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Table 1. Pre-clinical studies for evaluation of molecular antitumor effects made by genetic engineering bacteria
Bacterium Molecule Most relevant results Reference
Salmonella typhimurium
VNP20009 CCL21 Increased intratumoral production INFg, CXCL9 and CXCL1 Loeffler et al. [87]
VNP20009 LIGHT (TNFSF14) Prominent reduction in tumor growth was observed. Evidenced with an inflammatory Loeffler et al. [113]
infiltrate (B lymphocytes, CD4 ,CD8 in models treated with this bacterium
+
+
VNP20009 IL-18 Inhibition of tumor growth was observed. Evidenced with a leukocytic infiltrate Loeffler et al. [114]
(especially NK cells) and increased secretion of INF-g, TNF-a, IL-1b and GM-CSF
VNP20009 FASL Significant reduction of tumor size was observed in primary tumors and lung Loeffler et al. [115]
metastases, increasing neutrophil recruitment
VNP20009 TRAIL TRAIL expression increased tumor cells apoptosis dependent on caspase 3 and 8 Ganai et al. [116]
S. choleraesuis Endostatine Inhibition of tumor growth was observed in 40%-70%. Evidenced with a decrease in Lee et al. [117]
+
intratumoral microvasculature, VEGF expression and increase in T CD8 lymphocyte
recruitment
S. choleraesuis Thrombospondin Selective colonization was observed in a 1000:1 to 10000:1 ratio with respect to liver Lee et al. [118]
and spleen. Evidenced with inhibition of tumor growth and increase in survival by
angiogenic effects
Nula phoP/ RNAi-STAT3 RNAi inhibited significantly tumor growth, the number of metastatic lessions Zhang et al. [119]
phoQ LH430 decreased, increased survival rate in animal models
S. typhiTy21 VEGFR-2 Vaccination for this molecule showed inhibition of tumor growth, decreased Niethammer et al. [120]
metastasis growth and prevented new spontaneous metástasis, increasing survival
rate in models
aroA SL7207 PSA-CtxB* This vaccine administration conjugated with Salmonella showed protective effects by Fensterle et al. [121]
reducing tumor size in 8-14 days since its inoculation. This mechanism depends on T
+
CD8 lymphocyte activity and a prototype of the E. coli Hemolysin secretion system
Clostridium
C. beijerinckii NR Nitroreductase activity increased in vitro antitumor activity of CB in 1954, by a factor Lemmon et al. [122]
of 22
C. beijerinckii Citosine deaminase Tumor cells sensitivity to 5-fluorocytosine increased by 500 times Fox et al. [123]
C. sporogenes IL-12 Increased selective secretion of INF-g with effects on tumor growth, without signs of Zhang et al. [124]
toxicity
C. novyi-NT AC anti-HIFa A heterologous gene transfer was satisfactory in this bacterium. Showing increased Groot et al. [125]
antibody secretion (with adhesion capacity and specificity)
Listeria monocytogenes
Lm-LLO-E7 HPV16-E7* This therapy induced regression in 75% of tumors expressing E7 antigen. This Gunn et al. [126]
+
+
response depends on TCD4 and TCD8 lymphocytes and INFg secretion
ADXS31–164 HER-2/neu An increase in TCD8/Tregs ratio was observed with this therapy. It also prevented Shahabi et al. [127]
(Human)* more breast tumor formation and delayed more metastasis growth than other
vaccines based on this bacterium
LM-LLO- MAGE-b* The most effective vaccine for breast tumors, decreasing number of metastasis Kim et al. [128]
Mage-b/2nd by 96%, correlating to a strong CD8 lymphocytic response in spleen after
+
restimulation with antigen use
Lm-LLO- HMW-MAA This therapy immunization prevented tumor growth not only in models that expressed Maciag et al. [129]
HMW-MAA-C the antigen, but in melanoma, renal carcinoma and breast carcinoma. TCD4 and
+
+
TCD8 lymphocytes were needed to achieve this
*Antigen expressed on tumor
cytokines [114,136,137] , including IL-18, is important to enhance cytokine production in T lymphocytes and NK
+
cells, to increase MHC-1 expression, and to favor differentiation of Th1 CD4 cells; leading to an immune
+
response mediated by NK cells, macrophages, and T CD8 cells [114,138] .
Bacteria induce expression of ligands in cancerous cells with antitumor activity. For example, the FAS
ligand (FASL), member of TNF family, enhances chemotaxis and IL-23 production from dendritic cells
with T cell proliferation [115] . TNF related to apoptosis inducing ligand (TRAIL) protein expression has been
achieved in models with breast cancer [116] , gastric cancer [139] and melanoma by employment of controlled
bacteria [140] .