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Heterogeneity of molecular targets on clonal cancer lines derived from a novel hormone‐refractory prostate cancer tumor system
Author(s) -
Freedland Stephen J.,
Pantuck Allan J.,
Paik Sun H.,
Zisman Am,
Graeber Thomas G.,
Eisenberg David,
McBride William H.,
Nguyen David,
Tso ChoLea,
Belldegrun Arie S.
Publication year - 2003
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.10226
Subject(s) - prostate cancer , biology , lncap , cancer research , metastasis , clone (java method) , cancer , gene , genetics
OBJECTIVE We recently described a new hormone refractory prostate cancer cell line, CL1, derived from LNCaP via in vitro androgen deprivation. To study gene expression during prostate cancer progression and to identify molecular targets for therapy, a pure clonal tumor system was generated. METHODS Limiting dilution of CL1 stably transfected with a green fluorescent protein, generated 35 single‐cell clones, which were expanded into stable cell lines. In vitro responses to various therapeutic modalities were assessed in each clone. Gene expression was determined using reverse transcriptase‐polymerase chain reaction and oligonucleotide microarrays. In vivo biology was assessed following orthotopic injection into intact and castrated severe combined immunodeficient mice. RESULTS In vitro, all clones demonstrated similar resistance to traditional therapeutic efforts including chemotherapy and radiation therapy, but differential sensitivity to cell‐mediated cytotoxicity. The clones demonstrated differential gene expression relative to each other and to the parental CL1 and LNCaP cell lines. Following orthotopic injection into mice, three distinct growth patterns were observed: fast growth with widespread metastasis; slower grower with widespread metastasis; and no tumor formation. Using oligonucleotide microarrays, several genes were identified as differentially expressed between the most aggressive and the nontumorigenic clone. CONCLUSIONS We have described a novel fluorescent‐labeled clonal hormone refractory prostate cancer tumor system that exhibited marked heterogeneity in its response to various therapeutic modalities, gene expression, and in vivo biology. Our data suggests that given the marked clonal heterogeneity, multi‐modality approaches directed against multiple molecular targets rather than single agent therapy will be necessary to adequately eradicate the entire malignant cell population. Clonal tumor lines may allow more accurate examination of molecular pathways involved in tumor progression and resistance to treatment. Prostate 55: 299–307, 2003. © 2003 Wiley‐Liss, Inc.