Clinical and experimental progression of a new model of human prostate cancer and therapeutic approach.
We report the clinical evolution of a prostate cancer, metastasizing to lungs and bones, recurring locally, and escaping from anti-androgen therapy. Key event of biological progression of the patient's tumor was the coincidence of allelic imbalance accumulation and of bone metastases occurrence. The recurrent tumor was established as the transplantable xenograft PAC120 in nude mice, where it grew locally. PAC120 displayed the same immunophenotype of the original tumor (positive for keratin, vimentin, prostatic acid phosphatase, and Leu-7) and expressed human HOXB9, HOXA4, HER-2/neu, and prostate-specific antigen genes, as detected by reverse transcriptase-polymerase chain reaction. It formed lung micrometastases detected by mRNA expression of human genes. Cytogenetic analysis demonstrated numerous alterations reflecting the tumor evolution. PAC120 was still hormone-dependent; its growth was strongly inhibited by the new gonadotropin-releasing hormone antagonist FE 200486 but weakly by gonadotropin-releasing hormone superagonist D-Trp(6)-luteinizing-hormone releasing hormone (decapeptyl). Tumor growth inhibition induced by anti-hormone therapy was linked to the hormone deprivation degree, more important and more stable with FE 200486 than with D-Trp(6)-luteinizing-hormone releasing hormone. Surgical castration of mice led to tumor regressions but did not prevent late recurrences. Transition to hormone-independent tumors was frequently associated with a mucoid differentiation or with a neuroendocrine-like pattern. Independent variations of mRNA expression of HER-2/neu and prostate-specific antigen were observed in hormone-independent tumors whereas HOXB9 gene expression was constant. In conclusion, PAC120 xenograft, a new model of hormone-dependent prostate cancer retained the progression potential of the original tumor, opening the opportunity to study the hormone dependence escape mechanism.
de Pinieux
G
G
Section de Recherche, Institut Curie, UMR-147-CNRS, 26 rue d'Ulm, 75231 Paris, France.
Legrier
M E
ME
Poirson-Bichat
F
F
Courty
Y
Y
Bras-Gonçalves
R
R
Dutrillaux
A M
AM
Némati
F
F
Oudard
S
S
Lidereau
R
R
Broqua
P
P
Junien
J L
JL
Dutrillaux
B
B
Poupon
M F
MF
D000818:Animals; D002455:Cell Division; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D004195:Disease Models, Animal; D018450:Disease Progression; D018734:Genes, erbB-2; D006727:Hormone Antagonists / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D007621:Karyotyping; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009842:Oligopeptides / Q000627:therapeutic use; D009919:Orchiectomy; D011110:Polymorphism, Genetic; D017430:Prostate-Specific Antigen / Q000032:analysis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous
D006727:Hormone Antagonists; D009842:Oligopeptides; D012333:RNA, Messenger; C431566:acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide; D017430:Prostate-Specific Antigen