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Cell, Tumor, and Stem Cell Biology |
Departments of 1 Medicine, 2 Pharmacology and Cancer Biology, and 3 Pathology, Duke University Medical Center, Durham, North Carolina
Requests for reprints: Gerard C. Blobe, 221B MSRB Research Drive, Box 2631, Duke University Medical Center, Durham, NC 27710. Phone: 919-668-1352; Fax: 919-668-2458; E-mail: blobe001{at}mc.duke.edu.
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Abstract |
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30% of prostate cancers, most prostate cancers become TGF-ß resistant without mutation or deletion of TßRI, TßRII, or Smads2, 3, and 4, and thus, the mechanism of resistance remains to be defined. Here, we show that type III TGF-ß receptor (TßRIII or betaglycan) expression is decreased or lost in the majority of human prostate cancers as compared with benign prostate tissue at both the mRNA and protein level. Loss of TßRIII expression correlates with advancing tumor stage and a higher probability of prostate-specific antigen (PSA) recurrence, suggesting a role in prostate cancer progression. The loss of TßRIII expression is mediated by the loss of heterozygosity at the TGFBR3 genomic locus and epigenetic regulation of the TßRIII promoter. Functionally, restoring TßRIII expression in prostate cancer cells potently decreases cell motility and cell invasion through Matrigel in vitro and prostate tumorigenicity in vivo. Taken together, these studies define the loss of TßRIII expression as a common event in human prostate cancer and suggest that this loss is important for prostate cancer progression through effects on cell motility, invasiveness, and tumorigenicity. [Cancer Res 2007;67(3):1090–8] |
Introduction |
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TßRIII, also known as betaglycan, is a 849-amino-acid proteoglycan with a short 41-amino-acid cytoplasmic domain (7, 8). TßRIII is the most abundantly expressed TGF-ß receptor and binds all three TGF-ß isoforms with high affinity. Due to its structural characteristics and lack of obvious signaling motifs, TßRIII was originally thought to function primarily as a TGF-ß coreceptor, serving to sequester and present ligand to TßRII (7–9), with ectodomain shedding producing a soluble extracellular domain (sTßRIII) that antagonizes TGF-ß signaling (10). This assumption has been challenged by recent studies demonstrating that mice lacking TßRIII die at gestational day 13.5 due to defects in the heart and liver (11), and that blocking TGF-ß2 binding specifically to TßRIII inhibits TGF-ß2–induced mesenchymal transformation in chick embryonic hearts (12). Recent studies have also expanded the role of TßRIII in mediating/regulating TGF-ß signaling through its short, but highly conserved cytoplasmic domain. Although the cytoplasmic domain of TßRIII is not required for ligand presentation, this domain is required for full promotion of TGF-ß signaling (13). TßRIII interacts through this cytoplasmic domain with the scaffolding proteins G
-interacting protein, C terminus (14), and ß-arrestin 2 (15), as well as with the autophosphorylated, active form of TßRII (13). The interaction of TßRIII and TßRII results in the phosphorylation of the cytoplasmic domain of TßRIII by TßRII, mediating the binding of ß-arrestin 2 to TßRIII and potentially the disassociation of TßRIII from TßRII (13). Whereas G-interacting protein, C terminus, binding stabilizes TßRIII on the cell surface to increase TGF-ß responsiveness (14), ß-arrestin 2 binding results in the internalization of both TßRIII and TßRII and down-regulation of TGF-ß signaling (15).
