Beyond TGFβ: Roles of other TGFβ superfamily members in cancer

Nature Reviews Cancer

Volumn 13, Issue 5, 2013, Pages 328-341

  Wakefield, Lalage M ^a   Hill, Caroline S ^b  

^a NATIONAL CANCER INSTITUTE   (United States)

^b IMPERIAL CANCER RESEARCH FUND   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIVIN; BIIB 015; BONE MORPHOGENETIC PROTEIN 10; BONE MORPHOGENETIC PROTEIN 2; BONE MORPHOGENETIC PROTEIN 4; BONE MORPHOGENETIC PROTEIN 9; DALANTERCEPT; DEXAMETHASONE; GEMCITABINE; GROWTH DIFFERENTIATION FACTOR; GROWTH DIFFERENTIATION FACTOR 1; GROWTH DIFFERENTIATION FACTOR 10; GROWTH DIFFERENTIATION FACTOR 15; GROWTH DIFFERENTIATION FACTOR 3; GROWTH DIFFERENTIATION FACTOR 5; GROWTH DIFFERENTIATION FACTOR 6; GROWTH DIFFERENTIATION FACTOR 9; INHIBIN A; LENALIDOMIDE; LY 2157299; LY 2495655; MYOSTATIN; OSTEOGENIN; PF 03446962; PROTEIN NODAL; SOTATERCEPT; TRANSFORMING GROWTH FACTOR BETA; TRANSFORMING GROWTH FACTOR BETA1; TRANSFORMING GROWTH FACTOR BETA2; TRANSFORMING GROWTH FACTOR BETA3; UNCLASSIFIED DRUG;

ACUTE MEGAKARYOCYTIC LEUKEMIA; ADVANCED CANCER; ANEMIA; BLASTOCYST; BRAIN CANCER; BREAST CANCER; CACHEXIA; CANCER GROWTH; CELL DIFFERENTIATION; CELL MIGRATION; CYTOPLASM; EMBRYO DEVELOPMENT; EMBRYONIC STEM CELL; ENDODERM; ENDOMETRIUM CANCER; ENZYME ACTIVITY; EPITHELIAL MESENCHYMAL TRANSITION; GLIOBLASTOMA; HUMAN; IN VITRO STUDY; LIVER CANCER; LIVER CELL CARCINOMA; MESODERM; METASTASIS; MULTIPLE MYELOMA; MYELOFIBROSIS; MYELOPROLIFERATIVE NEOPLASM; NEOPLASM; OSTEOLYSIS; OVARY CANCER; PANCREAS CANCER; PERITONEUM CANCER; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHENOTYPE; PLEURA MESOTHELIOMA; PREDICTION; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; REVIEW; SIGNAL TRANSDUCTION; SKIN CANCER; SOLID TUMOR; TUMOR MICROENVIRONMENT; UTERUS CANCER; WNT SIGNALING PATHWAY;

ANIMALS; CELL DIFFERENTIATION; CELL PROLIFERATION; EMBRYONIC DEVELOPMENT; HUMANS; MOLECULAR TARGETED THERAPY; NEOPLASMS; NEOPLASTIC STEM CELLS; PROTEIN PROCESSING, POST-TRANSLATIONAL; SIGNAL TRANSDUCTION; TGF-BETA SUPERFAMILY PROTEINS; TUMOR MICROENVIRONMENT;

EID: 84876817355     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc3500     Document Type: Review

References (113)

