title: Initial modulation of the tumor microenvironment accounts for thalidomide activity in prostate cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Eleni
authors.initials: E
authors.lastname: Efstathiou
authors.forename: Patricia
authors.initials: P
authors.lastname: Troncoso
authors.forename: Sijin
authors.initials: S
authors.lastname: Wen
authors.forename: Kim-Anh
authors.initials: KA
authors.lastname: Do
authors.forename: Curtis A
authors.initials: CA
authors.lastname: Pettaway
authors.forename: Louis L
authors.initials: LL
authors.lastname: Pisters
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: McDonnell
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D000328:Adult; D000368:Aged; D015820:Cadherins / Q000096:biosynthesis; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D003131:Combined Modality Therapy; D004847:Epithelial Cells / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000097:blood; D053823:Hedgehog Proteins / Q000096:biosynthesis; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D008875:Middle Aged; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000097:blood; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D017154:Stromal Cells / Q000473:pathology; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D015820:Cadherins; D053823:Hedgehog Proteins; D015850:Interleukin-6; C509239:SHH protein, human; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D013792:Thalidomide; D017430:Prostate-Specific Antigen; D020782:Matrix Metalloproteinases