Page 63 - Read Online

Page 10 of 25 Torres et al. J Cancer Metastasis Treat 2018;4:4 I http://dx.doi.org/10.20517/2394-4722.2017.49

on both histologic slides and MRI [156] . Employment of these magnetic features implies new advances with
clinical use potential.

Regarding PET scans, other modified strains of E. coli: E. coli Nissle (EcN) 1917 [152] along with pyrimidine
nucleotide analogs have been considered for diagnosis of breast tumors. Increased local accumulation
of radio-isotopes has shown a positive correlation with the number of bacteria containing radioactive
drugs. These bacteria selectively colonized tumors, making them detectable via PET. Other bacterium
employed for these studies was Salmonella VNP20009-TK. The latter has had similar results with a positive
correlation between intratumor bacteria and fialuridine sequestration (FIAU), a radio-marked nucleoside
analog used for tumor identification [157] .

Other bacteria diagnostic features can be used in oncology. This includes their employment as probiotics
in cancer screening [158] . Use of EcN with modified genetic circuits enhances detection of focal metastasis
in urine samples. Two principles were applied: first, bacteria produced a luminous signal that can be
detected through imaging techniques; and second, LacZ enzymatic activity on a substrate composed of
luciferine and galactose (LuGal) results in luciferine traveling into the circulatory system and serving as a
colorimetric indicator with fluorescent or luminescent features; these features could be detected in urine
samples [158] .

Current perspective in bacteria based therapy in medicine
Recently, bacterial strains with therapeutic characteristics against cancer have been discovered.
Mycobacterium bovis (BCG) is considered a prototype. It is an obligate anaerobic, acid-alcohol-resistant,
facultative intracellular and non-motile bacterium that has been employed in the past for tuberculosis
vaccine manufacturing [159] . For more than 30 years it has been utilized in bladder cancer patients as
immunotherapy. A decrease in tumor recurrence has been observed with this therapy along with its well
tolerated adverse effects [160] . Even though the first-choice treatment for non-muscle invasive bladder cancer
(NMIBC) is still transurethral resection for bladder tumor (TURBT), a high recurrence (50%-70%) and
progression rates (10%-20%) after two years have been observed with this procedure [161] . In these cases,
intravesical instillation with BCG is one of the main therapeutic options, decreasing long term appearance
of distant metastasis [162] ; also an increase in global survival in 5 years with long term maintenance of
this therapy has been observed [163] . However, its long term use may have adverse effects such as drug
induced cystitis, hematuria, and systemic toxicity [164] . Despite of this, BCG is still considered the standard
treatment for NMIBC after transurethral resection for bladder tumor has been performed in patients with
[12]
intermediate and high risk of progression or recurrence .

The mechanism behind these benefits has not been clarified, but the antitumoral effects of BCG are
considered to come from the immune response [165,166] . Once urothelial cells or macrophages internalize the
bacillus, they induce an immune response with secretion of TNF-α, IL-6, IL-10, INF-γ, FEC-GM, CC and
expression of CXC chemokine receptors [167-169] ; this stimulates recruitment of neutrophils, macrophages,
+
T-CD4 cells and increases expression of MHC-I, MHC-II and IL-2 receptors [170-172] . TRAIL is one of the
main mediators in bacteria based therapy. This ligand appears to be upregulated in response to INF-γ,
causing urothelial cell death [173,174] . BCG remains as reference for novel cancer therapies in development
such as vaccines, and also for nonbacterial therapies, having similar efficacy and reliability (NCT02010203).
Next sections discuss the most important bacteria used for these goals, going from their experimental
research to current clinical evidence [Table 2].

Clostridium: heading to tumor specificity
Necrosis and hypoxia in tumor tissues make them resistant to conventional therapies [106] , therefore,
research on Clostridium began because of its natural anaerobic features [101] . In regards to utilization of this