Endothelin-1 inhibits prostate cancer growth in vivo through   vasoconstriction of tumor-feeding arterioles.
The vasoactive peptide endothelin-1 (ET-1) has been implicated in promoting the progression of prostate and other cancers though its precise mechanism(s)-of-action remain unclear. To better define the role of ET-1 in prostate cancer progression, we generated prostate cancer cell lines (PC-3 and 22Rv1) that express elevated levels of ET-1. As anticipated, increased ET-1 lead to modest autocrine growth stimulation of PC-3 cells in monolayer culture and increased colony formation in soft agar by both cell lines. Unexpectedly, however, metastatic colonization of 22Rv1 cells expressing elevated levels of ET-1 was reduced, as was the size of subcutaneous tumors produced by both 22Rv1- and PC-3 cells. Based on these data, we hypothesized that high levels of ET-1 may negatively impact the tumor microenvironment. We found that increased ET-1 expression did not consistently inhibit angiogenesis, indicating that this was not the cause of poor tumor growth. As an alternative explanation, we examined whether elevated ET-1 results in local vasoconstriction and thus reduces the blood supply available to the tumor. Consistent with this hypothesis, treatment of mice bearing PC-3 xenografts with a vasodilator increased tumor perfusion and partially restored tumor growth. Moreover, analysis of tumor vascular casts indicated vasoconstriction of tumor-feeding arterioles. Taken together, our data suggest that the local concentration of the ET-1 peptide is critical for determining a balance between its previously unrecognized tumor growth-suppressing activity (vasoconstriction) and known growth-promoting (mitogenesis, survival and angiogenesis) activities. These findings may have implications for the modification of current prostate cancer therapies involving ET-1.
Weydert
Christine J
CJ
Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA.
Esser
Alison K
AK
Mejia
Ruth A
RA
Drake
Justin M
JM
Barnes
J Matthew
JM
Henry
Michael D
MD
D000818:Animals; D001160:Arterioles / Q000378:metabolism / Q000473:pathology*; D019332:Endothelin-1 / Q000502:physiology*; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011471:Prostatic Neoplasms / Q000098:blood supply*; D014661:Vasoconstriction
D019332:Endothelin-1