| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Commentary |
1 Cancer Stem Cell Section, Laboratory of Cancer Prevention, National Cancer Institute at Frederick, Center for Cancer Research, Frederick, Maryland 21702, USA
2 Medical Oncology Branch, National Cancer Institute, Center for Cancer Research, Building 10, Room 5A01, Bethesda, Maryland 20892, USA
(Correspondence should be addressed to N Sharifi; Email: nima.sharifi{at}nih.gov)
 |
Abstract |
|---|
 Top Abstract TextReferences |
|---|
|
Text |
|---|
|
TopAbstractTextReferences |
|---|
Accordingly, resistance to TGF-ß signaling is mediated by perturbations in various members of this pathway. The mechanisms of resistance in many solid tumors are well defined. For example, mutations in TGFßRII are frequently found in colon cancer (Grady et al. 1999) and SMAD4 deletions are found in pancreatic tumors (Hahn et al. 1996). In prostate cancer, loss of TGFßRI or TGFßRII expression is found in about 30% of cases (Kim et al. 1996, Guo et al. 1997), but the mechanism of TGF-ß resistance in the majority of prostate cancers remained undefined. This prompted two recent studies of TGFßRIII in prostate cancer, both of which suggest that loss of TGFßRIII expression is the most commonly perturbed TGF-ß pathway component in prostate cancer (Sharifi et al. 2007, Turley et al. 2007).
Sharifi et al. (2007) sought to address changes in the expression of TGF-ß pathway components in prostate cancer. Using Oncomine, a freely available web-based database of DNA microarray studies of various malignancies (Rhodes et al. 2004), they found that TGFßRIII is the most commonly downregulated TGF-ß component across seven DNA microarray studies of benign prostate versus localized prostate cancer. Then, TGFßRIII mRNA was also found to be downregulated in the majority of prostate cancer cell lines tested. To determine if TGFßRIII downregulation might play a role in development of prostate intraepithelial neoplasia (PIN), a precursor to invasive prostate cancer, the effect of TGFßRIII downregulation on markers of carcinogenesis was evaluated. These studies showed that TGFßRIII levels had significant effects on vimentin expression. shRNA knockdown of TGFßRIII in noncancerous prostate epithelial cells leads to downregulation of vimentin mRNA and protein loss, indicating that TGFßRIII controls vimentin expression. This is significant because vimentin expression is decreased in the transition from benign prostate to local prostate cancer in the majority of DNA microarray studies in Oncomine, and previously published findings show that vimentin protein is expressed in benign prostate and lost in prostate cancer and PIN (Nagle et al. 1991). Since vimentin expression is lost as early as PIN and is dependent on TGFßRIII for expression, it follows that TGFßRIII may be lost as early as PIN. This hypothesis was confirmed in another set of studies by Turley et al. (2007) who examined TGFßRIII protein by immunohistochemistry and showed decreased expression in clinical prostate cancer specimens. Loss of TGFßRIII at the mRNA level was confirmed using Oncomine. Furthermore, it was found that the protein is downregulated in the transition from benign prostate to high-grade PIN and that TGFßRIII loss occurs continuously throughout progression of prostate cancer.
These two studies also reveal the phenotypic and genetic consequences of TGFßRIII expression. Sharifi et al. (2007) showed that shRNA knockdown of TGFßRIII in an immortalized prostate epithelial cell line causes focus formation, increased cell surface expression of a prostate stem cell marker and downregulation of one of the most potent inhibitors of angiogenesis, SERPINF1 (also known as pigment epithelium derived growth factor; Doll et al. 2003). Turley et al. (2007) reexpressed TGFßRIII in a prostate cancer cell line that had lost expression, and showed decreased cell migration, invasiveness and tumorigenicity. Together, these studies strongly support a role for TGFßRIII as a tumor suppressor in prostate cancer.
