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Torres et al. J Cancer Metastasis Treat 2018;4:4 I http://dx.doi.org/10.20517/2394-4722.2017.49 Page 9 of 25

An interesting fact about cancer prognosis is the advanced stage by the time it is diagnosed, decreasing
patient survival. Therefore, bacteria have been employed to work as vaccine vectors. These vaccines would
increase tumor antigen expression on cancerous cells. Among these: prostatic specific antigen (PSA) in
prostate cancer [121] , C-rapidly accelerated fibrosarcoma in pulmonary adenoma [141] , and alpha-fetoprotein
(α-FP) for hepatocellular carcinoma [142] . They can work by inducing an adaptive immune response to
+
protect against these tumors. APCs recognition of these antigens is followed by a specific T-CD8 cell
proliferation with immunologic memory, in contrast to systemic administration of antibodies or adoptive
T cell leading to loss of immunotolerance and healthy tissues affected [143] .

Other use as therapeutic vectors
Expression of hemolytic toxins could be achieved in tumors resistant to conventional therapy. Cytolisin A
(Clya) with E. coli K-12 use [144] is an example of these. Transcription factors could be induced in cases with
S. Typhimurioum JRG5356 where genes for HlyE activation are expressed so pore-forming cytolysins are
[85]
made by activating the FF+20 promoter . On the other hand, inhibition of angiogenetic processes with
TSP-1 or endostatin genes could be used to decrease capillary density and reduce expression of vascular
endothelial growth factors (VEGF) [117,118] .

Lastly, protein repression could also be induced using RNA interference (RNAi). Bacteria carrying plasmids
such as pSi-Stat3 are capable of changing specific portions of DNA and increase expression of small
interference RNA (siRNA) [145] or short hairpin RNA (shRNA). All of these cause degradation of specific
mRNA sequences leading to a dysfunctional tumor gene expression [146,147] .

POTENTIAL OF BACTERIA UTILIZATION IN ONCOLOGY
Research on bacteria employment against malignant tumors in human subjects is expanding in diagnostics
(for their selective colonization and external control) and therapeutics (for their antitumor effect). The next
sections will discuss experimental and clinical evidence supporting bacteria utilization against cancer.

Bacteria utilization as cancer diagnostic method and to monitor therapeutic efficacy
Bacteria utilization is not limited to the therapeutic scope but also to diagnostic methods. Developments
in genetic engineering have shown expression of bacterial genes that can be detected and monitored
[90]
externally by fluoroscopy [148] , magnetic resonance imaging (MRI) and positron emission tomography
(PET) [149] scan. These genes can code for light-emitting proteins, such as luciferase and green fluorescent
protein (GFP), making them observable in real time under low light image processing; and also under
micro-to-micro fluorescent microscopes [150] . E. coli bacterium remains as a prototype carrying PLITE201
plasmid that codes for luxCDABE protein [151] giving luminescent features. This bacterium also carries
the pMW211 plasmid that codes for dsred protein [152] making cancerous cells recognizable in their
exact localization by turning them luminescent without any invasive approach. Salmonella typhimyrium
and Vibrio cholerae remain under study for their utilization in colon and breast cancer diagnosis,
respectively [153] .

MRI is routinely used for tumor diagnosis and treatment evaluation. Magneto spirillum is a bacterium
employed in this radiologic study. It consists of a microaerophilic microorganism with magnetic properties
on its magnetosome which contains magnetic crystals formed mainly of magnetite (Fe3O4) covered by a
lipid bilayer membrane [154] . Experiments with AMB-1 strains of this bacterium have shown positive contrast
[90]
features in T1-enhanced imaging when they were cultured under iron deprived (FeCl3) conditions .
Contrast was intensified with expression of MagA gene. This gene codes for an iron transporter that gets
positively regulated in presence of low iron concentrations [155] . In vitro experiments with colon carcinoma
models in HT-29 human subjects did not show any evidence of toxicity and tumor necrosis was observed