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could induce cell entrance from G0/G1 to S/G2/M and reduced significant portion of cells in quiescent
state, making them sensible to chemotherapy [200,201] .

Other approach in gene modification of Salmonella was the study of strains to decrease or inactivate gene
expression. This inactivation could be achieved with utilization of iRNA [119,202] . S. typhimurium LH340 strain
was made with deletion on popP/phoQ operon required for its virulence resulting in its attenuation [203,204] .
The signal transducer and activator of transcription protein-3 (STAT3) is the goal with these therapies.
Confirmation of its role in immune system depression [205] and expression of target genes such as VEGF,
Cyclin D1, Cyclin D2, c-Myc, p53, Bcl-XL, Bcl-2, Mcl-1 and Survivin have been observed [206] . A relationship
between inhibition of these genes expression and suppression of tumor growth was found [207] .

Strains with expression of iRNA for Stat3 suppressed tumor growth significantly, reduced metastasis and
increased survival in experimental models with prostate [119] and hepatocellular carcinoma [202] . These tumors
are usually highly vascularized and angiogenesis inhibition through plasmids required for endostatin
codification (SL/pEndostatin) may increase efficacy to the novel therapy [133] . By introducing Stat3, (SL/
pEndo-Si-Stat3) more antitumor effects were observed. These effects were related to angiogenesis
+
inhibition and increase in TCD8 lymphocyte proliferation, NK cytotoxicity and T-regs proliferation. The
later came from inhibition probably by stimulation of INF-γ and TNF-α secretion with significant decrease
in TGF-β concentrations [202] .

In clinical settings Salmonella typhi Ty21a is one of the new therapy prospects. It was studied to find a
vaccine to prevent typhoid fever [173] . The bacterium was introduced to cancer therapy strategies with the
VXM01 vaccine. This is an oral vaccine made of live attenuated strains of S. typhi ty21a capable to induce
a T cell response; it also contains a plasmid that codes for VEGFR2 and plays an important role in tumor
angiogenesis [208] . It can also induce both humoral and cellular responses [176] observed in experimental
models with melanoma, colorectal cancer and lung cancer. Suppression of primary tumor growth and
+
metastatic lesions mediated by T-CD8 cells activity was observed in these models [117] . In clinical settings,
it was recently evaluated on 45 patients with stage IV pancreatic cancer and it showed the importance of
preexisting immunologic memory for effector T cells to achieve an antiangiogenic effect [176] .

Clinical trials have shown that Salmonella still lacks therapeutic efficacy and selective tumor colonization
but could be considered as a multi-use bacterium for its diverse features. It can work as a vector, and a
better inducer of antitumoral response because of its efficient type III secretion system [209] . Prospecting
studies should be focused on this objective with specific molecules for each cancer type, getting major
effectiveness.

Listeria monocytogenes: the perfect antigenic vector
Listeria monocytogenes (Lm) is a gram positive, facultative intracellular bacterium [131] . Over the last
few decades multiple studies have shown that it can work cancer therapeutic agent with multiple effect
or mechanisms [210] . It can be used against primary and metastatic tumors in an immune-privileged
microenvironment. The latter helps its selective colonization and favors their elimination with ROS
production [211] . In addition to this, Lm decreases T-regs cells and immunomodulation molecules such
as TGFβ and IL10 in tumor microenvironment [212] . However, main feature of Lm consists on selectively
infecting APCs favoring self-antigen and heterolog antigens processing and presentation [213] . These
characteristics make Lm to be considered as a valuable immunostimulant agent.

Intracellular life cycle of Lm favors its use as an immunotherapeutic agent. Once infection has ocurred, Lm
strongly activates innate immunity with the release of proinflammatory cytokines such as IL-2, IL-6, IL-