Abstract
Various treatments like radiotherapy, chemotherapy and immunotherapy are used to kill malignant tumours however they can affect normal cells, and are unable to completely eradicate the tumour and drug resistance can hinder the treatment progress. To overcome these challenges bacteria stands as potential therapeutic. They specifically target tumour cells and proliferate within the tumor to initiate anti tumor immune responses. Bacteria are capable of growing in the tumour’s hypoxic environment and they can be genetically modified to deliver anticancer drugs, used for detection and as a potential therapeutic with minimal side effects.
Keywords - Cancer, bacteria, antitumor activity, therapeutics
Introduction
Cancer is one of the leading causes of death in the world. It occurs when normal cell functions are altered causing them to multiply rapidly and form tumours. Bacteria are capable of invading the tumours and can grow in the anaerobic environment, safe from the actions of the immune system. Live bacteria can cause various side effects in the patients therefore they must be inactivated by heating or by genetically engineering them to be less harmful.
The first bacteria mediated cancer therapy was performed 100 years ago by William Coley, he used a mixture of heat inactivated Streptococcus pyrogenes and Serratia marcescens which was known as Coley’s toxin. This treatment was very effective for inoperable sarcoma with common side effects of repeated episodes of fever. With the advent of radiotherapy and chemotherapy the bacteria therapy was abandoned due to its side effects and no available technology for its modification. With the advancement of genetic engineering, bacteria can be programmed to have lower pathogenicity and increased anti-tumour efficacy.
The commonly used bacteria are of genera Salmonella, Clostridium, Escherichia, Pseudomonas, Bifidobacterium, Lactobacillus, Caulobacter, Listeria, Proteus, and Streptococcus. A successful example of bacteria therapy is bacillus Calmette- Guerin BCG vaccine for in situ treatment of bladder cancer. This treatment is used as first line adjuvant treatment.
Mechanism
Solid tumours have a distinct microenvironment, which facilitates their growth. They display abnormal blood vessel vasculature which results in hypoxia condition and a necrotic core. Bacteria can be administered via intravenous injection and reach the tumour site through the blood vessels. Facultative anaerobic bacteria can colonize in these hypoxic regions and act as an oncolytic agent, this ensures that only the hypoxic area is infected and not the
surrounding cells with normal oxygen concentration. By modifying it, they can eliminate tumour cells, release toxins to induce apoptosis or act as an immunostimulant. Clostridium butyricum M55 and Salmonella typhimurium serovar VNP20009 strains were reported to colonize tumours in mouse models and could be used to deliver drugs without any severe side effects.
Genetic engineering has paved a way for the further development of bacteria therapy and came up with various applications of bacteria.
1. Detect tumours
Imaging techniques like PET, MRI and CT scan are used to detect malignant macroscopic tumours but microscopic tumours can be undetected by these techniques. Bacteria can be used as tumour targeting probes, salmonella can accumulate and replicate in tumours. They are engineered to be non-pathogenic by partial deletion of msbB gene and express a fluorescent protein which can be detected by imaging techniques.
2. Immunostimulation
A tumour can escape immune surveillance and create an immunosuppressive environment which can affect the activation and growth of immune cells. Bacteria at tumour site can be used to elicit an immune response. TLRs expressed by innate immune cells can recognize the PAMPs (pathogen associated molecular patterns) on bacteria which induces release of TNF α, IFN, and IL12 which recruit dendritic cells and facilitate their activation and present the tumour antigens to incoming T cells. E. coli can invade the tumour and stimulate the immune response, which promotes the T cell production which has anti-tumour activity. The CD8+ T cells eliminate the bacterial infected tumour cells.
3. Bacterial toxins and antibiotics
Compounds produced by bacteria have emerged as a promising alternative. Antibiotics, bacteriotoxins, peptides etc. have anticancer activity. Antibiotics like actinomycin D, bleomycin, doxorubicin, mitomycin are used as cancer therapeutics. Actinomycin was the first reported antibiotic having anticancer properties, it inhibits transcription and it can also induce p53 independent apoptosis. Doxorubicin blocks the replication and transcription of rapidly dividing cells. It is a FDA approved chemotherapy drug and is used to treat various kinds of cancer.
Bacteriotoxins like nisin produced by Lactobacillus lactis has potent cytotoxic activity against different cancerous cells both in vitro and in vivo, also it is non-toxic and safe to humans and is approved by WHO for human consumption. Colicins produced by different strains of E. coli are reported to have anticancer activities against variety of human tumour cell lines in vitro.
4. Drug delivery
Bacteria can be programmed to carry antitumor drugs and release them at the tumour site. Inside the tumour the bacteria multiply and in presence of a chemical the bacteria are lysed to release the drug. For example, Cytolysin A is a pore forming protein expressed by many bacterial strains of E. coli or attenuated salmonella strain are engineered to express this protein from a promoter in presence of inducers like arabinose or doxycycline. In Synchronized lysis circuit, a lysis gene and production of drug is regulated by quorum sensing. When bacteria population reaches a certain density, they lyse and release the drug; the advantages of this system are 1. Release of bacterial components which can trigger immune system 2. Controlling the bacterial population. This circuit is capable of driving periodic drug delivery which can improve the efficiency of the treatment.
Conclusion
Bacteria can specifically target tumour cells and eliminate them. By genetic engineering they are programmed to be less pathogenic and more tumour specific thus causing minimal side effects to the host. Engineered bacteria and its products have shown promising results in clinical studies on animal models and human cancer cell lines. Bacteria therapy can be used in combination with traditional cancer therapies for better treatment.
Vincy Chacko
Department of Biochemistry and Biotechnology
St. Xavier’s College, Ahmedabad
References
1. Song, S., Vuai, M. S., & Zhong, M. (2018). The role of bacteria in cancer therapy – enemies in the past, but allies at present. Infectious Agents and Cancer, 13(1). https://doi.org/10.1186/s13027-018-0180-y
2. P.S.J.R.B.D.P.A.M.B.D.B. (2010). Bacteria in cancer therapy: A novel experimental strategy. Journal of biomedical science. Bacteria in Cancer Therapy: A Novel Experimental Strategy. Journal of Biomedical Science. Published.
3..Felgner, S., Kocijancic, D., Frahm, M., & Weiss, S. (2016). Bacteria in CancerTherapy: Renaissance of an Old Concept. International Journal of Microbiology,
2016, 1-14. doi:10.1155/2016/8451728
4. Patyar, S., Joshi, R., Byrav, D. P., Prakash, A., Medhi, B., & Das, B. (2010). Bacteria in cancer therapy: A novel experimental strategy. Journal of Biomedical Science, 17(1), 21.
5. Duong, M. T., Qin, Y., You, S., & Min, J. (2019). Bacteria-cancer interactions: Bacteria-based cancer therapy. Experimental & Molecular Medicine, 51(12), 1-15. https://doi.org/10.1038/s12276-019-0297-0
6. Baindara, P., & Mandal, S. M. (2020). Bacteria and bacterial anticancer agents as a promising alternative for cancer herapeutics. Biochimie, 177, 164-189. https://doi.org/10.1016/j.biochi.2020.07.020
7. Ashu, E. E., Xu, J., & Yuan, Z. (2019). Bacteria in cancer therapeutics: A framework for effective therapeutic bacterial screening and identification. Journal of Cancer, 10(8), 1781-1793. https://doi.org/10.7150/jca.31699
8. Chien, T., Doshi, A., & Danino, T. (2017). Advances in bacterial cancer therapies using synthetic biology. Current Opinion in Systems Biology, 5, 1-8. https://doi.org/10.1016/j.coisb.2017.05.009