# The Use of Bacteria in Cancer Treatment: A Review from the Perspective of Cellular Microbiology

Authors: Hilla Mills; Ronald Acquah; Nova Tang; Luke Cheung; Susanne Klenk; Ronald Glassen; Magali Pirson; Alain Albert; Duong Trinh Hoang; Thang Nguyen Van
Journal: Emergency Medicine International
 (2022)

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## Abstract

Cellular microbiology, which is the interaction between harmful microbes and infected cells, is important in the determination of the bacterial infection processes and in the progression of data of different cellular mechanisms. The therapeutic role of bacteria has gained attention since the known methods such as radiation, chemotherapy, and immunotherapy have got drawbacks. Bacteria have demonstrated a favorable impact in treating cancer through eradication of tumors. Bacteria, in cancer treatment, have proven to be promising and have been shown in some of the previous work that it can successfully suppress the growth of tumors. In this paper, we analyzed the difficulties and settlement for using bacteria in cancer therapy as well the mechanisms in which bacteria works in order to achieve tumor eradication. Future works may focus on the use of bacteria along with other treatments in order to achieve effective tumor therapy.


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## Body

## 1. Introduction

Cancer is a fatal disease and has caused quite a lot of deaths all over the world to an extent that it is predicted that by 2030 the number of deaths related to cancer will be approximately 20 million [1]. This brings a major concern over looking for new drugs which can be employed in the treatment of cancer because of the drawbacks that the known cancer treatments have. The other cause is the side effects that come along from the common utilize of chemotherapeutic operators for the treatment of cancer [2]. Healthy cells are damaged during chemotherapy and eventually cells become drug resistant; therefore, it is very complicated to treat cancer in such a way that causes more damage. The drug resistance that frequently develops lessens the initial efficacy of chemotherapy, which eventually results in poor management of tumors. It is also very difficult to treat different malignancies because of the complex physiology that tumors have [3].A good strategy that could be able to get around some of the abovementioned drawbacks of usual treatments to date is the use of therapeutic microorganisms particularly bacteria. Although some of the cancers are caused by bacteria as shown in Figure1, a number of studies have proven that microbes are also capable of curing the deadly disease, considering that their genes can be altered so as to modify their capacity to produce and release in particular very toxic chemicals which have anticancer properties [4].Figure 1
Bacteria involved in causing different types of cancer.Bacteria with altered genes have proved to be much efficient in the treatment of cancer as they have fewer side effects. Currently, in most studies, they have utilized recombinant DNA technology to come up genetically engineered bacteria which is then capable of delivering the toxins through reporter genes in the treatment of cancer [5]. Bacterial species of Salmonella and Clostridium butyricum M55 are the ones which have been mostly used in experimental studies using mice with tumors to express reporter genes that encodes for enzymes from bacteria that destroy tumors. The enzymes that are required to be expressed involve those belonging to the category of deaminases and nitroreductases. The genetically modified strains of Salmonella and Clostridium showed to activate the immune system of the host, increasing the production of cytokines, specifically the interleukins [6].Bacteria includingSalmonella amongst many others are involved in the curing of cancer and have the capability of invading the hypoxic tumor sites which is very crucial towards the destruction of tumor cells. This will definitely review the capability of bacteria to produce enzymes and toxic chemicals that are capable of limiting the growth of tumors in experimental models [6]. The enzyme have receptors and use mechanisms at the molecular level to kill solid tumors, for example, ClyA is a bacterial enzyme that achieves solid tumor destruction by creating holes in the membrane of the tumor which results in death of the tumor cells [6]. Some of the bacterial strains with the ability to produce ClyA toxin belongs to the genus of Staphylococcus as this was confirmed in a recent study [7]. The other toxins that bacteria produce are specialized in blocking cell division and these are called cyclomodulins. E. coli is amongst bacteria that are capable of producing enzymes or toxins that block cell division. It has been reported that it produces a necrotizing factor that has been proved by a number of studies carried out using mice models that it increases replication of DNA whilst maintaining the number of cells, which eventually leads to apoptosis. This was shown to be achieved because of the nature of the necrotizing factor. It is able to cause multinucleate and this prevents cells from dividing hence stimulating apoptosis [8]. Scientists may as well try to explore the use of bacteria as vectors that deliver the drugs that destroys tumors. Some of the bacteria strains involved in cancer therapy are shown in Figure 2.Figure 2
Bacteria involved in treating different types of cancer.The invasions of bacteria on tumors have shown to result in suppressed growth of tumors and in some instances, clearance of the tumors [8]. Bacteria with the capability of destroying tumors consume supplements required by the tumor for its growth [8], such that in some cases anaerobic bacteria end up multiplying in deoxygenated tumors [9].


