The genes slyA, STM3120 and htrA are required for the anticancer ability of VNP20009.
VNP20009 is a very effective anti-cancer agent and can specifically target tumors and inhibit tumor growth. It was assumed that the tumor targeting ability of VNP20009 correlated to its anticancer capacity. However, our observation contradicted to this assumption. Three VNP20009 mutant strains (ΔslyA, ΔSTM3120 and ΔhtrA) with reduced fitness in normal tissues and unchanged fitness in tumors partially or completely lost their anti-cancer capacities. The genes slyA, STM3120 and htrA were required for survival within macrophages and were indispensable for tumor microenvironment remodeling by VNP20009. The infiltration of immune cells occurred less in the tumors of mice infected with the mutant strains. In addition, the mRNA levels of TNF-α and IL-1β were significantly decreased in the tumors of mice treated with the mutant strains. Our results indicate that the immune responses elicited by bacteria rather than the bacterial titer in tumors play a "decisive" role in VNP20009-mediated bacterial cancer therapy, which provides a novel perspective for the underlying mechanism of bacterial cancer therapy.
The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, 210023, Jiangsu, China.
Xiaoxin
X
Zhang
The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, 210023, Jiangsu, China.
Qiaoqiao
Q
Xu
The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, 210023, Jiangsu, China.
Lirun
L
Yang
The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, 210023, Jiangsu, China.
Yueyang
Y
Lai
The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, 210023, Jiangsu, China.
Zhuangzhuang
Z
Zhang
The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, 210023, Jiangsu, China.
Chao
C
Han
The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, 210023, Jiangsu, China.
Chizhou
C
Jiang
The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, 210023, Jiangsu, China.
Jiahuang
J
Li
The School of Life Sciences and the Center for Infectious Diseases and Vaccinology at the Biodesign Institute, Arizona State University, Tempe, Arizona, 85287-4501, USA.
Yixin
Y
Shi
The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, 210023, Jiangsu, China.|Changzhou High-Tech Research Institute of Nanjing University and Jiangsu TargetPharma Laboratories Inc., Changzhou, 213164, Jiangsu, China.|The State Key Lab of Natural Medicines, China Pharmaceutical University, Nanjing 210017, China.|The State Key Laboratory of Bioelectronics, Southeast University, Nanjing 210008, China.
Zi-Chun
ZC
Hua
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics* / Q000276:immunology; D001428:Bacterial Vaccines / Q000494:pharmacology*; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D033903:Periplasmic Proteins / Q000235:genetics* / Q000276:immunology; D000067996:RAW 264.7 Cells; D019779:Salmonella enterica / Q000235:genetics* / Q000276:immunology; D012697:Serine Endopeptidases / Q000235:genetics* / Q000276:immunology; D012878:Skin Neoplasms / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000628:therapy*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000276:immunology; D047368:Tumor Burden; D059016:Tumor Microenvironment; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
D001426:Bacterial Proteins; D001428:Bacterial Vaccines; D006360:Heat-Shock Proteins; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D033903:Periplasmic Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C465023:VNP 20009; C056785:salmolysin; C061682:DegP protease; D012697:Serine Endopeptidases
VNP20009; bacteria; cancer; immune response; tumor-targeting