Self-renewing Pten-/- TP53-/- protospheres produce metastatic adenocarcinoma cell lines with multipotent progenitor activity.
Prostate cancers of luminal adenocarcinoma histology display a range of clinical behaviors. Although most prostate cancers are slow-growing and indolent, a proportion is aggressive, developing metastasis and resistance to androgen deprivation treatment. One hypothesis is that a portion of aggressive cancers initiate from stem-like, androgen-independent tumor-propagating cells. Here we demonstrate the in vitro creation of a mouse cell line, selected for growth as self-renewing stem/progenitor cells, which manifests many in vivo properties of aggressive prostate cancer. Normal mouse prostate epithelium containing floxed Pten and TP53 alleles was subjected to CRE-mediated deletion in vitro followed by serial propagation as protospheres. A polyclonal cell line was established from dissociated protospheres and subsequently a clonal daughter line was derived. Both lines demonstrate a mature luminal phenotype in vitro. The established lines contain a stable minor population of progenitor cells with protosphere-forming ability and multi-lineage differentiation capacity. Both lines formed orthotopic adenocarcinoma tumors with metastatic potential to lung. Intracardiac inoculation resulted in brain and lung metastasis, while intra-tibial injection induced osteoblastic bone formation, recapitulating the bone metastatic phenotype of human prostate cancer. The cells showed androgen receptor dependent growth in vitro. Importantly, in vivo, the deprivation of androgens from established orthotopic tumors resulted in tumor regression and eventually castration-resistant growth. These data suggest that transformed prostate progenitor cells preferentially differentiate toward luminal cells and recapitulate many characteristics of the human disease.
Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Wassim
W
Abou-Kheir
Paul G
PG
Hynes
Philip
P
Martin
Juan Juan
JJ
Yin
Yen-Nien
YN
Liu
Victoria
V
Seng
Ross
R
Lake
Joshua
J
Spurrier
Kathleen
K
Kelly
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001859:Bone Neoplasms / Q000473:pathology; D001932:Brain Neoplasms / Q000473:pathology / Q000556:secondary; D002369:Castration; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055786:Gene Knockout Techniques; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008297:Male; D051379:Mice; D008954:Models, Biological; D039902:Multipotent Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009362:Neoplasm Metastasis; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000378:metabolism
D000728:Androgens; D014408:Biomarkers, Tumor; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse