## 6 _Salmonella_ Diminishes Tumor Metastasis  
The prevention of metastatic activity by _Salmonella_ through various mechanisms prevent tumor cells from migrating (Figure 1 and Table 1). Failure to detect the advancement of tumor into metastatic state where cancer cells gain access to different sites of the body leads to a significantly poor prognosis which, in turn, dramatically affects patients' survival. This is primarily due to the changes in the behavior of cells in the primary tumor causing migration and aggressive invasion of the proximal and even distal organs forming secondary lesions [52; 53]. The initiation of angiogenic sprouting in tumor marks the dramatic shift from dormancy to tumor progression [2; 54]. Angiogenesis is not only critical to tumor growth per se, but also to tumor migration because the new blood vessels formed provide the major route used by disintegrating tumor cells to escape from the primary tumor and start migration [55]. Many studies have already demonstrated the role of this angiogenesis in tumor metastasis and, thus, that the inhibition of angiogenic sprouting may help contain the tumor and stop its metastatic activity. The regulation of angiogenic sprouting is orchestrated by the angiogenic factors _vascular endothelial growth factor-A_ (VEGF-A) and thrombospondin-1 (TSP-1) that either stimulates or inhibits cell-surface receptors, respectively [56]. In the tumor microenvironment, the presence of oncogenic signals and hypoxic condition activate certain transcription regulators such as _hypoxia-inducible factor 1-alpha_ (HIF-1\(\alpha\)) to induce upregulation of VEGF [57; 58; 59] that largely influences tumor vascularization. In a study by [PERSON] et al. [49], _Salmonella_ inhibited angiogenesis by negatively regulating VEGF expressions in two tumor cells namely, B16F10 and 4T1. The downregulation of VEGF is attributed to the downregulation of its gene regulator HIF-1\(\alpha\), suggesting that the anti-angiogenic activity of _Salmonella_ targets the HIF-1\(\alpha\) dependent pathway. The activation of HIF-1\(\alpha\) is mediated by AKT/mTOR/p70S6K cascade [49; 59; 60; 61] which was found to be significantly reduced after _Salmonella_ treatment as indicated by decline in AKT, mTOR and p70S6K phosphorylation. Interestingly, the frequency of viable human microvascular endothelial cells (HMEC-1) declined significantly post-treatment with conditioned medium of either _Salmonella_-treated B16F10 or 4T1 cells [49]. Consistent with the findings already mentioned, in vivo study using tumor-bearing mice showed reduced VEGF levels in tumor tissue and reduced tumor microvessel density that is necessary to confine tumor in the primary site [49]. For metastatic tumor to escape primary site and eventually migrate to other organs to seed secondary tumors, metastatic tumor cells rely on an important process involving proteolytic degradation of extracellular matrix (ECM) by proteinases such as matrix metalloproteinase [62]. Matrix metalloproteinase, a member of the zinc-dependent endopeptidases family, is known to modulate ECM remodeling in normal development, inflammation, and wound healing [63; 64; 65; 66]. In various types of tumors, MMP-9 expression is primarily implicated in metastatic phenotypes by acting upon the ECM components thereby altering adhesive capability and in promoting tumor vascularization [67; 68; 69]. MMP-9 expression contributes to the epithelium to mesenchymal transition (EMT), serving as one of the markers of cancer stem cells [70]. It is therefore advantageous to utilize therapeutic strategies targeting MMP-9 expression. Negative regulation of MMP-9 expression has also been demonstrated to suppress metastatic activity of prostate cancer [71; 72] malignant glioma [73] and renal cell carcinoma [74]. When _Salmonella_ is used as an antitumor agent, it inhibits not only tumor