| Initial modulation of the tumor microenvironment accounts for thalidomide activity in prostate cancer. | |
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MedLine Citation:
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PMID: 17317833 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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PURPOSE: Disruption of stromal-epithelial interactions favoring prostate cancer progression may affect the phenotype of the disease. We did a preoperative study to test the hypothesis that thalidomide, an active agent in metastatic disease, is a modulator of the tumor microenvironment. EXPERIMENTAL DESIGN: Eighteen men with high-risk prostate cancer were given thalidomide at doses escalated to 600 mg for 12 weeks, followed by radical prostatectomy. We constructed tissue microarrays from prostatectomy specimens from 15 treated patients and 15 matched untreated control subjects to assess effects of thalidomide on the tumor microenvironment. We compared the immunohistochemical expression of three groups of markers linked to angiogenesis, stromal-epithelial interactions, or the epithelial compartment. Levels of circulating basic fibroblast growth factor, interleukin-6, tumor necrosis factor-alpha, and vascular endothelial growth factor were also assessed. RESULTS: Thalidomide was well tolerated and induced a median reduction in prostate-specific antigen of 41% without affecting testosterone. Tissue microarray analyses indicated modulation of vascular marker expression accompanied by a reduction in microvessel density in the treated group. Comparison of broader stromal-epithelial interaction markers between treated and control groups suggested a transition to a less aggressive phenotype as a result of thalidomide treatment. Hedgehog signaling was attenuated and the ratio of matrix metalloproteinases to E-cadherin shifted to favor E-cadherin. No differences were noted in proliferation or apoptosis in the epithelial compartment. CONCLUSIONS: These findings are the first clinical evidence to support the hypothesis that the reported thalidomide clinical efficacy is attributable to early modulation of the tumor microenvironment and suggest that stromal-targeting therapies will be effective against prostate cancer. |
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Authors:
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Eleni Efstathiou; Patricia Troncoso; Sijin Wen; Kim-Anh Do; Curtis A Pettaway; Louis L Pisters; Timothy J McDonnell; Christopher J Logothetis |
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Publication Detail:
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Type: Clinical Trial; Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. |
Journal Detail:
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Title: Clinical cancer research : an official journal of the American Association for Cancer Research Volume: 13 ISSN: 1078-0432 ISO Abbreviation: Clin. Cancer Res. Publication Date: 2007 Feb |
Date Detail:
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Created Date: 2007-02-23 Completed Date: 2007-07-18 Revised Date: 2007-12-03 |
Medline Journal Info:
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Nlm Unique ID: 9502500 Medline TA: Clin Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 1224-31 Citation Subset: IM |
Affiliation:
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Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenocarcinoma
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drug therapy*,
metabolism,
pathology*,
surgery Adult Aged Cadherins / biosynthesis Cell Communication / drug effects, physiology Combined Modality Therapy Epithelial Cells / pathology Fibroblast Growth Factor 2 / blood Hedgehog Proteins / biosynthesis Humans Interleukin-6 / blood Male Matrix Metalloproteinases / biosynthesis Middle Aged Prospective Studies Prostate-Specific Antigen / blood Prostatectomy Prostatic Neoplasms / drug therapy*, metabolism, pathology*, surgery Stromal Cells / pathology Thalidomide / administration & dosage, adverse effects, blood, therapeutic use* Tumor Necrosis Factor-alpha / blood Vascular Endothelial Growth Factor A / blood |
| Grant Support | |
ID/Acronym/Agency:
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CA84964/CA/NCI NIH HHS; CA90270/CA/NCI NIH HHS; ES07784/ES/NIEHS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cadherins; 0/Hedgehog Proteins; 0/Interleukin-6; 0/SHH protein, human; 0/Tumor Necrosis Factor-alpha; 0/Vascular Endothelial Growth Factor A; 103107-01-3/Fibroblast Growth Factor 2; 50-35-1/Thalidomide; EC 3.4.21.77/Prostate-Specific Antigen; EC 3.4.24.-/Matrix Metalloproteinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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