Hypoxia preconditioning of mesenchymal stromal cells enhances PC3 cell lymphatic metastasis accompanied by VEGFR-3/CCR7 activation.
Mesenchymal stromal cells (MSCs) in bone marrow may enhance tumor metastases through the secretion of chemokines. MSCs have been reported to home toward the hypoxic tumor microenvironment in vivo. In this study, we investigated prostate cancer PC3 cell behavior under the influence of hypoxia preconditioned MSCs and explored the related mechanism of prostate cancer lymphatic metastases in mice. Transwell assays revealed that VEGF-C receptor, VEGFR-3, as well as chemokine CCL21 receptor, CC chemokine receptor 7 (CCR7), were responsible for the migration of PC3 cells toward hypoxia preconditioned MSCs. Knock-in Ccr7 in PC3 cells also improved cell migration in vitro. Furthermore, when PC3 cells were labeled using the hrGfp-lentiviral vector, and were combined with hypoxia preconditioned MSCs for xenografting, it resulted in an enhancement of lymph node metastases accompanied by up-regulation of VEGFR-3 and CCR7 in primary tumors. Both PI3K/Akt/IκBα and JAK2/STAT3 signaling pathways were activated in xenografts in the presence of hypoxia-preconditioned MSCs. Unexpectedly, the p-VEGFR-2/VEGFR-2 ratio was attenuated accompanied by decreased JAK1 expression, indicating a switching-off of potential vascular signal within xenografts in the presence of hypoxia-preconditioned MSCs. Unlike results from other studies, VEGF-C maintained a stable expression in both conditions, which indicated that hypoxia preconditioning of MSCs did not influence VEGF-C secretion. Our results provide the new insights into the functional molecular events and signalings influencing prostate tumor metastases, suggesting a hopeful diagnosis and treatment in new approaches.
Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Science, 2nd Affiliated Hospital, Zhejiang University, Hangzhou, 310009, China.
Xin
X
Huang
Kunkai
K
Su
Limin
L
Zhou
Guofang
G
Shen
Qi
Q
Dong
Yijia
Y
Lou
Shu
S
Zheng
D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D055879:Gene Knock-In Techniques; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D054400:Receptors, CCR7 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
C515370:CCR7 protein, human; D054400:Receptors, CCR7; D040321:Vascular Endothelial Growth Factor Receptor-3
CCR7; HYPOXIA PRECONDITIONING; LYMPHATIC METASTASIS; MESENCHYMAL STROMAL CELL; PROSTATE CANCER; VEGFR-3