## 2. Mechanisms of Bacterial Action in Cancer Treatment

Live strains ofStreptococci and Clostridia were the first strains to be used for trials in cancer treatment. A variety of techniques can be used on bacteria in order to achieve tumor therapy [10]. Bacteria belonging to the genus of Pseudomonas, Caulobacter, Listeria, Proteus, Bifidobacteria, and Salmonellae among many others have been shown to have the capability to destroy tumors through different mechanisms. Some of the mechanisms involve the use of their bacterial toxicity, producing immunotherapic constituents, producing enzymes, producing biofilms, producing bacteriocins, capability to carry out RNA interference as well as prodrug cleavage [11]. These bacterial species have also been tested for their therapeutic effect in cancer in animal models [12, 13]; however, more work has to be done so that the trials can be carried out in humans with different malignancies.


## 3. Bacteria as Anticancer Operators through a Triggering Immune Response

Bacteria has been shown to induce an immune response that activates specific types of host immune cells that recognize cancer cells as antigens and destroy them. This includes the activation of T lymphocytes and cytokines [14].


### 3.1. Activation of Cytokines

There are microbes such asSalmonella typhimurium that are able to activate cytokines. They achieve this by activating the pathways that increases the production of cytokine such as IL-1β, TNF-α, and Il-18. The production of these cytokines in abundance results in tumor destruction since interleukins are the ones that contribute more in fighting pathogens [15, 16].


### 3.2. Activation ofT Cell Lymphocytes

Escherichia coli (E. coli) have shown to have the capability of producing lymphocytes T cells which are very important in the destruction of tumors [17]. E. coli stimulates and activates the production of CD8+T which has been proved to have the ability to destruct tumors after bacterial infection [17]. E. coli also stimulates the production of CD4+T cells which also helps in the antitumor activity [17]. These T cell lymphocytes also have the ability to eradicate colon cancer and this was confirmed by a trial in severe infected mice which showed cancer reduction upon the administration of T cell lymphocytes [18].


### 3.3. Activation of Tumor Necrosis

Tumor necrosis factor (TN-α) contributes towards the formation of drainage in tumors. The bacterium is able to stimulate the production of tumor necrosis factor, which has been reported with Salmonella enterica serovar Typhimurium [19]. The mechanism in which it works also codes for the production of the neutrophilic granulocytes. The neutrophiles enhance the migration of bacteria to the site of infection, which is the tumor [19]. Studies have revealed that increase in host’s neutrophils decides the victory of bacteria-mediated tumor treatment; hence, the total clearance of recognized tumors is achievable with the expanding estimate of necrosis [19].


## 3.1. Activation of Cytokines

There are microbes such asSalmonella typhimurium that are able to activate cytokines. They achieve this by activating the pathways that increases the production of cytokine such as IL-1β, TNF-α, and Il-18. The production of these cytokines in abundance results in tumor destruction since interleukins are the ones that contribute more in fighting pathogens [15, 16].


## 3.2. Activation ofT Cell Lymphocytes

Escherichia coli (E. coli) have shown to have the capability of producing lymphocytes T cells which are very important in the destruction of tumors [17]. E. coli stimulates and activates the production of CD8+T which has been proved to have the ability to destruct tumors after bacterial infection [17]. E. coli also stimulates the production of CD4+T cells which also helps in the antitumor activity [17]. These T cell lymphocytes also have the ability to eradicate colon cancer and this was confirmed by a trial in severe infected mice which showed cancer reduction upon the administration of T cell lymphocytes [18].


