Tumor-homing bacteria

• Salmonella bacteria kill tumor cells by uncontrolled bacterial multiplication that can lead to the bursting of cancerous cells. Moreover, the macrophages and dendritic cells (type of white blood cells) in these Salmonella-colonized tumors secrete IL-1β, a protein responsible for anti-tumor activity.[3]
• S. Typhimurium flagellin increases both innate and adaptive immunity (nonspecific and specific defense mechanisms) of the bacteria by stimulating NK cells (Natural Killer cells) to produce interferon-γ (IFN-γ), an important cytokine (regulatory protein) for this immunity.[1]
• Listeria inhibits tumors through NADPH oxidase mediated production (nicotinamide adenine dinucleotide phosphate oxidase) of ROS (reactive oxygen species) which is a cell signaling process that activates CD8+ T cells (cells that kill cancerous tissue) which target primary tumors.[4]

• Clostridium, S. Typhimurium, Listeria produce exotoxins (e.g. phospholipases, hemolysins, lipases) that damage the membrane structure and the cellular functions of the tumor using apoptosis or autophagy which is programmed cell death.[2]
• Salmonella, Clostridium, and Listeria infections promote tumor elimination by increasing cytokines and chemokines (cell signaling regulatory proteins) that regulate infected sites using granulocytes and cytotoxic lymphocytes (WBC s that kill cancerous cells).[1]

• The usage of the live attenuated strain of Mycobacterium Bovis, also known as Bacillus Calmette-Guérin (BCG), is a confirmed treatment for bladder cancer. BCG therapy is done by intravesical instillation (drug administration into the urinary bladder via a catheter) and has been used since 1970 on cancer patients.[5]
• Due to the necrotic and hypoxic regions of tumor cells (area of treatment resistance), drug delivery of chemotherapy can be impaired. Therefore Salmonella can be combined with chemotherapy to provide treatment and transport as Salmonella is not affected by these regions. Moreover, the Salmonella mutant strain VNP20009 increased in number from this combination which causes further inhibition of cancerous cells by stimulating anti-tumor proteins.[6]

Tumor homing bacteria can be genetically engineered to enhance their anti-tumor activities and be used to transport therapeutic materials based on medical needs. They are usually transformed into a plasmid that contains the specific gene expression of these therapeutic proteins of the bacteria. After the plasmid reaches the target site, the protein’s genetic sequence is expressed and the bacteria can have its full biological effect. Currently, there is no approved treatment with genetically engineered bacteria. However, research is being conducted on Listeria and Clostridium as vectors to transport RNAi (suppresses genes) for colon cancer.[7]

• DNA mutations of the tumor homing bacteria in the body can lead to problems like extreme infection and failure of therapy as the genes that are expressed will be different and cause the bacteria to become non-functional.
• Incomplete tumor lysis or colonization by the bacteria can lead to delayed treatment and will necessitate the use of other cancer treatments such as chemotherapy or a combination of more. Delayed or combined treatment causes many effects on the body such as vomiting, nausea, loss of appetite, fatigue, and hair loss.[8]

• Deleting the msbB gene from Salmonella by genetic engineering leads to the loss of lipid A (a lipid responsible for the toxicity levels of gram-negative bacteria) and therefore reduces the toxicity of Salmonella by 10,000-fold.[9]
• Generating auxotrophic mutants (a strain of microorganism that will proliferate only when the medium is supplemented with some specific substance) that cannot replicate efficiently in an environment where a particular nutrient required by the mutant strain is scarce. Salmonella A1-R represents such a strain, which is auxotrophic for the amino acids leucine and arginine that are enriched in the tumor but not in normal tissues. Therefore in the tumor, Salmonella A1-R will grow but not in the normal tissues thereby preventing infections and increasing safety.[2]