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Center for Advanced Biotechnology and Medicine [M. J. K., R. B-G., W. A. B-P., N. D., M. M. S., C. A-S.], Departments of Neuroscience [M. J. K., R. B-G., W. A. B-P., C. A-S.], Medicine [C. A-S.], and Pediatrics [N. D., M. M. S.], The Cancer Institute of New Jersey [M. M. S., C. A-S.], University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854; Department of Anatomy, University of California, San Francisco, California 94143 [Y. W., S. W. H., G. R. C.]; and Center for Comparative Medicine, University of California, Davis, California 95616 [R. D. C.]
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ABSTRACT |
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Introduction |
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The Nkx3.1 homeobox gene is a key regulator of prostatic epithelial differentiation, while its loss-of-function in mice has been implicated in prostate cancer initiation (5, 6, 7) . In particular, Nkx3.1 null mutant mice display abnormal prostatic differentiation as well as epithelial hyperplasia and dysplasia prior to 1 year of age (6) . Human NKX3.1 maps to chromosome 8p21 (8 , 9) , which frequently undergoes loss of heterozygosity at early stages of prostate carcinogenesis (10 , 11) . Although NKX3.1 is not mutated in prostate cancer (9) , it undergoes epigenetic inactivation through loss of protein expression in human prostate cancer and in mouse models (7 , 12) . Here we demonstrate that Nkx3.1 mutant mice develop lesions that histopathologically resemble human PIN, consistent with a key role for Nkx3.1 inactivation in prostate cancer initiation. Furthermore, the susceptibility of Nkx3.1 mutant mice to PIN formation has facilitated our development of a tissue recombination assay to explore the relationship of PIN to prostate cancer.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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-IRES-GFP, a derivative of LZRSpBMN-Z (13)
. The Nkx3.1(L140S) mutant contains a substitution of leucine 140 to serine (position 16 of the homeodomain). Production of replication-defective mammalian retroviruses and infection of target cells has been described (14)
. Expression of Nkx3.1 protein was verified at the initiation and termination of each assay by Western blot analysis (Fig. 1A
and data not shown). After retroviral infection, PC3 (15)
or AT6 (AT6.3; Ref. 16
) cells were seeded in triplicate at a density of 5 x 103/cm2 or 1 x 103/cm2, respectively, in low-serum medium (0.5 or 0.25%, respectively); medium was replenished every second day. At the indicated days, cell number was determined by absorbance after staining with Napthol blue black (Sigma). Anchorage-independent growth was monitored by seeding AT6 cells in triplicate at a density of 1 x 103/cm2 in medium containing 0.35% agarose layered over 0.5% agar. After growth for 14 days, the number of GFP-expressing colonies was determined by counting under a fluorescence microscope. Tumor growth in nude mice (Taconic) was initiated by s.c. injection of AT6 (1 x 104 in serum-free medium) or PC3 (1 x 106 in 50% Matrigel) cells. Tumor size was monitored once per week for 4 (AT6) or 6 (PC3) weeks by caliper measurement, followed by determination of tumor weights at necropsy. Statistical analyses were performed using a two-sample t test for independent samples with unequal variances (Satterthwaite’s method).
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Tissue Recombination Assays.
Tissue recombination assays were performed using prostatic epithelium from Nkx3.1 homozygous mutant mice or wild-type littermates from ages 10 to 15 months. Regions of PIN-like lesions were identified by bright-field illumination under a dissecting microscope as hyperplastic ductal densities; 
300-µm segments of the hyperplastic prostatic ducts were isolated by microdissection. We confirmed that these hyperplastic ducts were enriched for PIN-like lesions by histological analyses (data not shown). These ducts (or normal ducts from wild-type littermates) were recombined with fetal rat or mouse urogenital sinus mesenchyme essentially as described (17)
. The tissue recombinants were incubated overnight at 37°C, followed by surgical implantation under the kidney capsule of male nude mouse hosts. After growth for 1–2 months, the tissue recombinants were processed for histological and immunohistochemical analyses. For serial transplantation, an 300-µm segment of the dissected tissue graft was recombined with fresh urogenital sinus mesenchyme and grafted in nude mice as before. Rat urogenital sinus mesenchyme was used for all recombinants used to calculate wet weights. In Fig. 3
, the recombinants shown in panels N, D, H, L, P, and T were made with rat urogenital sinus mesenchyme and the others with mouse; similar findings were obtained regardless of whether mouse or rat urogenital sinus mesenchyme was used (data not shown).