The TGF-ß signaling pathway has an important role in regulating normal prostate epithelium, inhibiting proliferation, differentiation, and both androgen deprivation–induced and androgen-independent apoptosis (16–18). During prostate cancer formation, as in other cancers, prostate cancer cells become resistant to the antiproliferative effects of TGF-ß (19). Although the loss of expression of either TßRI or TßRII has been documented in 31% of prostate cancers (20–22), most prostate cancers become resistant to the homeostatic effects of TGF-ß without mutation or deletion of TßRI, TßRII, or Smads2, 3, and 4. Thus, other mechanisms must enable prostate cancer cells to escape the tumor-suppressive properties of TGF-ß. Recently, loss of TßRIII expression has been reported in renal cell carcinoma (23) and endometrial cancer (24). Moreover, exogenous administration of sTßRIII suppresses tumorigenicity in vivo (25–27). Given that TßRIII has emerging roles in mediating and regulating TGF-ß signaling, and the expression and functional significance of TßRIII in prostate cancer has not been established, we investigated whether the loss of TßRIII expression is a mechanism through which prostate cancer cells escape the tumor-suppressive effects of TGF-ß.
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Materials and Methods |
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Oncomine microarray data and meta-analysis. Six independent gene profiling studies (28–33) publicly available on the Oncomine Cancer Profiling Database4 were used to investigate TßRIII mRNA levels in prostate cancer. For each study, the mean TßRIII expression and the SD for both tumor and normal prostate tissue were calculated. Using the statistical program, Comprehensive Meta-analysis (Biostat, Inc., Englewood, NJ), the standard difference in means between the normal and tumor TßRIII from the mean TßRIII expression, the SD, and sample number for each individual study were calculated, and the combined meta-analysis of all six studies, along with each 95% confidence interval, was plotted. A negative value indicates a decrease in TßRIII expression in tumor versus normal.
Cell culture and reagents. DU145 cells were purchased from the American Type Culture Collection (Manassas, VA). DU145 cells were maintained in modified Eagle's medium supplemented with 10% FCS and 1 mmol/L sodium pyruvate. Cells were kept incubated at 37°C in 5% CO2.
Stable cell line formation. DU145 cells were plated in six-well plates and grown to 80% confluency. Regular cell media was then replaced with Opti-MEM for transfection. In three wells of the six-well plate, 2 µg full-length, hemagglutinin-tagged rat TßRIII was transfected with 4 µL LipofectAMINE 2000 following the manufacturer's protocol. The empty vector pcDNA3.1 was transfected in the other three wells in the same fashion of TßRIII. The cells were incubated in the Opti-MEM containing the DNA and LipofectAMINE 2000 for 4 h, then the media was changed back to each cell line's regular media. After 48 h, cells were trypsinized, pooled, and replated in a 75-cm2 flask. Selection was started by supplementing cell media with 500 µg/mL G418 72 h after transfection. Cells were selected for 4 weeks until the flask becomes 100% confluent with G418-resistant stables. After five passages, TßRIII expression was confirmed with affinity labeling. DU145 cells stably expressing full-length TßRIII and the empty vector pcDNA3.1 were maintained by supplementing their media with 500 µg/mL G418.
Affinity labeling. Cells were labeled with 100 pmol/L 125I-TGFß1 in Krebs-Ringer-HEPES [50 mmol/L HEPES (pH 7.5), 130 mmol/L NaCl, 5 mmol/L MgSO4, 1 mmol/L CaCl2, 5 mmol/L KCl] plus 0.5% bovine serum albumin for 3 h at 4°C. Cells were rinsed with Krebs-Ringer-HEPES four times, then surface proteins were cross-linked with 0.5 mg/mL disuccinimidyl suberate for 15 min. The reaction was quenched by incubating with 20 mmol/L glycine for 10 min. Cells were again rinsed with Krebs-Ringer-HEPES, and then lysed in 100 µL 2x sample buffer. Proteins were resolved on 7.5% SDS-PAGE and detected by a phosphoimager.
Proliferation studies. Twenty thousand DU145 cells stably expressing the empty vector pcDNA3.1 or TßRIII were plated in triplicate in six-well plates and grown at 37°C in 5% CO2. Cells were counted in triplicate using a Coulter counter every 24 h for 6 days. New media supplemented with 10% fetal bovine serum was added to plates every 48 h. About 100 pmol/L TGF-ß treatment (or media supplemented with 10% fetal bovine serum) was added to select samples every 48 h. Cells were counted in triplicate using a Coulter counter every 24 h.
