Human cell lines as an in vitro/in vivo model for prostate carcinogenesis and progression.
BACKGROUND
The study of prostate carcinogenesis and tumor progression is made difficult by the lack of appropriate in vitro and in vivo models. High prevalence of prostatic intra-epithelial neoplasia and latent prostatic carcinoma, representing multiple steps in carcinogenesis to invasive carcinoma, are relevant targets for cancer prevention. From the RWPE-1, immortalized, non-tumorigenic, human prostate epithelial cell line, we have derived four tumorigenic cell lines with progressive malignant characteristics.


METHODS
Cell lines were derived by exposure of RWPE-1 to N-methyl-N-nitrosourea (MNU), selected and cloned in vivo and in vitro, and characterized by prostatic epithelial and differentiation markers, karyotype analysis, anchorage-independent growth, invasiveness, tumorigenicity, and pathology of the derived tumors.


RESULTS
Cytokeratins 8 and 18, androgen receptor, and prostate-specific antigen expression in response to androgen, confirm prostatic epithelial origin. RWPE-1 cells do not grow in agar and are not tumorigenic in mice, but the growth, tumorigenicity, and tumor pathology of the MNU cell lines correlate with their invasive ability. The WPE1-NA22 (least malignant) form small, well-differentiated, and WPE1-NB26 cells (most malignant) form large, poorly differentiated, invasive tumors. Overall, loss of heterozygosity for chromosomes 7q, 13q, 18q, and 22, and gain of 5, 9q, 11q, and 20, was observed. The MNU cell lines, in order of increasing malignancy are; WPE1-NA22, WPE1-NB14, WPE1-NB11, and WPE1-NB26.


CONCLUSIONS
This family of cell lines with a common lineage represents a unique and relevant model which mimics stages in prostatic intra-epithelial neoplasia (PIN) and progression to invasive cancer, and can be used to study carcinogenesis, progression, intervention, and chemoprevention.
Webber
M M
MM
Department of Zoology and Medicine, Michigan State University, East Lansing 48824-1312, USA. mwebber@msu.edu
Quader
S T
ST
Kleinman
H K
HK
Bello-DeOcampo
D
D
Storto
P D
PD
Bice
G
G
DeMendonca-Calaca
W
W
Williams
D E
DE
D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D015197:Carcinogenicity Tests; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D018929:Cell Culture Techniques / Q000379:methods*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002869:Chromosome Aberrations; D025063:Chromosome Disorders; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D007633:Keratins / Q000096:biosynthesis; D008297:Male; D008770:Methylnitrosourea / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009277:Nandrolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D017430:Prostate-Specific Antigen / Q000096:biosynthesis; D011471:Prostatic Neoplasms; D011944:Receptors, Androgen / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000378:metabolism
D000477:Alkylating Agents; D011944:Receptors, Androgen; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D007633:Keratins; D008770:Methylnitrosourea; D009277:Nandrolone; C100075:mibolerone; D017430:Prostate-Specific Antigen