Creatine promotes metastatic dissemination

AbstractTumor progression and metastatic dissemination are driven by cell-intrinsic and biomechanical cues that favor the growth of life-threatening secondary tumors. We recently identified pro-metastatic vascular regions with blood flow profiles that are permissive for the arrest of circulating tumor cells. We have further established that such flow profiles also control endothelial remodeling, which favors extravasation of arrested CTCs. Yet, how shear forces control endothelial remodeling is unknown. In the present work, we aimed at dissecting the cellular and molecular mechanisms driving blood flow-dependent endothelial remodeling. Transcriptomic analysis of endothelial cells revealed that blood flow enhanced VEGFR signaling, among others. Using a combination of in vitro microfluidics and intravital imaging in zebrafish embryos, we now demonstrate that the early flow-driven endothelial response can be prevented upon specific inhibition of VEGFR tyrosine kinase and subsequent signaling. Inhibitory targeting of VEGFRs reduced endothelial remodeling and subsequent metastatic extravasation. These results confirm the importance of VEGFR-dependent endothelial remodeling as a driving force of CTC extravasation and metastatic dissemination. Furthermore, the present work suggests that therapies targeting endothelial remodeling might be a relevant clinical strategy in order to impede metastatic progression.

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INDUCTION OF METASTASIS OF FROG CARCINOMA BY INCREASE OF ENVIRONMENTAL TEMPERATURE

Journal of Experimental Medicine ◽

10.1084/jem.89.3.269 ◽

1949 ◽

Vol 89 (3) ◽

pp. 269-278 ◽

Cited By ~ 31

Author(s):

Balduin Lucké ◽

Hans Schlumberger

Keyword(s):

Tissue Culture ◽

Elevated Temperature ◽

Constant Temperature ◽

Rana Pipiens ◽

Environmental Temperature ◽

Kidney Tumors ◽

Primary Tumors ◽

Metastatic Dissemination ◽

Leopard Frogs ◽

Tumor Bearing

Metastasis of the kidney carcinoma of leopard frogs (Rana pipiens) has been induced by exposing tumor-bearing animals for approximately 50 days to a constant temperature of 28°C. Under these conditions 54 per cent of the frogs developed secondary growths, whereas in groups kept at 18° or at 7° metastatic dissemination was found in only 6 per cent. Moreover, at the elevated temperature the metastases were usually more numerous and more widely disseminated; they were also fairly uniform in size, suggesting that they had developed at nearly the same time. Dissemination of the kidney tumors was influenced by the nutritional state of the frogs, occurring more readily in well nourished than in poorly nourished animals. Periodic Roentgen ray examinations showed that the size of the primary tumors was not significantly or uniformly affected during the course of the experiments. No correlation was found between change in size of the kidney tumors and the incidence of their metastasis. Although the mechanism by which temperature induces metastasis of frog carcinoma cannot as yet be elucidated, previous experiments with this tumor indicate that certain factors at least may be involved: Elevation of temperature has been found to cause more ready detachment of cells of frog carcinoma in tissue culture; to bring about increased velocity of locomotion of the detached cells; to lead more promptly and efficiently to vascularization of transplants; and to effect their greater invasiveness.

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