Tumor interstitial fluid promotes malignant phenotypes of lung cancer independently of angiogenesis.
Angiogenesis is necessary for cancer progression, but antiangiogenic therapy actually promotes tumor recurrence, progression, and metastasis. This study focused on the contribution of the tumor interstitial fluid (TIF) to lung cancer progression. TIF was isolated and quantified for 10 μg protein/mL. Malignant driver characteristics of TIF were examined by tumor-initiating cells (TIC), self-renewal, epithelial-mesenchymal transition (EMT), autophagy, and apoptosis in vitro. In vivo tumor model was used to investigate the mechanistic roles of TIF in lung cancer progression. In vitro, TIF exhibited distinct malignant driver characteristics, which led to increased numbers of TICs, increased self-renewal and EMT, as well as to decreased autophagy and apoptosis under cell starvation conditions. In vivo, the contribution of TIF was similar, as judged by increased TICs indicated by the cancer stem cell marker Nanog, the proliferation marker proliferating cell nuclear antigen, and the EMT marker N-cadherin; TIF also increased the formation of pulmonary tumors. Interestingly, the blockers of inflammation, Na-K-ATPase, and aldosterone receptor decreased TIF-induced tumor progression but increased angiogenesis. Further, we found that the water content of the tissue was positively correlated with the levels of plasma 5-hydroxyindoleacetic acid or tissue aquaporin-1 but not with CD31. However, vadimezan reduced angiogenesis but promoted TIF-induced tumor progression. Our results suggested that TIF could provide better nutrition to the tumor than angiogenesis and that it could promote the development of malignant phenotypes of lung cancer independently of angiogenesis.
Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province, China.
Hong
H
Li
Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province, China.
Ganggang
G
Li
Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province, China.
Linxin
L
Liu
Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province, China.
Zhenzhen
Z
Guo
Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province, China.
Xiaofang
X
Ma
Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province, China.
Ning
N
Cao
Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province, China.
Haihong
H
Lin
Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province, China.
Guang
G
Han
Department of Oncology, The First Hospital Affiliated to Henan University, Kaifeng, Henan Province, China. 724200@henu.edu.cn dgjlhh@163.com.
Yongjian
Y
Duan
Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province, China. 724200@henu.edu.cn dgjlhh@163.com.
Gangjun
G
Du
D000818:Animals; D017209:Apoptosis; D051398:Aquaporin 1 / Q000378:metabolism; D001343:Autophagy; D018827:Carcinoma, Lewis Lung / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D045604:Extracellular Fluid / Q000378:metabolism*; D005260:Female; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000737:chemistry; D007249:Inflammation; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000473:pathology; D009389:Neovascularization, Pathologic; D010641:Phenotype; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D014945:Wound Healing; D044004:Xanthones / Q000737:chemistry
D019408:Platelet Endothelial Cell Adhesion Molecule-1; D044004:Xanthones; C066668:vadimezan; D051398:Aquaporin 1; D006897:Hydroxyindoleacetic Acid