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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and data not shown). As a control, we compared the activity of Nkx3.1 to that of a mutated derivative [Nkx3.1(L140S)] that contains a substitution of a conserved homeodomain residue, which renders the protein inactive in DNA-binding and transcription assays.7
For these assays, we used a human (PC3) and rodent (AT6) prostate carcinoma cell line, neither of which expresses the endogenous Nkx3.1 gene (Fig. 1A)
. We found that overexpression of exogenous Nkx3.1, but not the mutated gene [Nkx3.1(L140S)], resulted in an 70% reduction in cellular proliferation in AT6 cells and 60% reduction in PC3 cells (Fig. 1A)
. In addition, Nkx3.1-expressing AT6 cells displayed an 60% reduction in anchorage-independent growth compared with those expressing the vector control, whereas the Nkx3.1(L140S)-expressing cells produced a modest increase (25%) in anchorage-independent growth (Fig. 1A)
. Moreover, Nkx3.1expressing AT6 and PC3 cells displayed an approximately 50 or 60% decrease, respectively, in tumor growth in nude mice relative to the control vector and/or Nkx3.1(L140S) (Fig. 1C)
. Similar results were obtained in all assays using a human NKX3.1 retrovirus, as well as stable tetracycline-inducible cell lines expressing mouse or human NKX3.1 (data not shown). Notably, these growth-suppressive activities of Nkx3.1 in cell culture and nude mice are consistent with the increased proliferation of prostatic epithelium observed for Nkx3.1 mutant mice (6)
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Formation of PIN-like Lesions in Nkx3.1 Mutant Mice.
Following an initial observation that homozygous and heterozygous Nkx3.1 mutant mice develop prostatic epithelial hyperplasia and dysplasia prior to 1 year of age (6)
, we have now found that prostate glands from older Nkx3.1 mutants display successively more severe histopathological alterations in both the epithelium and the stroma (Fig. 2)
. These morphological alterations represent a continuum of changes ranging from an increase in the number of luminal epithelial cells with crowded papillae to more complex and severe forms, such as the formation of crowded, multilayered epithelium (Fig. 2, B, D, F, and H)
. The epithelial nuclei of Nkx3.1 mutants are larger with a more open chromatin and prominent nucleoli but lack extensive pleomorphism (Fig. 2, D, H
, and insets). Accompanying these changes in the epithelium, the smooth muscle of the fibromuscular sheath becomes attenuated and is occasionally discontinuous (Fig. 2, M and N)
. Despite these extensive histopathological alterations, however, no cases of overt carcinoma have been observed to date, even in the oldest Nkx3.1 mutant mice (data not shown).
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; Table 1A
). Consistent with our previous findings indicating Nkx3.1 haploinsufficiency (6)
, an intermediate number of Nkx3.1 heterozygotes (36%; n = 11) developed PIN-like lesions with histopathological features indistinguishable from those in homozygotes (Table 1A
, data not shown). In addition to these findings for mice in a mixed C57Bl/6J-129/SvImJ strain background, we found that the Nkx3.1 prostatic phenotype was similar in three inbred backgrounds (C57Bl/6J, 129/SvImJ, and FVB/N); however, the occurrence of PIN-like lesions was more frequent in C57Bl/6J and FVB/N congenic mice but less frequent in the 129/SvImJ mice (Table 1B)
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(a) Using two distinct basal cell markers, cytokeratin 14 and p63, we observed an increased ratio of luminal to basal cells in PIN-like lesions; the multilayered epithelium in the interior of these lesions lacked staining for these markers (Fig. 2, I–L)
. These findings are consistent with the nonuniform basal cell layer that is a cardinal feature of human PIN (3
, 4) .
