Endothelin-1 inhibits prostate cancer growth in vivo through vasoconstriction of tumor-feeding arterioles

Christine J. Weydert, Alison K. Esser, Ruth A. Mejia, Justin M. Drake, J. Matthew Barnes, Michael D. Henry

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)720-729
Number of pages10
JournalCancer Biology and Therapy
Volume8
Issue number8
DOIs
StatePublished - Apr 15 2009

Keywords

  • Endothelin-1
  • Metastasis
  • Prostate cancer
  • Tumor arteriole
  • Vasoconstriction

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