DNA extraction. Eight different patient prostate tumor samples and eight matched patient normal prostate tissue were obtained from the Duke Tissue Resource Network. Each sample was paraffin embedded and mounted on glass microscope slides. The samples were deparaffinized by immersion in xylene. The tumor tissue was lifted with a scalpel blade, transferred into a microfuge tube, and digested overnight at 65°C in buffer containing proteinase K. The lysate was heated at 95°C for 10 min to inactivate proteinase K. Lysate volumes sufficient to provide 4 µg genomic DNA was used directly for PCR. Control DNA was obtained by digesting matched normal prostate tissue.
Microsatellite PCR loss of heterozygosity analysis. Genomic DNA extracted from human prostate cancer specimens and matching normal prostate tissue was kindly provided by the Duke Prostate Cancer Tissue Bank. Microsatellite markers, D1S1588, D1S2804, and D1S435, were used in PCR reactions in which the forward primer was synthesized with a 5' fluorescent tag (Integrated DNA Technology, Inc., Coralville, IA). PCR products were visualized using an ABI sequencer, and data was analyzed using GeneScan software. To determine the loss of heterozygosity (LOH), a ratio for each normal sample was calculated by dividing the total area calculated by the GeneScan software under the first peak by the total area under the second peak. The ratio of the peak areas for the tumor sample was calculated in the same fashion. Finally, the peak-area ratio for the normal prostate tissue was divided by the peak-area ratio for the tumor tissue. Criteria for LOH was a ratio >1.5 or <0.67.
Methylation and histone acetylation analysis. Prostate cancer cell lines DU145 and PC3 were treated with either 10 µmol/L 5-aza-2-deoxycytidine for 96 h and/or 500 nmol/L trichostatin A (TSA) for 24 h or with vehicle (no treatment). RNA was isolated using an RNeasy kit (Qiagen, Valencia, CA) and reverse transcribed. Quantitative SYBR Green real-time reverse transcription-PCR was done using TßRIII-specific or control glyceraldehyde-3-phosphate dehydrogenase primers. Data were normalized against glyceraldehyde-3-phosphate dehydrogenase levels and expressed relative to basal levels of TßRIII message levels from cell lines without treatment.
Wound-healing assay. DU145 cells were plated to confluence in six-well plates and scratched with a p200 tip to cause a wound. Images were taken using a Nikon Eclipse TE2000-U microscope under 10x magnification at multiple time points from 0 to 24 h. Cells were maintained in their selection media at 37°C in 5% CO2 during this time period. The percent of the wound remaining open ± SEM was calculated using Adobe Photoshop, with the 0-h time point being set to 100% for each sample type.
Fibronectin motility assay. A total of 50,000 DU145 cells stably expressing the empty vector pcDNA3.1 or TßRIII were seeded in serum-free media + 500 µg/mL G418 ± 150 pmol/L TGF-ß1 in the upper chamber of fibronectin-coated transwell filters. The lower chamber was loaded with regular media supplemented with 10% fetal bovine serum. After a 24-h incubation at 37°C in 5% CO2, the tops of the filters were scrapped, and cells that migrated through the fibronectin were fixed and stained using 3 Step Stain Set (Richard-Allan Scientific, Kalamazoo, MI). Cells that migrated to the lower surface of the membrane were counted in three fields under 10x magnification.
