Initial modulation of the tumor microenvironment accounts for thalidomide activity in prostate cancer.
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.
Efstathiou
Eleni
E
Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Troncoso
Patricia
P
Wen
Sijin
S
Do
Kim-Anh
KA
Pettaway
Curtis A
CA
Pisters
Louis L
LL
McDonnell
Timothy J
TJ
Logothetis
Christopher J
CJ
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
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