Despite the findings of TGFßRIII downregulation and characterization of phenotypic changes that correlate with TGFßRIII expression, the exact function of TGFßRIII in the prostate remains unclear. TGFßRIII can affect prostate epithelial signaling through at least four mechanisms. First, TGFßRIII acts as a coreceptor and enhances TGF-ß signaling by augmenting ligand binding to TGFßRII (Wang et al. 1991). This function would support the role of TGFßRIII loss as a means of resistance to the canonical TGF-ß pathway early in prostate tumorigenesis. Second, involves the role of the soluble form of TGFßRIII. Soluble TGFßRIII is formed by proteolytic cleavage of the extracellular domain and can antagonize TGF-ß function by TGF-ß ligand sequestration (Lopez-Casillas et al. 1994). In this scenario, loss of TGFßRIII would lead to an increase in TGF-ß signaling, and increased inhibitory responses in the absence of other pathway perturbations. Third, is the possibility that TGFßRIII may function in a noncanonical pathway. TGFßRIII can interact with G
-interacting proteins and ß-arrestins (Turley et al. 2007). This supports a signaling role that may be independent of the SMADs. It is possible that this pathway is necessary for growth inhibitory responses or maintenance of normal tissue architecture.
A fourth and very interesting possibility, however, is that TGFßRIII downregulation plays an altogether different role in the prostate. In addition to acting as a coreceptor for TGF-ß ligands, TGFßRIII is also a receptor for and tightly binds inhibins, which are TGF-ß superfamily cytokines that have antagonistic actions to activins (Lewis et al. 2000). In most systems studied, activins have similar properties to TGF-ß and signal through the same SMAD pathway (Massague et al. 2005). The antagonistic property of inhibin has to do with inhibin binding the type II activin receptor and TGFßRIII, forming a complex that interferes with activin binding the type II receptor, thereby inhibiting signal transduction. Although inhibins are mechanistically antagonistic to activin-mediated signal transduction, a signaling mechanism for inhibins that does not involve activin antagonism has not been ruled out. Whatever the function of inhibins may be downstream of TGFßRIII, this may have hormonal and physiological implications for prostate biology.
Inhibins have an important role in male reproduction and reproductive organs (O'Connor & De Kretser 2004). Inhibin B is secreted by the testes, found in circulating blood, and correlates with male fertility. The following model that we propose is of a role for TGFßRIII and inhibin B in prostate biology that is antagonistic and may be physiologically complementary to the role of androgens. Androgens produced by the testes stimulate the growth of prostate cancer cells and androgen deprivation reverses this growth stimulation (Sharifi et al. 2005). Androgens are also involved in stimulating the development of PIN and early prostate tumorigenesis (Tomlins et al. 2007). Inhibins may act as a negative regulator of prostate growth, in which case TGFßRIII downregulation in prostate cancer may represent resistance to testicular inhibin B (Fig. 1). Furthermore, male inhibin- subunit knockout mice form tumors in both testes and adrenal glands (Matzuk et al. 1992, 1994), which may reflect loss of feedback inhibition on these organs. If gonadal inhibin is a prostate tumor suppressor, prostate cancer may be expected from inhibin knockout mice. However, these mice die of gonadal stromal tumors. To allow prolonged survival, inhibin knockout mice had to be gonadectomized and the consequent loss of this major source of androgens may explain why prostate tumors were not observed. It may also be physiologically relevant that both of the organs – testes and adrenals – that produce androgens and inhibins, form tumors when inhibin is knocked out in mouse. Together, these data combined with the observation of TGFßRIII downregulation in prostate cancer suggest that there may be a role for inhibin-mediated tumor suppression in prostate. Inhibins have had a controversial role in prostate cancer where its expression has been studied mainly in prostate tissue (Ball et al. 2004); it may be that the relevant perturbation in signaling had not been described prior to these two studies of TGFßRIII in the prostate. If TGFßRIII downregulation in prostate cancer signifies inhibin resistance, it may open a new window on hormonal physiology and an interplay between hormones and cancer.