Matrigel invasion assay. Matrigel invasion chambers were purchased from BD Biosciences (San Jose, CA). The BD BioCoat Matrigel Invasion chambers included Falcon Cell Culture inserts containing an 8-µm pore size PET membrane with a thin layer of Matrigel basement membrane matrix. DU145 cells lines (25,000–50,000 cells per well) were resuspended in 500 µL serum-free media with 500 µg/mL G418 ± 150 pmol/L TGF-ß1 and then seeded onto the upper compartment of each chamber. The lower compartment was filled with 700 µL of medium containing normal serum with 10% fetal bovine serum and 500 µg/mL G418. The chambers were then incubated for 48 h at 37°C. Noninvading cells were removed from the upper surface of the filter, and cells that had migrated through the filter were fixed and stained using the 3 Step Stain Set (Richard-Allan Scientific). Filters were allowed to dry and then were mounted onto a normal microscope slide. Cells that migrated to the lower surface of the filter were considered to have invaded through the overlying matrix and were counted in three fields using light microscopy.
Human prostate cancer xenograft model. Animal procedures were approved by the Institutional Animal Care and Use Committee of Duke University. A total of 1 x 106 DU145-Neo or DU145-RIII cells were injected s.c. into both flanks of athymic BALB/cAnNCr-nu/nu mice. The DU145-Neo group contained six mice, and the DU145-RIII contained five mice. Mice were weighed, and tumor width (W) and length (L) were measured every 3 days. Tumor volume was approximated using the formula V = 0.5 x L x W2. Tumor volume was followed for 36 days when some of the mice were reaching humane end points, at which time the mice were sacrificed. Upon autopsy, tumors were excised and weighed.
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Results |
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We also analyzed correlations of our mean immunohistochemistry TßRIII score with clinical stage, primary Gleason grade of the core, and total Gleason score of the prostate tumor. Although there was no correlation between immunohistochemistry TßRIII score and total Gleason score or primary Gleason grade (data not shown), there was a trend for decreased TßRIII expression between clinical T stages 2 and 3 (Fig. 1G; P = 0.0546). Clinical stages 1 and 4 were omitted due to insufficient sample number. These data suggest that the loss of TßRIII expression is a rather early event in prostate cancer progression, with loss beginning during the formation of high-grade intraepithelial neoplasia and increasing as these progress to invasive prostate cancer.
We then investigated whether there was also a loss of TßRIII expression at the mRNA level. Using six previously published gene profiling studies for benign prostate and prostate cancer specimens publicly available through the Gene Expression Omnibus repository and Oncomine Gene Profiling Databases, we established that the mean TßRIII mRNA levels were significantly decreased in prostate tumor tissue as compared with normal prostate tissue in all six studies (Fig. 2A ). Because TßRIII expression is high in the stroma, this decrease could potentially be due to a decrease in stromal contribution to the mRNA expression in tumor versus benign specimens. However, one of these studies, Yu et al. (30), used only normal peripheral zone prostate tissue with at least 60% glandular components and tumor tissues with at least 70% tumor, and another study, Lapointe et al. (31), found very few genes in which expression correlated with epithelial content, making this explanation less likely. Moreover, combining all six studies in a meta-analysis, we calculated the combined standard difference in means to be –1.855 ± 0.140 (95% confidence interval, –2.218 to –1.581; P < 0.001; Fig. 2B), confirming the loss of TßRIII expression in prostate cancer as compared with benign prostate.
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Analysis of data from Lapointe et al. (31) also confirmed a statistically significant decrease in TßRIII mRNA levels in clinical stage T3 as compared with clinical stage T2 (P = 0.0339; Fig. 2D) and established a decrease in TßRIII mRNA levels in patients with known PSA recurrence relative to those who did not have PSA recurrence (P = 0.0062; Fig. 2E). Taken together, these results show that TßRIII expression is decreased in prostate cancer at both the message and protein level, with decreased expression correlating with increasing clinical stage, metastatic disease, and PSA recurrence, but not Gleason score or grade.