(b) We observed that the stromal layer was significantly attenuated in Nkx3.1 mutants, as visualized by staining with anti-smooth muscle actin (Fig. 2, M and N)
, indicating an increased epithelial:stromal ratio that presumably reflects a decreased dependence of epithelial cells on the stromal layer.
(c) Expression of the luminal epithelial cell marker E-cadherin was increasingly heterogeneous in the PIN-like regions of Nkx3.1 mutants (Fig. 2, O and P)
, consistent with its altered expression in human prostate cancers (18
, 19)
.
(d) We noted that Nkx3.1 mutant mice displayed no increase in neuroendocrine cells, as assessed by immunostaining with anti-chromogranin A or synaptophysin (data not shown); generally, these cells are not up-regulated in PIN (20) .
Taken together, these findings demonstrate that Nkx3.1 mutant mice develop lesions that strongly resemble human PIN but do not display invasive carcinoma.
A Tissue Recombination Assay for Neoplastic Progression.
The susceptibility of Nkx3.1 mutant mice to develop PIN-like lesions, but not carcinoma, prompted us to establish an experimental model system to test the capability of PIN to undergo neoplastic progression. For this purpose, we used a tissue recombination approach that circumvents the normal growth control of the prostatic epithelium. The rationale for this approach is based on our observations that although the prostatic epithelium is relatively growth quiescent in the context of the intact gland (even in Nkx3.1 mutants), such epithelium displays robust proliferation in the presence of embryonic urogenital sinus mesenchyme (17)
. Specifically, we have found that embryonic mesenchyme can induce a relatively small (300 µm) segment of an adult prostatic duct, composed of 5000 epithelial cells (<1 mg), to generate several million epithelial cells in 1 month after grafting in male nude mouse hosts (wet weight of recovered recombinant at round 1, 39.5 ± 11.7 mg, n = 8). When wild-type prostatic tissue is used, the resulting tissue recombinants have prostatic ducts that are histologically normal in appearance and produce secretory proteins (Ref. 17
and Fig. 3, A and E
). Serial transplantation of such tissue recombinants leads to their continued expansion and proliferation for two additional transplant generations, but not further (wet weight at round 2, 19.3 ± 5.3 mg, n = 8; at round 3, 18.5 ± 5.5 mg, n = 8; round 4, none recovered, n = 8). Thus, we reasoned that the robust stimulation of epithelial proliferation after serial transplantation of tissue recombinants would provide an ideal model system to test whether the PIN-like lesions of Nkx3.1 mutants could undergo increasingly severe histopathological alterations.
Using this approach, we found that the initial round and serially transplanted tissue recombinants of prostatic epithelium from wild-type (Nkx3.1+/+) mice retained a recognizable papillary architecture surrounded by an organized fibromuscular stroma (n = 13; Fig. 3, A and E
, and data not shown). The papillary fronds were lined by a single layer of columnar epithelium with a normal distribution of basal cells, uniform expression of markers such as E-cadherin, and copious production of secretory fluids (Fig. 3, A, E, I, M, and Q)
. Notably, the pattern of the round 1 (initial) transplant did not change upon serial transplantation, although the size of the transplants diminished in serial passages (compare wet weights from initial with rounds 2 and 3 above).
