# Bacteria-Mediated Modulatory Strategies for Colorectal Cancer Treatment
## 2 Bacterotherapy in CRC Treatment
### Mechanisms Used in Bacterotherapy in CRC
#### 2.1.2 Bacterial Peptides  
Peptides acting as anti-tumor agents, including several bacterial peptides, are mainly characterized by having low molecular weight and hydrophobicity. These properties seem to be of great importance for the peptides to migrate into the tumor, where cells partly exhibit an altered surface compared to normal cells. Within the tumor, bacterial peptides can unfold their anti-cancer and immune-modulating activity in different ways dependent on their characteristics [26]. _A: Bacterial Toxins_  
The use of bacterial peptides as bacterial toxins demonstrates another CRC treatment approach. Bacterial toxins are substances and metabolites secreted by bacteria that have been shown to suppress tumor growth in numerous studies [58]. They are synthesized by almost all bacterial species and have already been identified for a large number of bacterial strains. Under physiological conditions, bacteriins help bacteria to protect themselves from competing microorganisms by killing them [59; 60]. So far, two types of bacterial anti-cancer toxins have been identified: toxins that conjugate to surface antigens of malignant cells and secondly toxins that conjugate to ligands of cancer cells [61]. Since CRC cells present a great number of tumor-specific antigens on their surface, mainly functioning as receptors, bacterial toxins represent a powerful tool to specifically bind them [60]. In the following, we will present some of these bacterial toxins that have been demonstrated to be effective against CRC (Table 1). _Enterotoxin_  
Enterotoxin (CPE) for example, which is produced by _C. perfringens_, a gram-positive anaerobic bacterium, represents one of the most effective bacterial toxins used in CRC therapy by binding to Claudin-3 and -4 surface receptors that are prevalent in malignant cells, which finally leads to cellular osmotic balance breakdown and cancer cell lysis [62; 63]. In addition, [PERSON] et al. found an optimized CPE expressing vector that targets Claudin-3 and Claudin-4 expression in SW480, HCT-116, SW620, Caco-2, HT-29 and PDX colon cancer cells, demonstrating CPE as a gene transfer system that could be used as a therapeutic agent in CRC treatment directed against Claudin-3 and -4 that causes fast tumor cell death, as shown in vitro and in vivo [62; 63]. Moreover, several other bacteriins showing anti-cancer properties have been found, such as Diphteria toxin (DT), Nisin, Colicin, Microcin and Pediocin [64]. _Diphteria Toxin_  
Diphteria toxin, consisting of two subunits A and B, is released by gram-positive Coryneb bacterium diphtheria bacteria. Via subunit B, the bacterium is able to bind to cancer cells, while the catalytically active subunit A is able to block the protein synthesis via ADP-ribosylation of cytoplasmic elongation factor 2 (EF-2), finally resulting in cancer cell death [65; 66]. A non-toxic attenuated form of DT (CRM197) has been demonstrated to bind to HBEGF (heparin-binding epidermal growth factor) and to suppress cancer proliferation and angiogenesis while inducing apoptosis in vivo. These anti-cancer effects of DT have also been found in the treatment of colon cancer cell lines SW480, SW620, HCT116, CaCo-2 and HT-29 [67; 68]. _Nisin_  
Nisin, a polycyclic peptide secreted by the bacterial strain _Lactococcus lactis_, has shown a significant cytotoxic effect on Caco-2 and HT-29 CRC cell types, whereby hole formation in the cell membrane of target cancer cells was promoted, which finally lead to cytoplasmic membrane depolarization and apoptosis [69]. Furthermore, Nisin has also been demonstrated to prevent metastatic gene expression of MMP-2, MMP-9, cytotlethal distending toxins and the cycle inhibiting factor in CRC cell lines, namely LS-180, HT-29, SW480 and Caco-2, further supporting Nisin's role as an anti-cancer agent [70; 71]. The application of Nisin, combined with conventional therapy, has already been shown to help reduce the therapeutic doses of various anti-cancer medications by increasing their cytotoxicity [71].