LOH of the TGFBR3 genomic locus in human prostate cancer. Previous studies have shown that chromosome 1p, where TGFBR3 is located, exhibits a loss of heterozygosity in a number of human cancers, including prostate cancer (34). To examine whether LOH represents a mechanism for decreased TßRIII expression in human prostate cancer, we did a preliminary study using PCR-based LOH analysis on eight patient prostate cancer specimens with matching normal adjacent prostate tissue using three microsatellite markers (D1S1588, D1S2804, and D1S435) that are informative for the TGFBR3 genomic locus at 1p32. Using these three microsatellite markers, we were able to establish that 37.5% (3:8) of our samples showed LOH at the TGFBR3 locus (Fig. 3A and B ). In addition, by examining TßRIII expression by immunohistochemistry in these specimens, we were able to confirm that the loss of TßRIII expression correlated with LOH in all three cases (Fig. 3C and D). Thus, these studies confirm that LOH of the TGFBR3 locus is one mechanism through which TßRIII expression is lost during prostate cancer progression.
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TßRIII does not alter prostate cancer cell proliferation. To explore the functional significance of TßRIII in prostate cancer, we analyzed TGF-ß receptor expression in the PC-3 and DU145 prostate cancer cells lines and the immortalized prostate epithelial cells LHS and LHSR (35). The LHS and LHSR cells were immortalized by infecting prostate epithelial cells with retroviruses expressing LT, hTERT, and ST and SV40 LT, hTERT, ST, and H-ras, respectively (35). Both LHS and LHSR cells expressed high levels of TßRIII, suggesting that prostate epithelial cells normally express high levels of TßRIII (data not shown). Although the PC-3 cell line also expressed high-level TßRIII, the DU145 prostate cell line expressed low levels of TßRIII and relatively normal levels of TßRII and TßRI (Supplementary Fig. S1A, data not shown). Thus, we chose the DU145 cell line to investigate the functional consequences of the loss of TßRIII expression. We established a DU145 stable cell line re-expressing TßRIII (DU145-RIII) and a control DU145 cell line expressing empty vector, pcDNA3.1 (DU145-Neo). Expression of TßRIII was verified by performing 125I-TGFß1 binding and cross-linking studies, with DU145-RIII expressing all three TGF-ß receptors and DU145-Neo cells expressing very low levels of TßRIII (Supplemental Fig. S1A). TßRII and TßRI levels were equivalent in both DU145-RIII and DU145-Neo cells. We then tested whether TßRIII effects cell proliferation in the presence and absence of TGFß1. Exogenous expression of TßRIII had no effect on basal DU145 cell proliferation because the growth curves of DU145-Neo and DU145-RIII were similar (Supplemental Fig. S1B). In addition, in the presence of 100 pmol/L TGFß1, exogenous expression of TßRIII had no effect on TGFß1-regulated DU145 cell proliferation because, again, the growth curves of DU145-Neo and DU145-RIII were similar (Supplemental Fig. S1C). These results show that expression of TßRIII had no effect on cellular proliferation in vitro and did not alter responsiveness to TGFß1 in the DU145 cell line.
TßRIII decreases prostate cancer cell migration. The decrease in TßRIII expression in prostate cancer relative to benign prostate and in higher stage and metastatic prostate cancers relative to lower stage and nonmetastatic prostate cancers all suggested a potential role for TßRIII in regulating cell migration and/or invasion. To examine the role of TßRIII in regulating cell migration, we first used a monolayer wound-healing assay and monitored wound closure over a 24-h time course (36). DU145 prostate cancer cells stably expressing TßRIII consistently migrated slower than control DU145-Neo cells (Fig. 4A and B ). Although wounds in DU145-Neo cells closed completely by 24 h, wounds in confluent DU145-RIII cells remained 32.7 ± 3.7% open at 24 h (Fig. 4A and B). These studies suggested that expression of TßRIII was sufficient to inhibit cellular migration.
