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1 Department of Immunology,
2 Program in Cell and Molecular Biology,
3 Department of Molecular and Cellular Biology, and
4 Department of Pathology, Baylor College of Medicine, Houston, Texas
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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30,000 lives in the United States in 2003 (1)
, largely due to the absence of effective treatment for metastatic disease. More accurate modeling of CaP is required to better understand the molecular signaling events and pathological stages associated with disease progression, and to facilitate development of more effective therapeutics. Several mouse models of CaP have been developed previously (2)
. These models fall into two broad categories, the more aggressive SV40 T antigen-based models, such as TRAMP (3)
or "Lady" (4)
that target multiple tumor suppressor genes, and a variety of other less aggressive models that target a single proto-oncogene or tumor suppressor molecule, such as FGF-8 (5)
or PTEN (6)
. Whereas the single-gene models tend to highlight the early stages of progression, TRAMP mice consistently develop metastatic CaP by 28 weeks of age, allowing for therapeutic studies that span a relatively short time (7
, 8)
. Whereas both sets of models can help determine genetic lesions capable of contributing to disease, neither permits temporal ordering of deleterious genetic events or highlights whether those genetic changes only initiate disease or are also required for disease maintenance, and may, therefore, be targeted for therapeutic intervention. To achieve temporal control of the FGFR axis implicated in early changes associated with CaP (9) we used CID technology, which allows rapid activation of target proteins, such as growth factor receptors, that are naturally activated by oligomerization (10) . CID-inducible growth factor receptors are engineered by substituting the ligand-binding extracellular domain of the receptor with a cytoplasm-localized drug-binding domain (e.g., FKBP12 variants), which, on binding of a lipid-permeable dimeric drug (e.g., AP20187), causes receptor oligomerization, transphosphorylation, and activation of downstream signaling cascades (11, 12, 13, 14) . Because the investigator dictates the schedule of AP20187 administration, temporal control in the activation and inactivation of the receptor is possible, highlighting the pathological features dependent on the growth factor receptor for both initiation and maintenance of phenotype. Additionally, unlike bigenic transcription switch (e.g., tet) -regulatable systems or conditional lesions based on recombination (e.g., Cre/lox), this approach requires only a single transgenic change, greatly simplifying breeding strategies.
In the currently accepted model of FGF signaling in the normal prostate, stromal-derived FGF7/keratinocyte growth factor and FGF10 help maintain epithelial differentiation and survival through glandular epithelium-confined FGFR2-IIIb, contributing to epithelial dependence on the stroma. During progression to malignancy, the observed molecular changes in the FGF signaling axis that occur in the epithelium include loss of normal FGFR2 signaling (by isoform changes that alter ligand binding or by loss of FGFR2 expression), acquisition of FGFR1 expression, and up-regulation of distinct FGF family members. These changes likely allow autocrine signaling via FGFR1 and possibly FGFR2, permitting independence from stromal-derived FGFs and, thus, deregulated growth of the epithelium (9 , 15) . In addition to observed changes in CaP, these alterations are common in bladder and salivary adenocarcinomas, where up-regulation of FGFR1 is associated with tumor progression, and ectopic expression of FGFR2 inhibits progression and growth of transplanted tumors (16 , 17) . Despite accumulating data in model tumor systems, the effects of these two receptors have not been investigated before in a normal prostate epithelium, although overexpression of FGFs in the prostate has led to the development of prostatic hyperplasia and PIN (5 , 18, 19, 20) .
In this study we focused on the hyperplasia-stimulating effects of ectopic FGFR1 signaling on normal prostatic epithelium, demonstrating diverse effects of iFGFR1 and iFGFR2 in a normal prostate background, and showing dependence of hyperplasia and proliferation on continued iFGFR1 signaling. Whereas the profound hyperplasia that is seen after only 1 month of FGFR1 stimulation is completely reversible, neovascularization, which is well established by 2 months, is associated with hyperplastic cells becoming largely independent of iFGFR1 signaling for their survival. Moreover, moderate-term (i.e., <6 months) iFGFR1 signaling can promote high-grade (i.e., type IV) PIN that is associated with a thickened stroma, fulminant glandular hyperplasia, nuclear atypia, and basement membrane herniation. This is the first reported example of a conditionally reversible CaP model, and the first study of the diverse effects of FGFR1 and FGFR2 signaling in the context of a normal mouse prostate.
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MATERIALS AND METHODS |
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Mice and Reagents.