1. Hardwick, J. C., Kodach, L. L., Offerhaus, G. J. & van den Brink, G. R. Bone morphogenetic protein signalling in colorectal cancer. Nature Rev. Cancer 8, 806-812 (2008).
2. Oshimori, N. & Fuchs, E. The Harmonies played by TGFβ in stem cell biology. Cell Stem Cell 11, 751-764 (2012).
3. Wu, M. Y. & Hill, C. S. TGFβ superfamily signaling in embryonic development and homeostasis. Dev. Cell 16, 329-343 (2009).
4. Huminiecki, L., et al. Emergence, development and diversification of the TGFβ signalling pathway within the animal kingdom. BMC Evol. Biol. 9, 28 (2009).
5. Pang, K., Ryan, J. F., Baxevanis, A. D. & Martindale, M. Q. Evolution of the TGFβ signaling pathway and its potential role in the ctenophore, Mnemiopsis leidyi. PLoS ONE 6, e24152 (2011).
6. Constam, D. B. & Robertson, E. J. Regulation of bone morphogenetic protein activity by pro domains and proprotein convertases. J. Cell Biol. 144, 139-149 (1999).
7. Constam, D. B. & Robertson, E. J. SPC4/PACE4 regulates a TGFβ signaling network during axis formation. Genes Dev. 14, 1146-1155 (2000).
8. Mueller, T. D. & Nickel, J. Promiscuity and specificity in BMP receptor activation. FEBS Lett. 586, 1846-1859 (2012).
9. Shi, Y. & Massague, J. Mechanisms of TGFβ signaling from cell membrane to the nucleus. Cell 113, 685-700 (2003).
10. Kang, J. S., Liu, C. & Derynck, R. New regulatory mechanisms of TGFβ receptor function. Trends Cell Biol. 19, 385-394 (2009).
11. Goumans, M. J., et al. Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFβ/ALK5 signaling. Mol. Cell 12, 817-828 (2003).
12. Daly, A. C., Randall, R. A. & Hill, C. S. Transforming growth factor ?induced Smad1/5 phosphorylation in epithelial cells is mediated by novel receptor complexes and is essential for anchorage-independent growth. Mol. Cell. Biol. 28, 6889-6902 (2008).
13. Liu, I. M., et al. TGFβ-stimulated Smad1/5 phosphorylation requires the ALK5 L45 loop and mediates the pro-migratory TGFβ switch. EMBO J. 28, 88-98 (2009).
14. Wrighton, K. H., Lin, X., Yu, P. B. & Feng, X. H. Transforming growth factor ? can stimulate Smad1 phosphorylation independently of bone morphogenic protein receptors. J. Biol. Chem. 284, 9755-9763 (2009).
15. Chu, G. C., Dunn, N. R., Anderson, D. C., Oxburgh, L. & Robertson, E. J. Differential requirements for Smad4 in TGFβ-dependent patterning of the early mouse embryo. Development 131, 3501-3512 (2004).
16. Levy, L. & Hill, C. S. Smad4 dependency defines two classes of transforming growth factor ? (TGFβ) target genes and distinguishes TGFβinduced epithelial-mesenchymal transition from its antiproliferative and migratory responses. Mol. Cell. Biol. 25, 8108-8125 (2005).
17. Gronroos, E., et al. Transforming growth factor ? inhibits bone morphogenetic protein-induced transcription through novel phosphorylated Smad1/5Smad3 complexes. Mol. Cell. Biol. 32, 2904-2916 (2012).
18. Ross, S. & Hill, C. S. How the Smads regulate transcription. Int. J. Biochem. Cell Biol. 40, 383-408 (2008).
19. Chen, X., Rubock, M. J. & Whitman, M. A transcriptional partner for MAD proteins in TGFβ signalling. Nature 383, 691-696 (1996).
20. Bruce, D. L. & Sapkota, G. P. Phosphatases in SMAD regulation. FEBS Lett. 586, 1897-1905 (2012).
21. Schmierer, B. & Hill, C. S. TGFβ-SMAD signal transduction: molecular specificity and functional flexibility. Nature Rev. Mol. Cell Biol. 8, 970-982 (2007).
22. Ramel, M. C. & Hill, C. S. Spatial regulation of BMP activity. FEBS Lett. 586, 1929-1941 (2012).
23. Massague, J. TGFβ signalling in context. Nature Rev. Mol. Cell Biol. 13, 616-630 (2012).
24. Singh, A. M., et al. Signaling network crosstalk in human pluripotent cells: a Smad2/3regulated switch that controls the balance between self-renewal and differentiation. Cell Stem Cell 10, 312-326 (2012).