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TßRIII decreases prostate cancer cell invasiveness. Although alterations in motility are necessary for prostate cancer cells to metastasize, they also need to invade through the basement membrane. To examine the role of TßRIII in regulating prostate cancer cell invasiveness, we used the reconstituted basement membrane, Matrigel, to model the basement membrane (37). In a manner similar to the fibronectin motility assays, the addition of 150 pmol/L TGF-ß1 increased invasion of DU145-Neo stable cells by 36.6 ± 12% and DU145-RIII cells by 108.8 ± 57.1% relative to the same cell lines without TGF-ß1 treatment. Strikingly, expression of exogenous TßRIII in DU145 prostate cancer cells significantly inhibited their ability to invade Matrigel by 61.6 ± 14.8% in the absence of TGF-ß1 and 54.9 ± 2.1% in the presence of TGF-ß1 (Fig. 5 ; P = 0.0143, Kruskal-Wallis test). Again, these differences were not due to differences in proliferation as established by our growth curves (Supplement Fig. S1B and C). Taken together, these results suggest that one potential consequence of the progressive loss of TßRIII expression from preinvasive to invasive to metastatic prostate cancer is the ability for these cells to become more motile and invasive.
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Discussion |
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How might the loss of TßRIII expression result in increased cell motility and invasiveness? TßRIII functions as a coreceptor for the TGF-ß signaling pathway, enhancing ligand binding to TßRII and increasing TGF-ß signaling. In addition to this role, TßRIII through its cytoplasmic domain interacts with the scaffolding proteins G-interacting protein, C terminus (14) and ß-arrestin 2 (15) which have the potential to scaffold TßRIII to Smad-independent signaling pathways, including the mitogen-activated protein kinase pathways (38). TßRIII is also proteolytically cleaved in the extracellular domain to produce soluble TßRIII (sTßRIII) that can sequester TGF-ß ligand and antagonize TGF-ß signaling (10). In terms of prostate cancer, sTßRIII has been shown to decrease tumor growth and angiogenesis in a xenograft model (27). Thus, decreasing TßRIII expression could result in decreased TGF-ß–mediated Smad-dependent or Smad-independent signaling or in decreased expression of sTßRIII. The mechanism by which reduced TßRIII expression enhances prostate cancer cell motility and invasiveness remains an active area of investigation.
TßRIII is on the short arm of chromosome 1, 1p32, a region that is frequently deleted in human cancers, including breast, colon, endometrial, gastric, kidney, lung, ovarian, and testicular cancer (34, 39). Although there are other potential tumor suppressor genes in this region, including TP73 (40) and RUNX3 (41), previous studies have not established these as the tumor suppressors in these cancers. In the present study, we established LOH at the TßRIII locus in 37% of the patients, with LOH correlating with decreased TßRIII expression, supporting TßRIII as a tumor suppressor gene in human prostate cancer. TßRIII has also been reported to be lost at an early stage in renal cell carcinogenesis (23). Whether TßRIII is the tumor suppressor gene on chromosome 1p32 in renal cell and other human cancers remains to be defined.
Although most cases of early prostate cancer can be cured with localized approaches and locally advanced and metastatic prostate cancer can often be controlled with hormonal therapy, many patients ultimately become hormone refractory and succumb to their disease, with 27,350 U.S. deaths expected in 2006. Thus, better treatment options are required for advanced hormone refractory prostate cancer. Given the role of the TGF-ß signaling pathway in regulating normal prostate epithelial homeostasis, including androgen depletion–induced and androgen-independent apoptosis, this pathway is a promising target for treatment of advanced-stage, hormone refractory prostate cancer. To effectively target this pathway, increased understanding of the mechanisms through which prostate cancer cells become resistant to the tumor suppressor effects of TGF-ß is needed. Our current data support that loss of TßRIII receptor expression as a common mechanism through which prostate cancer cells escape TGF-ß–mediated tumor suppression. Given that treatment of the TßRIII-deficient cell line DU145 with the TSA and 5-aza-2'-deoxycytidine resulted in increased TßRIII expression, our data suggest that TßRIII levels could be restored in some cases via histone deacetylase inhibitors and 5-aza-2'-deoxycytidine analogs. In addition, because the ectodomain of TßRIII is normally shed, some endogenous properties of TßRIII could be restored by the administration of exogenous sTßRIII, as was recently validated in a preclinical model of prostate cancer (27). The role of epigenetic regulation of TßRIII expression and the role of soluble TßRIII are currently being further defined.