## 3.3. Activation of Tumor Necrosis

Tumor necrosis factor (TN-α) contributes towards the formation of drainage in tumors. The bacterium is able to stimulate the production of tumor necrosis factor, which has been reported with Salmonella enterica serovar Typhimurium [19]. The mechanism in which it works also codes for the production of the neutrophilic granulocytes. The neutrophiles enhance the migration of bacteria to the site of infection, which is the tumor [19]. Studies have revealed that increase in host’s neutrophils decides the victory of bacteria-mediated tumor treatment; hence, the total clearance of recognized tumors is achievable with the expanding estimate of necrosis [19].


## 4. Bacteria as Anticancer Operators through Discharged Substances

Bacteria discharge substances which could either be proteins or toxins which are able of hindering the development of tumors. These toxins infiltrate the infected cells and they may change the way that cells function resulting in death of tumor cells.


### 4.1. Bacteriocins

The synthesis of bacteriocins (cationic) peptides occurs almost in all groups of bacteria. Bacteriocins have cancer cell specific toxicities, are known to be nonimmunogenic, and are also biodegradable. They are much better compared to ordinary cancer drugs [20]. Types of bacteriocins include colicin, pediocin, pyocin, and microcin amongst many others. Colicin, discharged from Escherichia coli, has been found to destruct tumors especially in breast cancer [21]. Microcin E492 discharged from Klebsiella pneumoniae was also found to have the capability of actuating whereas pediocin produced from Pediococcus genus was found to be effective against colon cancer [22]. Similar studies have further proved this finding [23, 24]. Beside, pyocin from the Pseudomonas genus had an effect on fibroblast cell line in an experiment carried out on severely infected mice [25, 26].


### 4.2. Phenazine1, 6-Di-Carboxylic Metabolite

Bacteria can produce numerous metabolites belonging to the phenazine group that have the potential of treatingCandida albicans [27] and an example of the bacteria is Pseudomonus aeruginosa. It was also reviewed that the P. aeruginosa’s metabolites are effective on a wide range of cancer cells [28].


## 4.1. Bacteriocins

The synthesis of bacteriocins (cationic) peptides occurs almost in all groups of bacteria. Bacteriocins have cancer cell specific toxicities, are known to be nonimmunogenic, and are also biodegradable. They are much better compared to ordinary cancer drugs [20]. Types of bacteriocins include colicin, pediocin, pyocin, and microcin amongst many others. Colicin, discharged from Escherichia coli, has been found to destruct tumors especially in breast cancer [21]. Microcin E492 discharged from Klebsiella pneumoniae was also found to have the capability of actuating whereas pediocin produced from Pediococcus genus was found to be effective against colon cancer [22]. Similar studies have further proved this finding [23, 24]. Beside, pyocin from the Pseudomonas genus had an effect on fibroblast cell line in an experiment carried out on severely infected mice [25, 26].


## 4.2. Phenazine1, 6-Di-Carboxylic Metabolite

Bacteria can produce numerous metabolites belonging to the phenazine group that have the potential of treatingCandida albicans [27] and an example of the bacteria is Pseudomonus aeruginosa. It was also reviewed that the P. aeruginosa’s metabolites are effective on a wide range of cancer cells [28].


## 5. Biofilms in Cancer Treatment

Bacteria have been recognized to use the strategy of using biofilms in cancer therapy [29] and this has been shown in previous studies [30–33]. Bacteria belonging to the Streptococcus genus have been proven to clear tumors by discharging polysaccharides which repress the attachment of cancer cells to endothelial cells [34]. In an experiment [35], they used press oxide nanowires from a biofilm by Mariprofundus ferroxydans for cancer treatment and it was successful. However, microbe biofilm in metastasis diversion requires further studies.


## 6. Bacteria Serving As Carriers of Cancer Therapeutics

Bacteria with the capability of clearing tumors can be utilized as carriers that delivers the anticancer medicine for cancer therapy [36]. One part of this inventive technology involves the implication of genetic engineering of the bacteria which will result in effective killing of cancerous tumors [37].