All of the mice were FVB (bred in-house) background and kept pathogen free in the Texas Mouse Facility under veterinary supervision. AP20187 was dissolved in 16.7% propanediol, 22.5% PEG400, 1.25% Tween 80 and injected i.p. biweekly at 2 mg/kg. On the basis of an estimated half-life in vivo of 7 h6
and an EC50 in vitro of 10 nM (data not shown), this level was calculated to evoke signaling for 2–3 days in vivo. Alternatively, carrier alone was injected. Initiation of treatments was staggered so that all of the mice were the same age when prostates were harvested.
Immunoprecipitation and Western Blot Analysis.
Organs were harvested, frozen, pulverized, and then lysed in 200–300 µl of radioimmunoprecipitation assay buffer [0.01 M Tris-CL (pH 8.0), 0.14 M NaCl, 1% Triton X-100, 1% sodium deoxycholate, and 0.1% SDS] with 1 mM phenylmethylsulfonyl fluoride and protease inhibitor mixture (Sigma-Aldrich, St. Louis, MO) and incubated on ice for 2 h. SDS-PAGE was performed as described previously (22)
. Membranes were incubated with primary antibody HA.11 (Covance, Richmond, CA) at 1:1500 or 
-tubulin (Santa Cruz Biotechnology, Santa Cruz, CA) diluted 1:500 for 1 h and then with secondary horseradish peroxidase-linked polyclonal goat antimouse antibody (1:2000; Santa Cruz Biotechnology) for 30 min. Membranes were washed 3X with Tris-Buffered Saline plus 0.1% Tween-20 (TBST) for 5–15 min after each antibody step. Bands were visualized with SuperSignal chemiluminescence substrate (Pierce, Rockford, IL). Immunoprecipitation was carried out using the IMMUNOcatcher kit (Cytosignal Research Products, Irvine, CA) following the manufacturer’s protocol using 2 µg antiphosphotyrosine antibody 4G10 (Upstate, Lake Placid, NY) for immunoprecipitation and HA.11 immunoblotting as above. Phosphatase inhibitor I and II (Sigma) were added to lysates.
Histology and Immunohistochemistry.
Microdissected prostates were placed overnight in 10% neutral phosphate-buffered formalin, transferred to 50% neutral phosphate-buffered formalin/50% ethanol for 1 h and then 70% ethanol until paraffin embedding. After sectioning (5 µM) and mounting onto ProbeOn-Plus slides (Fisher, Pittsburgh, PA), slides were deparaffinized and hydrated with progressive xylene washes followed by a gradient of ethanol and PBS. Slides were either directly stained with H&E or immunostained. For antigen retrieval, slides were either placed into boiling 10 mM citric acid for 30 min and allowed to cool at 25°C or were proteinase K-treated. Both sets were quenched in 3% H2O2, blocked with Power Block (Biogenex Laboratories, San Ramon, CA) for 10 min at 25°C, and incubated with either anti-Ki-67 antibody (Novacastra, Newcastle upon Tyne, United Kingdom) at 1:1000, anti-CD31/PECAM (BD PharMingen, San Diego, CA) at 1:100, or anti-phospho-Erk (Cell Signaling Technology, Beverly, MA) at 1:100 in Power Block overnight at 4°C, followed by incubation with biotin-conjugated goat antirabbit antibody (Vector Laboratories, Burlingame, CA) at 1:2000 or goat antimouse biotin-conjugated antibody (Santa Cruz Biotechnology) at 1:100 for 1 h. After each incubation, slides were washed with PBS plus 0.1% Tween for 2 h. Immunostaining was visualized using the ABC kit (Vector Laboratories), and slides were counterstained with methyl green and dehydrated using a gradient of ethanol to xylene before mounting under coverslips.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. FVB blastocysts were injected separately with both constructs, leading to two founder lines of iFGFR1, collectively named JOCK-1, and one founder line expressing iFGFR2, named JOCK-2. All three of the lines expressed detectable transgene by Western blotting of prostate tissue, and the highest expressing JOCK-1 line was chosen for additional study (data not shown). To determine the tissue-specificity of the transgenes, multiple organs from 12-week-old transgenic mice were homogenized, and tissue lysates were separated by SDS-PAGE followed by anti-HA immunoblotting. This analysis revealed that ARR2PB-driven transgene expression was primarily prostate-specific, consistent with previous reports (Refs. 23
, 24
; Fig. 1B
). Furthermore, to determine expression within the various distinct lobes of the murine prostate, microdissected anterior (coagulating gland), ventral, dorsal, and lateral lobes were also analyzed for specific transgene expression. In ventral lobes, relatively high-level transgene expression was comparable between JOCK-1 and JOCK-2, and in lateral and anterior lobes, weak but equivalent expression was also seen. However, significantly higher transgene expression was seen in the dorsal prostate of JOCK-2 (Fig. 1C)
. In both JOCK-1 and JOCK-2 mice, immunohistochemistry with antibodies to HA shows equivalent localization and transgene expression in the luminal epithelial cells of the ventral prostate (Fig. 1, D and E)
, as well as higher transgene expression in the luminal epithelial cells of the dorsal prostate of JOCK-2 mice (data not shown), matching the expression levels observed by anti-HA immunoblotting. Thus, due to high-level comparable transgene expression, we focused most comparative studies on the ventral prostate lobes of JOCK-1 and JOCK-2 mice.
