FGFR1 and WT1 are markers of human prostate cancer progression
© Devilard et al; licensee BioMed Central Ltd. 2006
Received: 09 October 2006
Accepted: 30 November 2006
Published: 30 November 2006
Androgen-independent prostate adenocarcinomas are responsible for about 6% of overall cancer deaths in men.
We used DNA microarrays to identify genes related to the transition between androgen-dependent and androgen-independent stages in the LuCaP 23.1 xenograft model of prostate adenocarcinoma. The expression of the proteins encoded by these genes was then assessed by immunohistochemistry on tissue microarrays (TMA) including human prostate carcinoma samples issued from 85 patients who had undergone radical prostatectomy.
FGFR1, TACC1 and WT1 gene expression levels were associated with the androgen-independent stage in xenografts and human prostate carcinoma samples. MART1 protein expression was correlated with pT2 tumor stages.
Our results suggest that each of these four genes may play a role, or at least reflect a stage of prostate carcinoma growth/development/progression.
Prostate adenocarcinoma is the most common cancer in men in western countries, and is responsible for about 6% of overall cancer deaths . Localized prostate adenocarcinoma is usually treated by either surgery or radiotherapy. In the early stages, tumor growth is dependent on androgen stimulus and androgen ablation may be used as a complementary therapy. The tumor then progresses to an androgen-independent stage against which hormone therapy has no effect. Currently, there is no effective therapy against androgen-independent prostate cancer.
The molecular biology of prostate cancer is not well understood. Several previous reports have proposed candidate molecules linked to hereditary prostate cancer [3, 4]. GSTP1, PTEN, TP53, and androgen receptor (AR) are mutated or deregulated in sporadic prostate cancer  and may become targets for innovative therapies. Recently, DNA microarrays experiments have identified other potential prognostic markers and/or targets, such as Hepsin/TMPRSS1, PSMA, and MMR genes [6, 7] and gene fusions . Overall, little is known about the progression from androgen-dependent to androgen-independent stages .
The LuCaP 23.1 human prostate carcinoma xenograft model  mimics the different stages of tumor growth and may be an adequate system to identify the molecular events associated with cancer progression . Like for human samples, DNA microarray analyses of xenograft model systems have led to the discovery of several genes associated with cancer progression. However, although xenograft model systems are invaluable for gene discovery studies, as well as for experimental therapeutics, there is concern that growth of human cancer cells in an immunocompromised mouse host may not always be representative of progression of cancer in patients . Combined gene and protein expression profilings – e.g. DNA microarrays and tissue microarrays (TMA)  – may allow easier or quicker validation of results provided by xenograft studies.
In the present work, we used DNA microarrays to identify candidate genes correlated with progression to androgen-resistant stage in the LuCaP 23.1 xenograft model. The expression of candidate genes with available and well-performing antibody was then assessed by immunohistochemistry (IHC) on TMA including human prostate carcinoma samples from 85 patients who had undergone radical prostatectomy.
Patients and tumor characteristics.
All patients (n = 85)
Median age (years)
Median follow-up (months)
Metastatic relapse (n)
LuCaP 23.1 xenograft model
Fresh frozen tumor samples were obtained from four different mice bearing the LuCaP 23.1 xenograft . Each mouse was sampled three times, reflecting three distinct stages of tumor progression: primary tumor (day 1 post-transplantation), hormone sensitive (HS) tumor (day 7 post-transplantation), and hormone refractory (HR) tumor (day 114 post- transplantation).
Total RNA was extracted from tissue samples by lysis in guanidium isothiocyanate and centrifugation over a cesium chloride cushion following standard protocols . RNA quality was assessed by denaturing formaldehyde agarose gel electrophoresis and reverse-transcribed PCR (RT-PCR) amplification of the β2-microglobulin transcript.