25. Levine, A. J., Levine, Z. J. & Brivanlou, A. H. GDF3 is a BMP inhibitor that can activate Nodal signaling only at very high doses. Dev. Biol. 325, 43-48 (2009).
26. Candia, A. F., et al. Cellular interpretation of multiple TGFβ signals: intracellular antagonism between activin/BVg1 and BMP2/4 signaling mediated by Smads. Development 124, 4467-4480 (1997).
27. Itoh, S. & ten Dijke, P. Negative regulation of TGFβ receptor/Smad signal transduction. Curr. Opin. Cell Biol. 19, 176-184 (2007).
28. Galvin, K. E., Travis, E. D., Yee, D., Magnuson, T. & Vivian, J. L. Nodal signaling regulates the bone morphogenic protein pluripotency pathway in mouse embryonic stem cells. J. Biol. Chem. 285, 19747-19756 (2010).
29. Mesnard, D., Guzman-Ayala, M. & Constam, D. B. Nodal specifies embryonic visceral endoderm and sustains pluripotent cells in the epiblast before overt axial patterning. Development 133, 2497-2505 (2006).
30. Arnold, S. J. & Robertson, E. J. Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo. Nature Rev. Mol. Cell Biol. 10, 91-103 (2009).
31. Schier, A. F. Nodal signaling in vertebrate development. Annu. Rev. Cell Dev. Biol. 19, 589-621 (2003).
32. Bianco, C., et al. Role of Cripto1 in stem cell maintenance and malignant progression. Am. J. Pathol. 177, 532-540 (2010).
33. Pera, M. F. & Tam, P. P. Extrinsic regulation of pluripotent stem cells. Nature 465, 713-720 (2010).
34. Vallier, L., et al. Activin/Nodal signalling maintains pluripotency by controlling Nanog expression. Development 136, 1339-1349 (2009).
35. Miyazono, K., Kamiya, Y. & Morikawa, M. Bone morphogenetic protein receptors and signal transduction. J. Biochem. 147, 35-51 (2010).
36. Wagner, D. O., et al. BMPs: from bone to body morphogenetic proteins. Sci. Signal. 3, mr1 (2010).
37. Strizzi, L., Hardy, K. M., Kirschmann, D. A., Ahrlund-Richter, L. & Hendrix, M. J. Nodal expression and detection in cancer: experience and challenges. Cancer Res. 72, 1915-1920 (2012).
38. Magee, J. A., Piskounova, E. & Morrison, S. J. Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell 21, 283-296 (2012).
39. Blanpain, C. & Fuchs, E. Epidermal homeostasis: a balancing act of stem cells in the skin. Nature Rev. Mol. Cell Biol. 10, 207-217 (2009).
40. Bond, A. M., Bhalala, O. G. & Kessler, J. A. The dynamic role of bone morphogenetic proteins in neural stem cell fate and maturation. Dev. Neurobiol. 72, 1068-1084 (2012).
41. He, X. C., et al. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt?catenin signaling. Nature Genet. 36, 1117-1121 (2004).
42. Kosinski, C., et al. Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors. Proc. Natl Acad. Sci. USA 104, 15418-15423 (2007).
43. Waite, K. A. & Eng, C. From developmental disorder to heritable cancer: it's all in the BMP/TGFβ family. Nature Rev. Genet. 4, 763-773 (2003).
44. Jaeger, E., et al. Hereditary mixed polyposis syndrome is caused by a 40kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. Nature Genet. 44, 699-703 (2012).
45. Haramis, A. P., et al. De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. Science 303, 1684-1686 (2004).
46. Itasaki, N. & Hoppler, S. Crosstalk between Wnt and bone morphogenic protein signaling: a turbulent relationship. Dev. Dyn. 239, 16-33 (2010).
47. Auclair, B. A., Benoit, Y. D., Rivard, N., Mishina, Y. & Perreault, N. Bone morphogenetic protein signaling is essential for terminal differentiation of the intestinal secretory cell lineage. Gastroenterology 133, 887-896 (2007).
48. Scheel, C., et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 145, 926-940 (2011).
49. Panchision, D. M. & McKay, R. D. The control of neural stem cells by morphogenic signals. Curr. Opin. Genet. Dev. 12, 478-487 (2002).