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, and anterior prostate (data not shown). In contrast, similarly treated JOCK-2 mice showed no obvious phenotypic changes in any lobe, including the ventral and dorsal-lateral prostate (Fig. 2, E and F)
, suggesting that these homologous receptors have fundamental differences. Furthermore, AP20187 had no effect on wild-type mice treated for 12 weeks (Fig. 2, A and B)
, consistent with Phase I clinical trials of AP20187 analogue, AP1903 (26)
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. This suggests that iFGFR2 is activated in the ventral prostate, leading to direct or indirect modification. Also, phenotypic differences between the ventral prostates of CID-treated JOCK-2 mice versus JOCK-1 mice may still be due to quantitatively lower FGFR2 activation.
Because iFGFR2 tyrosine phosphorylation was observed in intact JOCK-2 prostates, we wanted to determine whether this phosphorylation was localized to the dorsal lobe where JOCK-2 mice show much higher transgene expression than JOCK-1 mice. As predicted, tyrosine phosphorylation of iFGFR2 was detected in the dorsal prostate (Fig. 2H)
. This suggests that FGFR2 activation is insufficient to induce phenotypic changes in the dorsal prostate after 12 weeks of CID treatment, whereas much lower levels of iFGFR1 are capable of driving the dorsal prostate to PIN II. This demonstrates for the first time that these two receptors can have broadly different effects on normal prostatic epithelial proliferation (Fig. 2, C and D
, versus Fig. 2, E and F
).
To determine the progressive effects of continuous (or semicontinuous) iFGFR1 signaling over time, we focused on phenotypic changes in the ventral lobe due to the consistent changes we observed in preliminary experiments. Within the first week of AP20187 treatment, increased vacuolization, a marker for increased metabolic activity, and modest hyperproliferation were already apparent (data not shown). From 2 to 4 weeks of CID treatment, JOCK-1 mice showed pronounced hyperproliferation in all lobes of the prostate. (Fig. 3B)
By 8 weeks of AP20187 administration, iFGFR1 activation led to the establishment of extensive intraductal vascularization (Fig. 3F)
, which was not evident in hyperplastic acini at 4 weeks (Fig. 3E)
. Additionally, increased nuclear atypia, chromatin condensation, and formation of papillary structures were observed (Fig. 3, C and F)
. By 12 weeks of activation, mice were determined to have low-grade PIN in all of the lobes examined, characterized by epithelial "piling-up," elongated and hyperchromatic nuclei, and cribiform glandular structures (Fig. 3D)
, as well as stromal thickening in the dorsal lobes of some mice. Longer-term treatments of 24 and 30 weeks led to the widespread development of "reactive" thickened stroma (Fig. 3J)
. Additionally, more extensive dysplastic nuclei and herniated acini with extraglandular extension were observed at 24 (Fig. 3, G and H)
and 30 weeks (Fig. 3I)
, consistent with grade IV PIN (25)
. As an additional indication of PIN, we observed increases in cytokeratin-8 as early as 12 weeks of age with more profound increases appearing by 24 weeks (data not shown; Ref. 25
). These results demonstrate iFGFR1-driven progression of normal epithelial cells to high-grade PIN and show a strong oncogenic effect of FGFR1 on normal prostate epithelium that is not shared by FGFR2.
