# Microbes as Medicines: Harnessing the Power of Bacteria in Advancing Cancer Treatment
## 2 Mechanism of Tumor Suppression
### Bacteria Quorum Sensing for Tumor Targeting  
Bacteria reside in close communities and establish cell to cell communication using signaling molecules. This mode of communication is referred to as quorum sensing (QS). The Gram-negative bacteria use N-acyl homoserine lactone whereas the Gram-positive bacteria use oligopeptides as signaling molecules. In addition, the autoinducer-2 synthesized by both the bacterial types is also used for signaling. Synthesis of these molecules occurs in a cell density dependent manner [101; 102; 103]. QS phenomenon can be used to design genetic circuits for identifying bacterial aggregation in tumor regions which can serve as biosensors [104]. [PERSON] et al. applied this technique to combine the genetic output interface encoding for invasin from _Yersinia pseudotuberculosisis_ in _E. coli_ with the _lux_ QS circuit of _Vibrio fischeri_ having hypoxia-responsive (fdhF) promoter or arabinose inducible promoter (araBAD) to identify the tumor environment. Invasion enabled _E. coli_ to invade into different cancer cells like epithelial, hepatocarcinoma, and osteosarcoma cell lines. The invasion mediated internalization is under the control of fdhF and araBAD promoters. This system can be used to engineer bacteria to sense the TME and propagate the entry and release of cytotoxic agents [105]. [PERSON] et. al. adopted the concept of quorum lysis in engineering _E. coli_ strain for the local delivery of CD47 antagonist nanobody. The _E. coli_ had a single plasmid encoding for synchronized lysis circuit, the bacteria expressing _luxl_ proliferated and synthesized QS molecules such as acylhomoserine lactone. On reaching a critical threshold, bacteriophage lysis protein is produced resulting in release of the therapeutic cargo. The authors reported that the CD47 blockade in syngeneic mouse model boosted tumor infiltrating T cells activation leading to rapid tumor regression. A major advantage of this approach was induction of systemic anti-tumor immunity by local delivery of abundant adjuvants, which also precludes the generation of anti-drug antibodies and limits systemic toxicity [106; 107]. The QS signaling molecules have also demonstrated anti-cancer potential. For instance, the D-Retroenantiomer of QS peptide (SYPGWSW) obtained from _Clostridium acetobutylcium_ possess the ability to cross the blood brain barrier and has excellent tumor homing properties. PEGylated micelles were prepared having surface modification with QS peptide for intracranial glioma targeting. These surface modified micelles when loaded with paclitaxel exhibited excellent tumor accumulation and strong anti-angiogenic and anti-tumor effect in the glioma region [108]. The quorum sensing signal molecule, N-3-oxo-dodecanoylL-L-homoserine lactone (O-DDHSL) exhibited cytotoxic effect by inducing apoptosis, inhibiting colony formation, and reducing colony formation in pancreatic carcinoma cells [109]. O-DDHSL has also proved to mitigate proliferation and viability and induced significant necrosis in malignant MDA-MB-231 breast cancer cells [110]. [PERSON] et al. synthesizedvarious QS analogs and tested its activity on [PERSON]'s lymphoma cells. The molecules proved to be cytotoxic and inactivated the NF-kB signaling in these cells [111]. Some microbiome related QS peptides from commensal or pathogenic bacteria such as the extracellular death factor (EDF) synthesized by the gut bacterium _E. coli_, PhrG peptide produced by _Bacillus subtilis_, a gut bacterium, and competence stimulating peptide from oral commensal bacteria _Streptococcus mitis_ exhibit pro-invasive characteristics and angiogenic properties [103]. The EDF derived peptides and Phr0662 (_Bacillus_ sp.) peptide from the human microbiome, have the possibility of causing cancer metastasis [102]. Thus, the identification of potential tumor targets and development of antagonists of such peptides can be a breakthrough in cancer therapy.