DNA microarrays preparation and analysis
We used DNA microarrays to compare the mRNA expression profiles of ~1.000 selected genes between primary, HS, and HR tumors in the LuCaP 23.1 xenograft model of prostate carcinoma. RNA extracts were pooled according to the three distinct stages of tumor progression in the LuCaP 23.1 model (4 samples/tumor stage). DNA microarray hybridizations were done as previously described [14, 15] on home-made nylon DNA microarrays (TAGC, Marseille-Luminy, France), which contained spotted PCR products from 945 human cDNA clones. Most genes were selected for a proven or putative implication in cancer and/or in immune reactions. Microarrays were hybridized with 33P-labeled probes made from 5 μg of total RNA. Probe preparations, hybridizations, and washes were done as previously described . Briefly, 5 μg of total RNA were retrotranscribed in the presence of [-33P] dCTP (Amersham Biosciences). Hybridizations were done during 48 hours at 68°C in a final volume of 10 mL of buffer. After washes, arrays were exposed for 24 hours to phosphorimaging plates. Detection scanning was done with a FUJI BAS 5000 machine at 25-μm resolution (Raytest, Paris, France) and quantification of hybridization signals with the ArrayGauge software (Fuji Ltd, Tokyo, Japan). All hybridization images were inspected for artifacts, and aberrant spots or microarray regions were excluded from analyses. Data were analyzed as previously reported . Hierarchical clustering was applied to the tissue samples and the genes using the Cluster program developed by Eisen .
All data are compliant with Minimum Information about Microarray Experiment (MIAME) guidelines and have been submitted to Gene Expression Omnibus (GEO) database [GEO: GSE6284].
Tissue microarray (TMA) construction
The TMA included 96 formalin-fixed, paraffin-embedded human prostate tissue samples. TMA was prepared as described  with slight modifications. For each tumor, one representative tumor area was carefully selected from a hematoxylin- and eosin-stained section of a donor block. Core cylinders with a diameter of 1,2 mm each were punched from each of these areas and deposited into a recipient paraffin block using a specific arraying device (Beecher Instruments, Silver Spring, MD). Five-μm sections of the resulting microarray block were made and used for IHC analysis after transfer to glass slides.
Antibodies and antigen retrieval procedures used for IHC
Primers used for mRNA amplification by RT-PCR.
PCR conditions for RT-PCR amplification
N° of cycles
Overexpression of FGFR1, MART1, TACC1, and WT1 mRNAs in tumor progression in the LuCaP 23.1 carcinoma model
27 and 9 genes differentially expressed between primary and HR, and between primary and HS LuCaP 23.1 xenografts.
HR vs LUCAP 23.1
Fibroblast growth factor receptor 1
Cyclin-dependent kinase 4
Autocrine motility factor receptor
Vegf receptor 1/FLT1
Integrin alpha 3/CD49C
Polymorphic epithelial mucin
NFKb, p65 subunit
Serum response factor
MAX transcription regulator
Neogenin homolog 1
Integrin beta 5
Retinoic X receptor alpha
Insulin-like growth factor binding protein
CREB binding protein
Membrane-type matrix metalloproteinase 2
MAD homolog 9
Apoptosis regulator bak
92 kDa gelatinase, matrix metalloproteinase-9
GATA-binding protein 1
ATP-binding cassette, sub-family C, member 5
PP2A BR gamma
Frizzled 5, WNT pathway
HS vs LuCaP 23.1
Nuclear receptor liver X receptor
Stathmin, phosphoprotein p19
signal transducer and activator of transcription 1
Cas-Br-M ectropic retroviral transforming sequence b
WNT factor 2
FGFR1, TACC1 and WT1 proteins display high levels of expression in advanced stages of human prostate carcinoma
We then assessed the expression of four candidate proteins – FGFR1, MART1, TACC1 and WT1 – in human prostate carcinoma samples by IHC. This choice was supported by the availability of a corresponding antibody performing well on paraffin-embedded sections. To this purpose, we constructed a TMA that included 85 prostate carcinoma samples from 85 patients and 11 benign prostate tissue samples issued from 11 of these 85 patients.
Expression of FGFR1, MART1, TACC1 and WT1 proteins in human prostate cancer.
No. of patients (%)
MART1, TACC1, and WT1 mRNA levels in human prostate samples correlate with IHC findings
MART1 mRNA was weakly expressed in only 1/6 pT2 carcinoma, without any expression in pT3 carcinoma or HR (N1 and/or M1) samples (Figure 3). TACC1 mRNA expression was stronger in pT2 and pT3 carcinomas than in benign prostate tissue samples (Figure 3). Furthermore, TACC1 mRNA expression was strong in HR stage carcinoma samples (Figure 3). A WT1 mRNA variant (706 bp) was expressed in 2 of 6 pT2 carcinoma samples, while the major WT1 mRNA was strongly expressed in pT3 and HR (N1 and/or M1) carcinoma samples.
