Cancer is one of the major causes of death in the world. Although a lot of research has been done to combat cancer, treatment of this disease didn’t give full hope to save the lives of cancer patients. Conventional chemotherapies used against cancer, have some drawbacks. For example, chemotherapeutic agents that kill cancer cells, have a non-specific toxic effect to the normal cells. Therefore, scientists have been trying to find new ways to fight this disease. Bacteria mediated cancer therapy is one of several therapies studied against cancer. Some facultative anaerobic bacteria can colonize the anoxic region of the tumor and cause cancer cell destruction. These bacteria include Salmonella typhimurium, E. coli, Klebsiella pneumonia, Bifidobacterium adolescentis etc. Here are several ways of how bacteria are used to fight against cancer cells.
Role of bacteria in cancer therapy:
By activating immune responses against cancer cells:
- Inducing inflammation:
Administration of Salmonella typhimurium strain induces activation of inflammasome pathways by ATPs secreted from damaged cancer cells or by engulfing damaged cancer cells by phagocytosis. Inflammasome pathways involves release of inflammatory cytokine such as IL-1β, TNF-α and IL- 18 in tumors, which results in suppression of tumor cell growth.
- Stimulating T cell responses:
Infection of host cells by E. coli causes the stimulation of host immune responses as well as the production of T lymphocyte cells. These T lymphocytes include CD4+ and CD8+ T cells that are involved in eradication of tumor cells. They are also effective to inhibit the growth of new tumor cells.
- Induction of TNF-alpha release:
Administration of attenuated S. typhimurium into the tumor cells induce release of TNF-alpha. TNF- alpha is a vasoactive agent increasing permeability in blood vessel endothelial cells. It breaks down the endothelial cell lining of blood vessels resulting in hemorrhage. This hemorrhaging causes bacterial colonization and necrosis on solid tumor. As necrosis is occurred due to disruption of blood vessels and blood flow is hampered, the supply of nutrients and oxygen will also be ceased. As a results the tumor cells will be starved and will start to die.
By releasing anticancer substances:
Bacteria produce several enzymes or substances to fight against tumor cells. These substances include bacteriocins and phenazine 1, 6-dicarboxylic acid.
Bacteriocins secreted by various bacteria are potential anticancer agents having cancer cell-specific toxicities. Cationic peptide bacteriocins are attracted to tumor cells membrane that has negative charges while the charge of other normal host cell membrane is neutral. Thus bacteriocins are selective to tumor cells rather than other normal host cells. There are several types of bacteriocins that causes strong inhibition of tumor cell growth through its cytotoxic ability. Colicins, released from E. coli, causes destruction of cancer cells such as breast cancer, cervix cancer, colon cancer, and bone cancer. Microcin E492, released from Klebsiella pneumoniae, causes apoptosis in a few malignant cancer cells without causing any harm to normal cells. Nisins released by Lactobacillus lactis causes inhibition of cell growth of breast cancer and liver cancer. Other bacteriocins such as pedicines (Pediococcus acidilactici) and pyocins (Pseudomonas aeruginosa) causes cytotoxic destruction to HeLa cell line and mice fibroblast cell line respectively.
- Phenazine 1, 6-dicarboxylic acid:
Phenazines, a group of nitrogen-containing heterocyclic compound, is obtained from a number of soil or marine bacteria such as Pseudomonas, Streptomyces. Being a small molecule, phenazine causes invasion into the tissue easily and causes inhibition of tumor cell growth.
Normally, there is a balance in the level of reactive oxygen species (ROS) in the tumor cells. This balance is disturbed by an excessive level of ROS resulting in oxidative stress that causes damage to cancer cells. On the other hand, since normal cells strongly tolerate oxidative stress, ROS can’t cause any harm to these normal cells.
Phenazine increases the production of reactive oxygen species (ROS) and takes part in tumor cell inhibition. Several studies showed that phenazine-1, 6-dicarboxylic acid inhibited the proliferation of SKOV3, Hela, Hep2, Ht1080, and DU145 cell lines
By formation of biofilm:
Biofilms – a multicellular complex of microbes – play a very important role in bacteria-mediated cancer therapy as they have strong tolerance against antibiotic treatment and host immune response. Salmonella and other bacteria cause hemorrhage on cancer cells stimulating the production of T lymphocytes and these T cells induce biofilm formation. Treatment with the anti-cancer drugs (e.g. hydroxyurea) and SOS response also cause biofilm formation that causes inhibition of cancer cell metastasis. Protein and DNA released during biofilm formation causes metastasis inhibition by coating tumor cells.
Metastasis is mediated by adherence to cancer cells to blood vessel endothelial cells. But polysaccharides secreted by Streptococcus agalactiae causes inhibition of this adhesion resulting in disruption of metastasis.
By targeting tumor cells directly:
- Acting as an anti-angiogenic agent:
Angiogenesis or blood vessel formation is an important part of tumor cell growth and metastasis. The inhibition of angiogenesis by bacterial species may be a better bacteria-mediated tumor therapy. Researchers showed that administration of Bifidobacterium adolescentis strains with endostatin gene into tumor-bearing mouse causes the production of anti-angiogenic protein inhibits both angiogenesis and local tumor growth. Combination therapy of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and endostatin also enhances this anti-tumor activity.
- Enhancing virus-mediated cancer therapy:
Viruses are potential to kill tumor cells when it starts its lytic cycle causing cell lysis. Bacteria can enhance the anti-tumor activity of the virus by disseminating it throughout the tumor and by sequestering it from immune responses. Researchers showed used a combination therapy of bacteria and viruses to reduce tumor cell growth. They showed that non-pathogenic bacteria E. coli containing the B18R gene causes a remarkable increase of oncolytic ability of the vesicular stomatitis virus (VSVΔ51) to suppress the growth of tumor cells.