumor agents or production of toxins, simply the enhanced immune response to the tumor can cause regression. Bacterial proteins have also been shown to preferentially enter and disrupt growth or induce apoptosis of cancer cells, as demonstrated by the well studied studied protein azurin. The potential behind these approaches is extensive and promising in numerous aspects, and with significant further research, may soon be clinically applied as primary cancer therapies.
References
(1) Bernardes N, Seruca R, Chakrabarty A, Fialho A, 2010. Microbial-based therapy of cancer, Bioengineered Bugs. 1 (3) 178-190.
(2) Hoffman RM. Salmonella thyphimurium mutants selected to grow only in tumors and eradicate them in nude mouse models. In: Fialho AM, Chakrabarty AM, editors. Emerging Cancer Therapy: Microbial approaches and Biotechnological Tools. Nutley N.J.: John Wiley; 2009
(3) Ryan RM, Green J, Lewis CE. Use of bacteria in anti-cancer therapies. Bioessays. 2005;28:84–94
(4) Yamada T, Goto M, Punj V, Zaborina O, Chen ML, Kimabara K, et al. Bacterial redox protein azurin, tumor suppressor protein p53 and regression of cancer. Proc Natl Acad Sci USA. 2002;99:14098–14103
(5) Zlotnik A. Chemokines and cancer. Int J Cancer. 2006;119:2026–2029.
(6) Punj V, Saint-Dic D, Daghfal S, Kanwar J. Microbial based therapy of cancer: A new twist to an age old practice. Cancer Biology & Therapy 2004; 3:708 - 714.
(7) Patyar S, Joshi R, Prasad DS, Byrav A, Medhi, Das BK Bacteria in cancer therapy: a novel experimental strategy. Journal of Biomedical Science 2010. 17; 21
(8) Jain RK: New approaches for the treatment of cancer. Adv Drug Delivery Rev 2001, 46:149-168.
(9) Nauts H, Fowler G, Bogatko F: A review of the influence of bacterial infection and of bacterial products (Coley's toxins) on malignant tumors in man.
(10) Avogadri F, Martinoli C, Petrovask L: Cancer Immunotherapy Based on Killing of Salmonella-infected tumor cells. Journal of Cancer Research. 2005. 65;3920.