In contrast, serial passage of prostatic tissue recombinants from Nkx3.1 mutant mice resulted in a progressive loss of organized ductal architecture that is far more severe than the histopathological defects observed in mutant mice (compare Figs. 2
and 3
). Although round 1 transplants retained a papillary architecture with columnar epithelium and a relatively unaltered relationship between the epithelium and stroma (n = 14; Fig. 3, B and F
), similar to the intact mutant prostate (Fig. 2)
, round 2 and 3 recombinants displayed a dramatically increased disorganization of the prostatic ducts and the surrounding stroma (n = 14; Fig. 3, C, D, G, and H
). These serially transplanted recombinants contained glandular epithelium that lost the papillary pattern and became subdivided into smaller glands with a variety of abnormal growth patterns, including solid masses, cribriform, and poorly differentiated (basalar or embryoid). This severely disorganized growth was also reflected by alterations in the basal cell layer (Fig. 3, O and P)
and by the heterogeneous expression of E-cadherin (Fig. 3, S and T)
. Furthermore, the relationship between the epithelium and stroma was drastically altered, such that the fibromuscular stroma did not form a uniform sheath around the glands, leaving gaps in the smooth muscle layer (Fig. 3, K and L)
. Notably, masses of smooth muscle appear in some transplants that had no apparent relationship with epithelium (Fig. 3, K and L)
, with frequent extensions into the renal parenchyma as "tongues" of smooth muscle (Fig. 3, K
, inset); this invasive behavior of the stroma was characteristic of the round 2 and 3 recombinants from the Nkx3.1 mutants but was never observed in wild-type recombinants. Taken together, these findings provide experimental evidence supporting the potential for mouse PIN-like lesions to undergo successive stages of neoplastic progression.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Our findings that NKX3.1 suppresses growth and tumorigenicity complement our previous observations that Nkx3.1 mutant prostates exhibit increased cellular proliferation (6) . Despite these activities, NKX3.1 differs from classical tumor suppressor genes such as RB, p53, or Pten, because it does not undergo mutational inactivation but instead is inactivated through loss of protein expression (7 , 12) . Moreover, unlike classical tumor suppressors, which have broad functions in many types of cancers, the consequences of Nkx3.1 loss-of-function are largely restricted to the prostate, in accordance with its tissue-specific expression pattern (6) . Instead, Nkx3.1 shares features in common with another homeobox gene, Cdx2, which displays gastrointestinal-specific expression in adults and whose loss-of-function results in epithelial dysplasia in mutant mice (21) . Similar to Nkx3.1, Cdx2 displays haploinsufficiency in mice, is inactivated by down-regulation of protein expression (21) , and displays growth-suppressing activities in cell culture (22) . These striking parallels suggest that Nkx3.1 and Cdx2 may represent a new class of growth-regulatory genes that display some features of classical tumor suppressors in experimental assays but are essentially mediators of tissue-specific differentiation in vivo. We propose that such growth-regulatory genes normally function to establish and/or maintain tissue-specific differentiation states but result in epithelial dedifferentiation and consequent predisposition to neoplasia when inactivated.
In recent years, the generation and analysis of mutant mouse models has demonstrated the validity of the mouse for studying human prostate carcinogenesis, as shown by the fundamental similarities in their histopathological characteristics as well as underlying molecular pathways (this work and reviewed in Refs. 1 , 23 , 24 ). However, unlike SV40-based gain-of-function transgenic mice (23 , 25) , loss-of-function mouse models are prone to develop PIN but rarely develop carcinoma (24) . Nonetheless, in the tissue recombination assay, we found that PIN lesions from Nkx3.1 mutants undergo increasingly severe histopathological changes consistent with neoplastic progression, although these recombinants have yet to display overt invasive carcinoma. These findings are consistent with our interpretation that Nkx3.1 is a regulator of terminal differentiation of luminal epithelial cells, and that loss of Nkx3.1 function requires additional cooperating events to result in overt carcinoma. Indeed, we have shown that mutant mice lacking both Nkx3.1 and the Pten tumor suppressor develop high-grade PIN/carcinoma in situ lesions (7) ; thus, we anticipate that tissue recombinants from Nkx3.1; Pten compound mutants may display histopathological changes consistent with carcinoma.
