A new murine model of osteoblastic/osteolytic lesions from human androgen-resistant prostate cancer.
BACKGROUND
Up to 80% of patients dying from prostate carcinoma have developed bone metastases that are incurable. Castration is commonly used to treat prostate cancer. Although the disease initially responds to androgen blockade strategies, it often becomes castration-resistant (CRPC for Castration Resistant Prostate Cancer). Most of the murine models of mixed lesions derived from prostate cancer cells are androgen sensitive. Thus, we established a new model of CRPC (androgen receptor (AR) negative) that causes mixed lesions in bone.


METHODS
PC3 and its derived new cell clone PC3c cells were directly injected into the tibiae of SCID male mice. Tumor growth was analyzed by radiography and histology. Direct effects of conditioned medium of both cell lines were tested on osteoclasts, osteoblasts and osteocytes.


RESULTS
We found that PC3c cells induced mixed lesions 10 weeks after intratibial injection. In vitro, PC3c conditioned medium was able to stimulate tartrate resistant acid phosphatase (TRAP)-positive osteoclasts. Osteoprotegerin (OPG) and endothelin-1 (ET1) were highly expressed by PC3c while dikkopf-1 (DKK1) expression was decreased. Finally, PC3c highly expressed bone associated markers osteopontin (OPN), Runx2, alkaline phosphatase (ALP), bone sialoprotein (BSP) and produced mineralized matrix in vitro in osteogenic conditions.


CONCLUSIONS
We have established a new CRPC cell line as a useful system for modeling human metastatic prostate cancer which presents the mixed phenotype of bone metastases that is commonly observed in prostate cancer patients with advanced disease. This model will help to understand androgen-independent mechanisms involved in the progression of prostate cancer in bone and provides a preclinical model for testing the effects of new treatments for bone metastases.
Institut National de la Santé et de la Recherche Médicale (INSERM), Unité U1033, Lyon, France ; Université de Lyon, Lyon, France.
Anaïs
A
Fradet
Hélène
H
Sorel
Baptiste
B
Depalle
Claire Marie
CM
Serre
Delphine
D
Farlay
Andrei
A
Turtoi
Akeila
A
Bellahcene
Hélène
H
Follet
Vincent
V
Castronovo
Philippe
P
Clézardin
Edith
E
Bonnelye
D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000556:secondary*; D016723:Bone Remodeling / Q000235:genetics; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D009919:Orchiectomy; D010006:Osteoblasts / Q000378:metabolism; D010014:Osteolysis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D023041:Xenograft Model Antitumor Assays
D024042:Collagen Type I