Oxidative stress in malignant melanoma enhances tumor necrosis factor-α secretion of tumor-associated macrophages that promote cancer cell invasion.
OBJECTIVE
Malignant melanoma is well known for abundant reactive oxygen species (ROS) that exist in the primary tumor environment. Within this microenvironment, tumor-associated macrophages (TAMs) play substantial roles in multiple steps of tumor development in terms of tumor growth, invasion, and metastasis. We therefore aimed to determine whether this high-level ROS in primary melanoma is capable to promote tumor invasiveness by influencing TAM properties. Moreover, we wanted to further investigate probable underlying mechanisms.


RESULTS
We characterized malignant melanoma TAMs as a heterogeneous phenotype, which possesses both M1 and M2 markers. We also revealed a role for high-level intracellular ROS in enhancing proinvasion signature of TAMs by strongly increasing their tumor necrosis factor α secretion, which is possibly attributed to ROS-enhanced peroxisome proliferator-activated receptor γ (PPARγ) translocation mediated by MAPK/ERK kinase 1.


METHODS
This is the first study demonstrating that high levels of ROS in the primary melanoma environment can influence TAM behaviors. Furthermore, we are also the first to indentify that nucleus-to-cytoplasm translocation of PPARγ is significantly upregulated by ROS and responsible for the proinvasiveness capacity of melanoma TAMs.


CONCLUSIONS
Taken together, our data describe how a high level of ROS plays a critical role in enhancing the proinvasion characteristic of TAMs in malignant melanoma.
1 State Key Laboratory of Pharmaceutical Biotechnology, and Model Animal Research Center (MARC) of Nanjing University, Nanjing University , Nanjing, China .
Xuzhu
X
Lin
Wei
W
Zheng
Jing
J
Liu
Ya
Y
Zhang
Haohan
H
Qin
Haochen
H
Wu
Bin
B
Xue
Yan
Y
Lu
Pingping
P
Shen
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D047495:PPAR gamma / Q000378:metabolism; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D047495:PPAR gamma; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D048369:MAP Kinase Kinase 1