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  current news   Press   selected story    
     
  16th November 2009  
 

Hypoxia-induced pathological angiogenesis mediates tumor cell dissemination, invasion, and metastasis in a zebrafish tumor model

 
 




Author
Samantha Lin Chiou Leea,b,1, Pegah Rouhia,1, Lasse Dahl Jensena, Danfang Zhanga, Hong Jia, Giselbert Hauptmannc,d, Philip Inghamb, and Yihai Caoa,2

Abstract
Mechanisms underlying pathological angiogenesis in relation to hypoxia in tumor invasion and metastasis remain elusive. Here, we have developed a zebrafish tumor model that allows us to study the role of pathological angiogenesis under normoxia and hypoxia in arbitrating early events of the metastatic cascade at the single cell level. Under normoxia, implantation of a murine T241 fibrosarcoma into the perivitelline cavity of developing embryos of transgenic fli1:EGFP zebrafish did not result in significant dissemination, invasion, and metastasis. In marked contrast, under hypoxia substantial tumor cells disseminated from primary sites, invaded into neighboring tissues, and metastasized to distal parts of the fish body. Similarly, expression of the hypoxia-regulated angiogenic factor, vascular endothelial growth factor (VEGF) to a high level resulted in tumor cell dissemination and metastasis, which correlated with increased tumor neovascularization. Inhibition of VEGF receptor signaling pathways by sunitinib or VEGFR2 morpholinos virtually completely ablated VEGFinduced tumor cell dissemination and metastasis. To the best of our knowledge, hypoxia- and VEGF-induced pathological angiogenesis in promoting tumor dissemination, invasion, and metastasis has not been described perviously at the single cell level. Our findings also shed light on molecular mechanisms of beneficial effects of clinically available anti-VEGF drugs for cancer therapy.

 

 
 

 
 


Figure Legend: Invasion, dissemination and metastasis of T241-VEGF tumors. Hypoxia is known to induce angiogenesis mainly via activation of hypoxia inducible factor (HIF)-VEGF pathway. To study if VEGF could also promote tumor cell dissemination and metastasis, T241 tumor cells were stably transfected to express VEGF at a high level. Similar to hypoxia, implantation of T241-VEGF tumor cells in developing zebrafish embryos led to extensive dissemination of tumor cells (Fig. 3D-F). Local invasion and distal metastases were detectable in T241-VEGF tumor-bearing zebrafish embryos, but not in the control group (Fig. 3A-C, H, and I). Quantification analysis showed while sizes of primary tumors were similar in both groups (Fig. 3G), total numbers of disseminated tumor cells and the maximal distance of metastasis in the T241-VEGF group were significantly greater than those in controls (Fig. 3H and I). Similarly, microvessel density in T241-VEGF tumors was significantly higher relative to control tumors (Fig. 3J). Time course analysis showed dissemination and invasion of T241-VEGF tumor cells occurred at a very early time point. At day 2 after implantation, a significant number of tumor cells invaded the neighboring tissues around primary tumors. At day 4, increasing numbers of invasive tumor cells were detected and were disseminated to distal parts of the fish body. Notably, tumor cell dissemination and metastasis were correlated with increased levels of tumor neovascularization. In contrast, T241-vector tumor-bearing zebrafish embryos lacked obvious tumor cell invasion, dissemination and metastasis.

Published in Proc Natl Acad Sci U S A. 2009 Nov 3. [Epub ahead of print]

For more information on Philip Ingham’s Lab, Please Click here.