50. Piccirillo, S. G., et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444, 761-765 (2006).
51. Lee, J., et al. Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell 13, 69-80 (2008).
52. Sneddon, J. B., et al. Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation. Proc. Natl Acad. Sci. USA 103, 14842-14847 (2006).
53. Buijs, J. T., et al. The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation. Oncogene 31, 2164-2174 (2012).
54. Upadhyay, G., et al. Stem cell antigen1 enhances tumorigenicity by disruption of growth differentiation factor10 (GDF10)-dependent TGFβ signaling. Proc. Natl Acad. Sci. USA 108, 7820-7825 (2011).
55. Zhang, L., et al. BMP4 administration induces differentiation of CD133+ hepatic cancer stem cells, blocking their contributions to hepatocellular carcinoma. Cancer Res. 72, 4276-4285 (2012).
56. Gruber, T. A., et al. An Inv(16)(p13.3q24.3)-encoded CBFA2T3GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia. Cancer Cell 22, 683-697 (2012).
57. McLean, K., et al. Human ovarian carcinoma-associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production. J. Clin. Invest. 121, 3206-3219 (2011).
58. Quail, D. F., Siegers, G. M., Jewer, M. & Postovit, L. M. Nodal signalling in embryogenesis and tumourigenesis. Int. J. Biochem. Cell Biol. 45, 885-898 (2013).
59. Topczewska, J. M., et al. Embryonic and tumorigenic pathways converge via Nodal signaling: role in melanoma aggressiveness. Nature Med. 12, 925-932 (2006).
60. Lawrence, M. G., et al. Reactivation of embryonic nodal signaling is associated with tumor progression and promotes the growth of prostate cancer cells. Prostate 71, 1198-1209 (2011).
61. Strizzi, L., et al. Potential for the embryonic morphogen Nodal as a prognostic and predictive biomarker in breast cancer. Breast Cancer Res. 14, R75 (2011).
62. Spiller, C. M., et al. Endogenous Nodal signaling regulates germ cell potency during mammalian testis development. Development 139, 4123-4132 (2012).
63. Bianco, C. & Salomon, D. S. Targeting the embryonic gene Cripto1 in cancer and beyond. Expert Opin. Ther. Pat. 20, 1739-1749 (2010).
64. Lonardo, E., et al. Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy. Cell Stem Cell 9, 433-446 (2011).
65. Postovit, L. M., et al. Human embryonic stem cell microenvironment suppresses the tumorigenic phenotype of aggressive cancer cells. Proc. Natl Acad. Sci. USA 105, 4329-4334 (2008).
66. Hardy, K. M., et al. Regulation of the embryonic morphogen Nodal by Notch4 facilitates manifestation of the aggressive melanoma phenotype. Cancer Res. 70, 10340-10350 (2010).
67. Costa, F. F., et al. Epigenetically reprogramming metastatic tumor cells with an embryonic microenvironment. Epigenomics 1, 387-398 (2009).
68. Seftor, R. E., et al. Tumor cell vasculogenic mimicry: from controversy to therapeutic promise. Am. J. Pathol. 181, 1115-1125 (2012).
69. Quail, D. F., et al. Embryonic protein nodal promotes breast cancer vascularization. Cancer Res. 72, 3851-3863 (2012).
70. Lonardo, E., Frias-Aldeguer, J., Hermann, P. C. & Heeschen, C. Pancreatic stellate cells form a niche for cancer stem cells and promote their self-renewal and invasiveness. Cell Cycle 11, 1282-1290 (2012).
71. Ocana, O. H., et al. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer prrx1. Cancer Cell 22, 709-724 (2012).
72. Tsai, J. H., Donaher, J. L., Murphy, D. A., Chau, S. & Yang, J. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22, 725-736 (2012).
73. Brabletz, T. To differentiate or not-routes towards metastasis. Nature Rev. Cancer 12, 425-436 (2012).
74. Polyak, K. & Weinberg, R. A. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nature Rev. Cancer 9, 265-273 (2009).