|
|
Acknowledgements |
|---|
|
References |
|---|
|
TopAbstractTextReferences |
|---|
from Venus or Mars?. Cytokine and Growth Factor Reviews 15 291–296[CrossRef][ISI][Medline]Doll JA, Stellmach VM, Bouck NP, Bergh AR, Lee C, Abramson LP, Cornwell ML, Pins MR, Borensztajn J & Crawford SE 2003 Pigment epithelium-derived factor regulates the vasculature and mass of the prostate and pancreas. Nature Medicine 9 774–780[CrossRef][ISI][Medline]
Elliott RL & Blobe GC 2005 Role of transforming growth factor beta in human cancer. Journal of Clinical Oncology 23 2078–2093
Grady WM, Myeroff LL, Swinler SE, Rajput A, Thiagalingam S, Lutterbaugh JD, Neumann A, Brattain MG, Chang J, Kim SJ et al. 1999 Mutational inactivation of transforming growth factor ß receptor type II in microsatellite stable colon cancers. Cancer Research 59 320–324
Guo Y, Jacobs SC & Kyprianou N 1997 Down-regulation of protein and mRNA expression for transforming growth factor-beta (TGF-ß1) type I and type II receptors in human prostate cancer. International Journal of Cancer 71 573–579[CrossRef][ISI][Medline]
Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH et al. 1996 DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271 350–353[Abstract]
Hanahan D & Weinberg RA 2000 The hallmarks of cancer. Cell 100 57–70[CrossRef][ISI][Medline]
Kim IY, Ahn HJ, Zelner DJ, Shaw JW, Lang S, Kato M, Oefelein MG, Miyazono K, Nemeth JA, Kozlowski JM et al. 1996 Loss of expression of transforming growth factor beta type I and type II receptors correlates with tumor grade in human prostate cancer tissues. Clinical Cancer Research 2 1255–1261[Abstract]
Lewis KA, Gray PC, Blount AL, MacConell LA, Wiater E, Bilezikjian LM & Vale W 2000 Betaglycan binds inhibin and can mediate functional antagonism of activin signalling. Nature 404 411–414[CrossRef][Medline]
Lopez-Casillas F, Payne HM, Andres JL & Massague J 1994 Betaglycan can act as a dual modulator of TGF-ß access to signaling receptors: mapping of ligand binding and GAG attachment sites. Journal of Cell Biology 124 557–568
Massague J, Seoane J & Wotton D 2005 Smad transcription factors. Genes and Development 19 2783–2810
Matzuk MM, Finegold MJ, Su JG, Hsueh AJ & Bradley A 1992 -inhibin is a tumour-suppressor gene with gonadal specificity in mice. Nature 360 313–319[CrossRef][Medline]
Matzuk MM, Finegold MJ, Mather JP, Krummen L, Lu H & Bradley A 1994 Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice. PNAS 91 8817–8821
Nagle RB, Brawer MK, Kittelson J & Clark V 1991 Phenotypic relationships of prostatic intraepithelial neoplasia to invasive prostatic carcinoma. American Journal of Pathology 138 119–128[Abstract]
O'Connor AE & De Kretser DM 2004 Inhibins in normal male physiology. Seminars in Reproductive Medicine 22 177–185[CrossRef][ISI][Medline]
Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A & Chinnaiyan AM 2004 ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 6 1–6[ISI][Medline]
Sharifi N, Gulley JL & Dahut WL 2005 Androgen deprivation therapy for prostate cancer. Journal of the American Medical Association 294 238–244
Sharifi N, Hurt EM, Kawasaki BT & Farrar WL 2007 TGFBR3 loss and consequences in prostate cancer. Prostate 67 301–311[CrossRef][ISI][Medline]
Shi Y & Massague J 2003 Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113 685–700[CrossRef][ISI][Medline]
Tomlins SA, Mehra R, Rhodes DR, Cao X, Wang L, Dhanasekaran SM, Kalyana-Sundaram S, Wei JT, Rubin MA, Pienta KJ et al. 2007 Integrative molecular concept modeling of prostate cancer progression. Nature Genetics 39 41–51[CrossRef][ISI][Medline]
Turley RS, Finger EC, Hempel N, How T, Fields TA & Blobe GC 2007 The type III transforming growth factor-ß receptor as a novel tumor suppressor gene in prostate cancer. Cancer Research 67 1090–1098
Wang XF, Lin HY, Ng-Eaton E, Downward J, Lodish HF & Weinberg RA 1991 Expression cloning and characterization of the TGF-ß type III receptor. Cell 67 797–805[CrossRef][ISI][Medline]
Received in final form 21 August 2007
Accepted 27 August 2007
Made available online as an Accepted Preprint 5 September 2007
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