Using three methods of analysis (DNA microarrays, TMA, and RT-PCR), we have shown that FGFR1, TACC1 and WT1 have much higher levels of expression in human prostate carcinoma than in benign prostate tissue samples, at both mRNA and protein levels. We have also found that FGFR1 and WT1 mRNA are preferentially expressed in pT3 and/or N1/M1 carcinoma samples, and that MART1 expression is correlated with HS stage LuCaP 23.1 carcinoma and pT2 prostate carcinoma.
High-throughput screening techniques provide opportunities to identify new diagnostic or prognostic markers and innovative therapeutic targets in the whole field of oncology. TMA is a powerful tool to validate DNA microarrays data and extend the scope of gene expression profiling to the post-transcriptional level. Several previous studies [17, 20, 22, 23] have emphasized how TMAs are useful to validate the use of candidate prostate carcinoma markers in routine (IHC) conditions .
Potential new markers for prostate cancer progression
We found that expression of FGFR1, WT1, and, to a lesser extent, TACC1 protein is upregulated in advanced stages (pT3 and/or N1/M1) of prostate cancer, whereas MART1 is mainly expressed in localized (pT2) stage prostate cancer. In the same way, we observed that the corresponding mRNAs – FGFR1, TACC1, and WT1 on the one hand, and MART1 on the other hand – are overexpressed in HR and HS stage LuCaP 23.1 prostate carcinoma, respectively.
FGFR1 codes for a tyrosine kinase receptor for members of the FGF family of growth factors. It is a potential oncogene, amplified in breast cancers and rearranged in hematopoietic diseases. The case of FGFR1 in prostate cancer is rather clear and our results are in perfect agreement with previous data. Expression of FGFR1 is associated with increased proliferation and aggressive behavior of prostate cancer [24, 25].
The MelanA/MART1 gene encodes a tyrosinase that is a marker of melanocytic differentiation . It can be recognized by cytotoxic T cells  and has been considered as a target for immunotherapy . A previous study has shown that the protein is expressed in lymph nodes from breast cancer patients . Our results showed mRNA overexpression in HS stage LuCaP 23.1 model and IHC expression of MART1 in about 20% of prostate carcinomas, mainly pT2 stages. MART1 expression was strictly restricted to carcinoma cells, without any staining in benign prostate tissue. Therefore, we suggest that MART1 may be a marker of some intermediate, hormone sensitive stage of prostate carcinoma, and that its transient expression might be shut down during cancer progression towards hormone resistant and/or advanced clinical stages (T3 and/or N+ and/or M+).
TACC1 belongs to the TACC/taxins (Transforming Acidic Coiled-Coil) protein family. Taxins are centrosome and spindle-associated proteins involved in cell division . Mammalian Taxins are probably involved in oncogenesis in different ways [29, 30]. TACC1 maps to 8p11, a region that is amplified and rearranged in many malignancies [29–31]. We observed upregulation of TACC1 expression in prostate carcinoma. This is in agreement with previous reports focusing on other tumors . Since we found TACC1 underexpressed in the majority of breast carcinoma , TACC1 role remains to be determined. As previously suggested, TACC1 might be involved in multiple complexes that may be deregulated in malignant conditions .
The WT1 (Wilms tumor 1) gene encodes a zinc finger transcription factor that modulates the expression of several genes encoding growth factors and receptors (epidermal growth factor receptor , insulin-like growth factor II , IGF1 receptor  and AR . In Wilms tumor, different point mutations have been described in the WT1 locus, suggesting that WT1 altered protein may be directly involved in tumor formation. High WT1 expression levels have been reported in several malignancies [38–41], and have been linked to a poor prognosis . WT1 expression and multidrug resistance are associated in some hematological malignancies, suggesting that WT1 may be a marker for chemoresistance . We found high expression levels of WT1 in pT3 stage carcinoma samples, and expression of wild-type WT1 mRNA in both advanced stages (≥ pT3) and HR stage LuCaP 23.1 carcinomas. These results suggest that WT1 expression in prostate carcinoma may be associated with progression towards hormone resistance and that WT1 may be considered as a potential hormone resistance and prognostic marker in human prostate carcinoma. These hypotheses are supported by the strong repression of AR promoter by WT1 .
We thank F. Birg and D. Maraninchi for encouragements. This work was supported by Institut Paoli-Calmettes and INSERM.
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