# Microbes as Medicines: Harnessing the Power of Bacteria in Advancing Cancer Treatment
## 2 Mechanism of Tumor Suppression
### Anti-Angiogenic Therapy  
Solid tumors witness pronounced angiogenesis resulting in proliferation of vast network of blood vessels around the tumor cells. New blood vessels trigger the growth and metastasis of solid tumors. However, the newly formed blood vessels are highly disorganized and have anatomical differences in terms of incomplete endothelial linings. This results in leaky vasculature which allows residence of the circulating bacteria [85]. The combination of tumor targeting bacteria and inhibition of angiogenesis would thereby enhance the possibility of tumor eradication [86; 87].  
[PERSON] et. al. engineered _Salmonella typhimurium_ ST8 harboring a plasmid encoding for angiogenic inhibitor, Endostatin fused with Type III secretion system (T3 SS) protein SopA. The T3 SS proteins interfere with the pro-angiogenic action of the growth factors in tumors. Administration of ST8/pSEndo in murine CT26 colon cancer mice showed effective tumor regression with low blood vessel density and severe tumor necrosis as compared to a mock control ST8/pSGFP [8]. Potent anti-angiogenic and tumor vessel normalization properties of Histidine-proline-rich glycoprotein (HPRG) were introduced in _S. typhimurium_ VNP20009 strain under the control of hypoxia-induced NirB promoter. VNP20009 mediated HPRG significantly reduced tumor growth and enhanced survival in primary B16F10 (melanoma mice model) and inhibited lung metastatic tumor growth in B16F10 metastatic tumor model [88]. Combination therapy of _S. typhimurium_ VNP20009 with triptolide, an antiangiogenic and anti-inflammatory compound was investigated for melanoma treatment. Tumor targeting VNP20009 triggers the migration of neutrophils, macrophages, and CD8+ T cells. Macrophages and neutrophils have a bactericidal effect and may suppress VNP20009. However, the combination therapy with triptolide, reduced the infiltration of neutrophils in the tumor as well as reduced the expression of vascular endothelial growth factor (VEGF) resulting into larger necrosis in the melanoma [89].  
Lipophilic AMPs from new endophytic bacterial strain, EML-CAP3 isolated from red pepper leaf (_Capsicum annuum_ L.) were studied by [PERSON] et al. The newly obtained AMP demonstrated potent tumor induced angiogenic inhibition by downregulating Hypoxia inducible factor-1 \(\alpha\) and its target gene VEGF in human umbilical vein endothelial cells [90]. [PERSON] et al. devised bacterial particles consisting of fixed bacteria _E. coli_ (TOP10), double attenuated (aroA- and dam-) _Salmonella typhimurium_ strain RE88, and _Streptococcus thermophilus_. The systemic administration of these bacterial particles in mice bearing subcutaneous CT26 colon cancer and LL2 Lewis lung cancer stimulated innate immune response by phagocytosis and inflammatory cytokines were released. The release of inflammatory cytokines enabled the bacterial particles to disrupt the tumor vasculature, induce tumor hemorrhage and necrosis resulting in extensive cell death in the TME. The effect of the destruction of the tumor vasculature due to the bacterial particles was similar to the combination of six inflammatory cytokines namely, TNF-\(\alpha\), KC, MCP-1, G-CSF, IP-10, and IL-6 [91].  
[PERSON] et al. investigated _Propionibacterium acnes_ in combination with melatonin for breast cancer treatment in a mice model. The combination had a synergistic action in stimulating interferon gamma (INF-\(\gamma\)) production and inhibiting VEGF expression. The resulting effect was reduced angiogenesis, enhanced apoptosis, and strong Th1-type cytokine anti-tumor immune response that led to tumor regression [92]. Anti-angiogenic therapy comprising of gemcitabine/bevacizumab and subsequent administration of _Salmonella typhimurium_ A1-R showed higher efficacy than the drug combination alone, in pancreatic cancer derived orthotopic xenograft model, hence indicating its potential in clinical applications [54].