Design and Construction of a Multi-Organ Microfluidic Chip Mimicking the in vivo Microenvironment of Lung Cancer Metastasis.
Metastasis is a complex pathophysiological process. As the main cause of cancer mortality in humans it represents a serious challenge to both basic researchers and clinicians. Here we report the design and construction of a multi-organ microfluidic chip that closely mimics the in vivo microenvironment of lung cancer metastasis. This multi-organs-on-a-chip includes an upstream "lung" and three downstream "distant organs", with three polydimethylsiloxane (PDMS) layers and two thin PDMS microporous membranes bonded to form three parallel microchannels. Bronchial epithelial, lung cancer, microvascular endothelial, mononuclear, and fibroblast cells were grown separated by the biomembrane in upstream "lung", while astrocytes, osteocytes, and hepatocytes were grown in distant chambers, to mimic lung cancer cell metastasis to the brain, bone, and liver. After culture in this system, lung cancer cells formed a "tumor mass", showed epithelial-mesenchymal transition (with altered expression of E-cadherin, N-cadherin, Snail1, and Snail2) and invasive capacity. A549 cells co-cultured with astrocytes overexpressed CXCR4 protein, indicating damage of astrocytes after cancer cell metastasis to the brain. Osteocytes overexpressed RANKL protein indicates damage of osteocytes after cancer cell metastasis to the bone, and hepatocytes overexpressed AFP protein indicates damage to hepatocytes after cancer cell metastasis to the liver. Finally, in vivo imaging of cancer growth and metastasis in a nude mice model validated the performance of metastasis in the organs-on-chip system. This system provides a useful tool to mimic the in vivo microenvironment of cancer metastasis and to investigate cell-cell interactions during metastasis.
Department of Respiratory Medicine, The Second Affiliated Hospital of Dalian Medical University , Dalian 116027, China.|Department of Respiratology, Qilu Hospital Shandong University , Jinan 250012, China.
Zhiyun
Z
Xu
Department of Respiratory Medicine, The Second Affiliated Hospital of Dalian Medical University , Dalian 116027, China.
Encheng
E
Li
Department of Respiratory Medicine, The Second Affiliated Hospital of Dalian Medical University , Dalian 116027, China.
Zhe
Z
Guo
Department of Respiratory Medicine, The Second Affiliated Hospital of Dalian Medical University , Dalian 116027, China.
Ruofei
R
Yu
Department of Respiratory Medicine, The Second Affiliated Hospital of Dalian Medical University , Dalian 116027, China.
Hualong
H
Hao
Department of Respiratory Medicine, The Second Affiliated Hospital of Dalian Medical University , Dalian 116027, China.
Yitong
Y
Xu
Department of Respiratory Medicine, The Second Affiliated Hospital of Dalian Medical University , Dalian 116027, China.
Zhao
Z
Sun
Department of Urology, The First Affiliated Hospital of Dalian Medical University , Dalian 116027, China.
Xiancheng
X
Li
Chinese Educational Ministry-Designated Key Laboratory of Laboratory Medicine and Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University , Wenzhou 325035, China.
Jianxin
J
Lyu
Department of Respiratory Medicine, The Second Affiliated Hospital of Dalian Medical University , Dalian 116027, China.
Qi
Q
Wang
D000818:Animals; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008168:Lung; D008175:Lung Neoplasms; D051379:Mice; D008819:Mice, Nude; D044085:Microfluidics; D009362:Neoplasm Metastasis; D059016:Tumor Microenvironment
cancer metastasis; cancer microenvironment; in vitro; lung cancer; multi-organ microfluidic chip