Bacteria are everywhere — from your skin to the surface of your smartphone. Occasionally, these single-celled organisms are able to breach our skin barrier and enter the bloodstream. Our immune system then responds by releasing white blood cells which identify foreign proteins on the surface of invading pathogens, distinguishing them from the body's own proteins. (Nicolson, 2016) Although bacteria have garnered a reputation as disease-causing organisms, they possess numerous benefits including the ability to treat cancer.
Tumor-targeting bacteria for cancer treatments
One flaw of conventional cancer treatments such as chemotherapy and radiotherapy is their ability to destroy normal cells in addition to cancer cells. This non-specific nature of such treatments has prompted the need to develop innovative treatments that are able to target only cancer-causing tumors without destroying healthy cells and incurring side effects. (Patyar et al., 2010) This is where tumor-targeting bacteria come into play. Bacteria such as Bifidobacterium and Clostridium are able to survive in environments without oxygen because they derive their energy from fermentation. (Dróżdż et al.,2020) As cancer tumors progress and increase in size, the amount of oxygen consumed by cancer cells outweighs its supply from blood vessels.(Li et al., 2021) This oxygen-lacking environment is, however, suitable for anaerobic bacteria, since these bacteria can shrink cancerous tumors by competing with them for nutrients. (Malmgren et al.,1955)
Engineered bacteria delivery systems
In addition to using certain bacteria’s innate properties to target tumors, researchers have found new ways to program them to produce beneficial responses in cancer cells.(Forbes, 2010)
By using genetic circuits, scientists can now engineer bacteria to deliver drugs to tumors based on conditions such as pH and oxygen levels.
In 2019, researchers demonstrated how bacteria could be genetically programmed to shrink cancer tumors and increase cancer immunity. In this study, the researchers modified E. Coli bacteria to break open once inside cancer tumors, releasing a nanobody called CD47nb. This nanobody targets CD47, a molecule that enables cancer cells to ‘hide’ from the immune system. (Chowdhury et al, 2019) Normally, CD47 acts as a signal, telling immune cells to ignore cancer cells. (n.d.) By blocking CD47 with CD47nb, the system removes this disguise and allows the immune system to attack cancer cells more effectively. (Jia et al, 2021)
How was the bacteria programmed to deliver CD47nb to tumors?
Genetic circuits (which act like a control system inside bacteria) allowed the bacteria to coordinate their actions once they traveled to tumor sites. Once an optimal amount of bacteria had accumulated in a tumor, they all burst open at the same time in a process called quorum lysing. (Din et al., 2016) This synchronized bursting released eSLC-CD47nb, the nanobody that helped the immune system to unmask cancer cells.
In experiments with mice, researchers found that this bacteria drug delivery system increased the activity of cancer-fighting T-cells and reduced the growth of tumors in mice with breast cancer cells, melanoma, and lung metastases. More interestingly, injecting these modified bacteria into one tumor site triggered immune responses that fought cancer in other parts of the body. (Chowdhury et al, 2019) This phenomenon known as abscopal effect, suggests that this approach could possibly be used to treat metastatic tumors that spread throughout the body. Furthermore, this approach addressed the lack of specificity in conventional treatments since the bacteria was solely concentrated in tumors and had not spread to organs such as the spleen, kidney, and liver. (Chowdhury et al, 2019)
Prospects
While our understanding of bacteria's role in cancer treatment is still evolving, recent developments present the opportunity to combine bacteria-based therapies with conventional treatments. Ongoing research into bacterial-based cancer therapies may transform our approach to cancer, offering new hope in the fight against this challenging disease.
References:
CD47. (n.d.). Institute for Stem Cell Biology
and Regenerative Medicine. https://med.stanford.edu/stemcell/CD47.html
Chowdhury, S., Castro, S., Coker, C., Hinchliffe, T. E., Arpaia, N., & Danino, T. (2019). Programmable bacteria induce durable tumor regression and systemic antitumor immunity. Nature Medicine, 25(7), 1057–1063. https://doi.org/10.1038/s41591-019-0498-z
Din, M. O., Danino, T., Prindle, A., Skalak, M., Selimkhanov, J., Allen, K., Julio, E., Atolia, E., Tsimring, L. S., Bhatia, S. N., & Hasty, J. (2016). Synchronized cycles of bacterial lysis for in vivo delivery. Nature, 536(7614), 81–85. https://doi.org/10.1038/nature18930
Dróżdż, M., Makuch, S., Cieniuch, G., Woźniak, M., & Ziółkowski, P. (2020). Obligate and facultative anaerobic bacteria in targeted cancer therapy: Current strategies and clinical applications. Life Sciences, 261, 118296.https://doi.org/10.1016/j.lfs.2020.118296
Forbes, N. S. (2010). Engineering the perfect (bacterial) cancer therapy. Nature Reviews Cancer, 10(11), 785–794. https://doi.org/10.1038/nrc2934
Jia, X., Yan, B., Tian, X., Liu, Q., Jin, J., Shi, J., & Hou, Y. (2021). CD47/SIRPα pathway mediates cancer immune escape and immunotherapy. International Journal of Biological Sciences, 17(13), 3281–3287. https://doi.org/10.7150/ijbs.60782
Li, Y., Zhao, L., & Li, X.-F. (2021). Hypoxia and the Tumor Microenvironment. Technology in Cancer Research & Treatment, 20, 153303382110363. https://doi.org/10.1177/15330338211036304
Malmgren, R. A., & Flanigan, C. C. (1955). Localization of the vegetative form of Clostridium tetani in mouse tumors following intravenous spore administration. Cancer Research, 15(7), 473–478. https://pubmed.ncbi.nlm.nih.gov/13240693/
Nicholson, L. B. (2016). The Immune System. Essays in Biochemistry, 60(3), 275–301. https://doi.org/10.1042/ebc20160017
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. https://doi.org/10.1186/1423-0127-17-21