### 6.1. The Use of Bacteria in Antiangiogenesis Treatment

Bacteria belonging to theSalmonella genus have been reported to weaken tumor development, as well as block tumor angiogenesis. In an experiment carried out on infected mice, Salmonella was administered and it resulted in the suppressed growth of the tumor through its ability to express endostatin [38]. A current study utilized Bifidobacterium adolescentis for the expression of endostatin inside tumors. The angiogenesis of the tumor was successfully inhibited through creating an antiangiogenic effect [39]. The bacteria-carrier therapy proved to be cost effective and has fewer side effects.


### 6.2. Combining Bacteria Therapy with Viruses in Cancer Treatment

The combined treatment of microbes and oncolytic infections has been detailed to be efficient against a wide variety of cancers [40, 41]. The treatment is advanced and comes with a package of benefits. One of the benefits is that it is less harmful compared to the current available treatment for cancer. Infections have phenomenal capacities to murder cancer cells [42]. Bacteria combined with viruses mediate a safe reaction against tumor antigens. Cronin et al. [43] found that Escherichia coli with the ability to express B18R improved the lysis capability of the vesicular stomatitis virus and in that particular study tumor suppression was achieved.


### 6.3. Bacteria-Based Microrobot (Bacteriobot)

A modern strategy of bacteria-based for tumor treatment, known as the bacteriorobot, employs the use of bacteria as microsensors that treat strong tumors [44]. Microrobots have been made utilizing the nanotechnology [45, 46]. The strategy was carried out in an experiment using Salmonella typhimurium and was successful in destroying the solid tumor cells, since encapsulation hides the bacteria from being destroyed by cells of the immune system [47]. Material technology has also been widely applied for medical and other biochemical applications [48].


## 6.1. The Use of Bacteria in Antiangiogenesis Treatment

Bacteria belonging to theSalmonella genus have been reported to weaken tumor development, as well as block tumor angiogenesis. In an experiment carried out on infected mice, Salmonella was administered and it resulted in the suppressed growth of the tumor through its ability to express endostatin [38]. A current study utilized Bifidobacterium adolescentis for the expression of endostatin inside tumors. The angiogenesis of the tumor was successfully inhibited through creating an antiangiogenic effect [39]. The bacteria-carrier therapy proved to be cost effective and has fewer side effects.


## 6.2. Combining Bacteria Therapy with Viruses in Cancer Treatment

The combined treatment of microbes and oncolytic infections has been detailed to be efficient against a wide variety of cancers [40, 41]. The treatment is advanced and comes with a package of benefits. One of the benefits is that it is less harmful compared to the current available treatment for cancer. Infections have phenomenal capacities to murder cancer cells [42]. Bacteria combined with viruses mediate a safe reaction against tumor antigens. Cronin et al. [43] found that Escherichia coli with the ability to express B18R improved the lysis capability of the vesicular stomatitis virus and in that particular study tumor suppression was achieved.


## 6.3. Bacteria-Based Microrobot (Bacteriobot)

A modern strategy of bacteria-based for tumor treatment, known as the bacteriorobot, employs the use of bacteria as microsensors that treat strong tumors [44]. Microrobots have been made utilizing the nanotechnology [45, 46]. The strategy was carried out in an experiment using Salmonella typhimurium and was successful in destroying the solid tumor cells, since encapsulation hides the bacteria from being destroyed by cells of the immune system [47]. Material technology has also been widely applied for medical and other biochemical applications [48].


## 7. Conclusion

Bacteria are viable in cancer treatment. The treatment of cancer using bacteria is conceivable. In most cases, the treatment has many side effects; therefore, weakened species of microbes able of treating cancer are now being used so as to overcome these side effects. The side effects have shown that they can also be overcome through genetic engineering of the bacteria that has the capability of treating cancerous cells and solid tumors. Effective therapy for cancer using bacteria can also be achieved through using the bacteria in combination with other cancer treatments such as radiotherapy and chemotherapy. The approach of using bacteria in solid tumor clearance is still quite new; therefore, further studies on this subject are of necessity.



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