Self-renewing Pten -/-TP53 -/- protospheres produce metastatic adenocarcinoma cell lines with multipotent progenitor activity

Wassim Abou-Kheir, Paul G. Hynes, Philip Martin, Juan Juan Yin, Yen Nien Liu, Victoria Seng, Ross Lake, Joshua Spurrier, Kathleen Kelly

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere26112
JournalPLoS One
Volume6
Issue number10
DOIs
Publication statusPublished - Oct 11 2011
Externally publishedYes

Fingerprint

prostatic neoplasms
adenocarcinoma
stem cells
Tumors
Adenocarcinoma
androgens
Cells
cell lines
Androgens
Prostatic Neoplasms
Cell Line
Stem Cells
metastasis
neoplasms
Neoplasms
Bone
lungs
Prostate
phenotype
Growth

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Self-renewing Pten -/-TP53 -/- protospheres produce metastatic adenocarcinoma cell lines with multipotent progenitor activity. / Abou-Kheir, Wassim; Hynes, Paul G.; Martin, Philip; Yin, Juan Juan; Liu, Yen Nien; Seng, Victoria; Lake, Ross; Spurrier, Joshua; Kelly, Kathleen.

In: PLoS One, Vol. 6, No. 10, e26112, 11.10.2011.

Research output: Contribution to journalArticle

Abou-Kheir, Wassim ; Hynes, Paul G. ; Martin, Philip ; Yin, Juan Juan ; Liu, Yen Nien ; Seng, Victoria ; Lake, Ross ; Spurrier, Joshua ; Kelly, Kathleen. / Self-renewing Pten -/-TP53 -/- protospheres produce metastatic adenocarcinoma cell lines with multipotent progenitor activity. In: PLoS One. 2011 ; Vol. 6, No. 10.
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