TßRIII expression may also have a prognostic value in prostate cancer. We have shown that TßRIII mRNA and protein levels decrease with increased clinical stage and correlate with higher PSA recurrence and metastatic disease. Whether immunohistochemical staining for TßRIII on tissue specimens obtained from radical prostatectomy could direct physicians in planning the quality and aggressiveness of adjunctive chemotherapy or radiotherapy requires prospective validation.
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Acknowledgments |
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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.
Tissue microarray slides were provided by the Cooperative Prostate Cancer Tissue Resource, which is funded by the National Cancer Institute.
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Footnotes |
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R.S. Turley and E.C. Finger contributed equally to this work.
Dr. Blobe was the recipient of the 2005-2006 AACR-Gertrude B. Elion Cancer Research Award.
Received 8/22/06. Revised 11/ 2/06. Accepted 11/30/06.
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References |
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-subunit and the inhibin coreceptor ß-glycan are downregulated in endometrial carcinoma. Eur J Endocrinol 2005;152:277–84.This article has been cited by other articles:
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  E. V. Verona, Y. Tang, T. K. Millstead, A. P. Hinck, J. K. Agyin, and L.-Z. Sun Expression, purification and characterization of BGERII: a novel pan-TGF{beta} inhibitor Protein Eng. Des. Sel., July 1, 2008; 21(7): 463 - 473. [Abstract] [Full Text] [PDF]
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 N. Hempel, T. How, S. J. Cooper, T. R. Green, M. Dong, J. A. Copland, C. G. Wood, and G. C. Blobe Expression of the type III TGF-{beta} receptor is negatively regulated by TGF-{beta} Carcinogenesis, May 1, 2008; 29(5): 905 - 912. [Abstract] [Full Text] [PDF]
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 K. C. Kirkbride, T. A. Townsend, M. W. Bruinsma, J. V. Barnett, and G. C. Blobe Bone Morphogenetic Proteins Signal through the Transforming Growth Factor-{beta} Type III Receptor J. Biol. Chem., March 21, 2008; 283(12): 7628 - 7637. [Abstract] [Full Text] [PDF]
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E. C. Finger, R. S. Turley, M. Dong, T. How, T. A. Fields, and G. C. Blobe T{beta}RIII suppresses non-small cell lung cancer invasiveness and tumorigenicity Carcinogenesis, March 1, 2008; 29(3): 528 - 535. [Abstract] [Full Text] [PDF]
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K. J. Gordon, M. Dong, E. M. Chislock, T. A. Fields, and G. C. Blobe Loss of type III transforming growth factor {beta} receptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression Carcinogenesis, February 1, 2008; 29(2): 252 - 262. [Abstract] [Full Text] [PDF]
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H. J. You, M. W. Bruinsma, T. How, J. H. Ostrander, and G. C. Blobe The type III TGF- receptor signals through both Smad3 and the p38 MAP kinase pathways to contribute to inhibition of cell proliferation Carcinogenesis, December 1, 2007; 28(12): 2491 - 2500. [Abstract] [Full Text] [PDF]
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 T. L. McCarthy, T. H. Pham, B. I. Knoll, and M. Centrella Prostaglandin E2 Increases Transforming Growth Factor-{beta} Type III Receptor Expression through CCAAT Enhancer-Binding Protein {delta} in Osteoblasts Mol. Endocrinol., November 1, 2007; 21(11): 2713 - 2724. [Abstract] [Full Text] [PDF]
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 N. Hempel, T. How, M. Dong, S. K. Murphy, T. A. Fields, and G. C. Blobe Loss of Betaglycan Expression in Ovarian Cancer: Role in Motility and Invasion Cancer Res., June 1, 2007; 67(11): 5231 - 5238. [Abstract] [Full Text] [PDF]
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