In conclusion, mouse models can overcome many inherent difficulties associated with studying human prostate carcinogenesis, including limitations of tissue availability and the characteristic heterogeneity of human prostate cancer. In particular, the prevalence of PIN in Nkx3.1 mutants has enabled our initial examination of the precursor relationship of PIN to prostate carcinoma. We envision that the tissue recombination assay described herein will ultimately provide valuable insights into the contributions of individual genes for each stage of prostate carcinogenesis.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by Grants UO1 CA84294 (to C. A-S., M. M. S., R. D. C., and G. R. C.), CA76501 (to C. A-S., M. M. S.), and CA64872, CA59831, and CA89520 (to G. R. C.) from the National Cancer Institute; Grants DK60887 (to M. M. S.) and DK52708 (to G. R. C.) from the National Institute of Diabetes and Digestive and Kidney Diseases; Grants DAMD17-00-1-0091 (to C. A-S.); Grant DAMD17-98-1-8532 (to M. M. S.) from the United States Army Prostate Cancer Research Program; and Grant 5JB-0014 from the University of California Breast Cancer Research Program (to R. D. C.). C. A-S., M. M. S., R. D. C., and G. R. C. are members of the Mouse Models of Human Cancer Consortium (National Cancer Institute). 
2 Present address: Molecular Pathology/Functional Genomics, Aventis Pharmaceuticals, Bridgewater, NJ 08807.
3 Present address: Department of Cancer Endocrinology, BC Cancer Agency, Vancouver, British Columbia, V5Z 1L3 Canada.
4 Present address: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN 37232.
5 To whom requests for reprints should be addressed, at CABM, 679 Hoes Lane, Piscataway, NJ 08854. Phone: (732) 235-5161 (C. A-S.) or (732) 235-5645 (M. M. S.); Fax: (732) 235-5789 (C. A-S.) or (732) 235-5373 (M. M..S.); E-mail: abate{at}cabm.rutgers.edu (C. A-S.) or mshen{at}cabm.rutgers.edu (M. M. S.).
6 The abbreviations used are: PIN, prostatic intraepithelial neoplasia; GFP, green fluorescent protein.
7 P. Sciavolino and C. A-S., unpublished observations.
Received 3/14/02. Accepted 4/16/02.
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REFERENCES |
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-catenin gene in human prostate cancer cells. Cancer Res., 53: 3585-3590, 1993.This article has been cited by other articles:
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S. B. Shappell, G. V. Thomas, R. L. Roberts, R. Herbert, M. M. Ittmann, M. A. Rubin, P. A. Humphrey, J. P. Sundberg, N. Rozengurt, R. Barrios, et al. Prostate Pathology of Genetically Engineered Mice: Definitions and Classification. The Consensus Report from the Bar Harbor Meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee Cancer Res., March 15, 2004; 64(6): 2270 - 2305. [Abstract] [Full Text] [PDF]
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R. I. Skotheim, K. S. Korkmaz, T. I. Klokk, V. M. Abeler, C. G. Korkmaz, J. M. Nesland, S. D. Fossa, R. A. Lothe, and F. Saatcioglu NKX3.1 Expression Is Lost in Testicular Germ Cell Tumors Am. J. Pathol., December 1, 2003; 163(6): 2149 - 2154. [Abstract] [Full Text]
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G. J. Miller, H. L. Miller, A. van Bokhoven, J. R. Lambert, P. N. Werahera, O. Schirripa, M. S. Lucia, and S. K. Nordeen Aberrant HOXC Expression Accompanies the Malignant Phenotype in Human Prostate Cancer Res., September 15, 2003; 63(18): 5879 - 5888. [Abstract] [Full Text] [PDF]
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C. Abate-Shen, W. A. Banach-Petrosky, X. Sun, K. D. Economides, N. Desai, J. P. Gregg, A. D. Borowsky, R. D. Cardiff, and M. M. Shen Nkx3.1; Pten Mutant Mice Develop Invasive Prostate Adenocarcinoma and Lymph Node Metastases Cancer Res., July 15, 2003; 63(14): 3886 - 3890. [Abstract] [Full Text] [PDF]
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J.-H. Park, J. E. Walls, J. J. Galvez, M. Kim, C. Abate-Shen, M. M. Shen, and R. D. Cardiff Prostatic Intraepithelial Neoplasia in Genetically Engineered Mice Am. J. Pathol., August 1, 2002; 161(2): 727 - 735. [Abstract] [Full Text] [PDF]
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