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4 weeks of AP20187 treatment, which is before initiation of obvious intraepithelial vascularization. Mice were treated biweekly with CID for 4 weeks, and then AP20187 administration was terminated for various times up to 8 weeks. Although dramatic changes in proliferation were apparent within days (Fig. 5A)
, loss of supernumerary epithelial cells was gradual over the 8-week period, resulting in a prostate almost indistinguishable from untreated tissue (Fig. 4A
versus B; data not shown). Thus, before extensive neovascularization, iFGFR1 signaling is required for maintenance of hyperplasia.
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Although regression was not observed in the ventral prostate, there was a decrease in proliferation, and additional progression to low-grade PIN was not observed (Fig. 4, E versus F
; data not shown). Thus, hyperplasia is reversible until established neovascularization, whereas prolonged iFGFR1 activation is required for continued proliferation and additional progression.
Increased Hyperplasia in JOCK-1 Is Driven Largely by Hyperproliferation.
Because hyperplasia can be caused by increased proliferation or decreased apoptosis, we wanted to determine the contributions of both to hyperplasia, as well as the mechanism(s) responsible for reversion to a normal phenotype after AP20187 removal. Staining for the proliferation marker, Ki-67, showed marked increases from 1% positive, observed in CID-treated wild-type or mock-treated transgenic mice, to 18% Ki-67-positive after 1 week of treatment (Fig. 5A)
. From 4 weeks of CID treatment onward, as cellular crowding in treated glands becomes widespread, Ki-67 staining stabilized at a lower level of 8%. When treatment was stopped after 4 weeks of AP20187 administration, a gradual decrease in Ki-67 levels was observed with levels dropping to 1.5% by 2 weeks post-treatment and eventually reaching a minimum of 0.1% at week 4 before gradually returning to normal. Similarly, in mice administered CID for 8 weeks followed by 8 weeks of CID removal, Ki-67-positive staining eventually returned to normal levels, demonstrating that even after neovascularization, proliferation is still reversible (Fig. 5A
; Fig. 4, E versus F
).
To determine whether CID treatment or withdrawal led to quantifiable changes in the rate of apoptosis, we conducted terminal deoxynucleotidyl transferase-mediated nick end labeling staining analysis. Although levels of proliferation were below normal after CID removal, partially accounting for reversion to a normal glandular appearance, no obvious increase in terminal deoxynucleotidyl transferase-mediated nick end labeling staining was observed at 1, 2, 4, 6, and 8 weeks after CID withdrawal that could account more fully for the complete reversion seen 8 weeks after discontinuation of treatment (data not shown). Likely reasons for failing to observe increased apoptosis include: (a) the possibility that dying cells had been shed into the lumen and rapidly cleared; and (b) rapid and efficient phagocytosis by intraductal macrophages or other scavenging cells.
Erk Signaling Correlates with Hyperplasia and Progression.
On the basis of prior in vitro studies of iFGFR1 signaling in TRAMP-derived iFGFR1-expressing cells, where we observed strong nuclear staining of p-Erk after iFGFR1 activation,7
we hypothesized that the FGFR targets, Erk1/2, might also be involved in the observed changes in proliferation in vivo. Therefore, we examined Erk activation and localization by immunohistochemistry using p-ERK-specific antibodies. In untreated JOCK-1 glands (Fig. 5B)
, as well as in treated JOCK-2 mice (data not shown), we observed strong apical cytoplasmic staining of p-Erk in the majority of epithelial cells in the ventral lobe. In the other lobes of the prostate, p-ERK appeared diffuse or nuclear-localized and did not change with iFGFR1 activation (data not shown). However, after 1 week or more of CID treatment, we observed nuclear translocation of p-Erk in epithelial cells of the ventral lobe (Fig. 5C)
. When AP20187 was withheld for 8 weeks after 4 weeks of treatment, p-Erk gradually returned to its apical cytoplasmic position (Fig. 5D)
corresponding to the loss of Ki-67 staining. Therefore, CID treatment leads to the reversible translocation of p-Erk from its polarized apical position to the nucleus.
