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Endothelin-1 inhibits prostate cancer growth in vivo through vasoconstriction of tumor-feeding arterioles
- Publication Year :
- 2009
-
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.
- Subjects :
- Male
Cancer Research
medicine.medical_specialty
Angiogenesis
Vasodilation
Biology
Article
Metastasis
Prostate cancer
Mice
Internal medicine
medicine
Animals
Autocrine signalling
Pharmacology
Tumor microenvironment
Endothelin-1
Neovascularization, Pathologic
Prostatic Neoplasms
medicine.disease
Endothelin 1
Arterioles
Endocrinology
Oncology
Vasoconstriction
Molecular Medicine
medicine.symptom
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....113f44757e9dc7321196693b4e07e71b