We additionally conjectured that if CID-mediated nuclear accumulation of p-Erk was causative, translocation should precede proliferation. To additionally investigate this possibility, we performed immunohistochemistry for Ki-67 and p-Erk on serial sections from JOCK-1 mice treated with CID for 2, 6, 12, or 24 h. Whereas apical p-Erk staining was primarily observed at all of the time points, an increase in nuclear staining was seen from 2 h (Fig. 5E)
to 24 h. Increased Ki-67 staining was not observed until 24 h (Fig. 5F)
. This suggests that signaling leads to nuclear accumulation of p-Erk, which precedes Ki-67-positive immunostaining. In contrast, JOCK-2 prostates, expressing iFGFR2, displayed no nuclear translocation of p-Erk even after 8 weeks of AP20187 administration, consistent with the lack of hyperplasia. Whereas we cannot explain the previously unreported, but consistent high-level apical staining of p-Erk, nuclear translocation correlates strongly with hyperplasia and progression.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The JOCK-1 model is reflective of what occurs during carcinogenesis when FGFR1, which is not expressed in adult epithelial cells, becomes expressed in the epithelial compartment. In contrast to FGFR1, FGFR2 signaling did not elicit observable changes in our model even after 12 weeks of CID treatment, consistent with a distinct role for FGFR2 in the normal prostate gland. Previously reported models overexpressing FGFR2-IIIb-binding FGFs (i.e., FGF-3 or FGF-7) slowly develop mild hyperplasia. For example, overexpression of FGF-7 in the prostate, under the control of either mouse mammary tumor virus (18) or minimal probasin promoter (20) , leads to hyperplasia after 9 months to a year. Whereas low transgene expression could account for the mild phenotype, an alternative explanation supported by our work is that FGFR2 signaling is insufficient for prostate transformation.
A similar hypothesis may explain the observed hyperproliferative effects of prostate-targeted FGF-3 also under the transcriptional control of the mouse mammary tumor virus promoter. In these mice, FGF-3 expression within the urogenital track led to extensive hyperplasia in all of the prostate glands (19) , seemingly at odds with the inability of iFGFR2 to trigger hyperproliferation. However, unlike FGF-7, FGF-3 can also signal through other FGFRs, such as FGFR1-IIIb, which has been found in the tumor vasculature of TRAMP mice (29) . Overexpression of FGF-8b, which signals through FGFR2-IIIc, FGFR3-IIIc, and FGFR4, also leads to the development of PIN (5) , suggesting that activation of other FGF receptors besides FGFR1 can participate in CaP progression.
Unlike in our model where FGFR2 signaling is targeted to the epithelium, ectopic FGFs likely act as paracrine factors of which the direct effects are harder to pinpoint. Thus, our models help to clarify the unique roles for distinct FGFRs. In this regard, we observed differences previously in osteopontin production and Erk phosphorylation between iFGFR1 and iFGFR2 in TRAMP cell lines (30) . Differential phosphorylation of FRS2, the major downstream substrate of FGFR, has also been observed between these two receptors (31) . Together, this suggests that dissection of the signaling differences between iFGFR1 and iFGFR2 should illuminate new targets for therapeutic intervention.
JOCK-1 mice show highly reproducible pathological changes and attain grade PIN IV 3 months to a year earlier than in other single genetic lesion-based CaP models (2 , 5 , 25) . Moreover, the effects of FGFR1 are highly penetrant, as 100% of JOCK-1 mice treated for as little as 12 weeks with AP20187 show PIN in virtually every acinus. Therefore, the JOCK-1 model should be ideal for studying the early stages of CaP and for testing early intervention strategies. Crossing JOCK-1 mice with other CaP susceptibility models may lead to metastatic CaP, providing novel metastatic CaP models as well. Finally, this approach can be easily adapted to virtually any cell surface receptor that is activated by cross-linking, a growing list that may even include G protein-coupled receptors (32) .
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Notes: Dr. Welm is currently in the Department of Anatomy, University of California, San Francisco, California.
Requests for reprints: David M. Spencer, Baylor College of Medicine, One Baylor Plaza/M929, Houston, TX 77030. Phone: (713) 798-6475; Fax: (713) 798-3033; E-mail: dspencer{at}bcm.tmc.edu
5 Abbreviations: CaP, cancer of the prostate; CID, chemically induced dimerization; HA, hemagglutinin; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; iFGFR, inducible fibroblast growth factor receptor; PIN, prostatic intraepithelial neoplasia; TRAMP, transgenic adenocarcinoma of the mouse prostate; JOCK, juxtaposition of CID and Kinase-1; p, phospho. 
6 T. Clackson, personal communication.
7 K. W. Freeman and D. M. Spencer, unpublished observations.
8 Internet address: http://www.ariad.com/regulationkits/.
Received 5/22/03. Revised 9/11/03. Accepted 9/18/03.
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