75. Buijs, J. T., et al. BMP7, a putative regulator of epithelial homeostasis in the human prostate, is a potent inhibitor of prostate cancer bone metastasis in vivo. Am. J. Pathol. 171, 1047-1057 (2007).
76. Ding, Z., et al. SMAD4dependent barrier constrains prostate cancer growth and metastatic progression. Nature 470, 269-273 (2011).
77. Bailey, J. M., Singh, P. K. & Hollingsworth, M. A. Cancer metastasis facilitated by developmental pathways: Sonic hedgehog, Notch, and bone morphogenic proteins. J. Cell Biochem. 102, 829-839 (2007).
78. Gao, H., et al. The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell 150, 764-779 (2012).
79. Kobayashi, A., et al. Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J. Exp. Med. 208, 2641-2655 (2011).
80. Samavarchi-Tehrani, P., et al. Functional genomics reveals a BMP-driven mesenchymal-toepithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell 7, 64-77 (2010).
81. Tarragona, M., et al. Identification of NOG as a specific breast cancer bone metastasis-supporting gene. J. Biol. Chem. 287, 21346-21355 (2012).
82. Katsuno, Y., et al. Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway. Oncogene 27, 6322-6333 (2008).
83. Nishimori, H., Ehata, S., Suzuki, H. I., Katsuno, Y. & Miyazono, K. Prostate cancer cells and bone stromal cells mutually interact with each other through bone morphogenetic protein-mediated signals. J. Biol. Chem. 287, 20037-20046 (2012).
84. Cunha, S. I. & Pietras, K. ALK1 as an emerging target for antiangiogenic therapy of cancer. Blood 117, 6999-7006 (2011).
85. Cunha, S. I., et al. Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis. J. Exp. Med. 207, 85-100 (2010).
86. HuLowe, D. D., et al. Targeting activin receptor-like kinase 1 inhibits angiogenesis and tumorigenesis through a mechanism of action complementary to anti-VEGF therapies. Cancer Res. 71, 1362-1373 (2011).
87. Strizzi, L., et al. Nodal as a biomarker for melanoma progression and a new therapeutic target for clinical intervention. Expert Rev. Dermatol. 4, 67-78 (2009).
88. Hedger, M. P., Winnall, W. R., Phillips, D. J. & de Kretser, D. M. The regulation and functions of activin and follistatin in inflammation and immunity. Vitam. Horm. 85, 255-297 (2011).
89. Antsiferova, M., et al. Activin enhances skin tumourigenesis and malignant progression by inducing a pro-response. Nature Commun. 2, 576 (2011).
90. Roth, P., et al. GDF15 contributes to proliferation and immune escape of malignant gliomas. Clin. Cancer Res. 16, 3851-3859 (2010).
91. Corre, J., et al. Bioactivity and prognostic significance of growth differentiation factor GDF15 secreted by bone marrow mesenchymal stem cells in multiple myeloma. Cancer Res. 72, 1395-1406 (2012).
92. Harada, K., et al. Serum immunoreactive activin A levels in normal subjects and patients with various diseases. J. Clin. Endocrinol. Metab. 81, 2125-2130 (1996).
93. Vallet, S., et al. Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. Proc. Natl Acad. Sci. USA 107, 5124-5129 (2010).
94. Zhou, X., et al. Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 142, 531-543 (2010).
95. Fields, S. Z., et al. Activin receptor antagonists for cancer-related anemia and bone disease. Expert Opin. Investig. Drugs 22, 87-101 (2013).
96. Pellagatti, A., et al. Lenalidomide inhibits the malignant clone and upregulates the SPARC gene mapping to the commonly deleted region in 5q-syndrome patients. Proc. Natl Acad. Sci. USA 104, 11406-11411 (2007).
97. Matzuk, M. M., et al. Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice. Proc. Natl Acad. Sci. USA 91, 8817-8821 (1994).
98. Johnen, H., et al. Tumor-induced anorexia and weight loss are mediated by the TGFβ superfamily cytokine MIC1. Nature Med. 13, 1333-1340 (2007).
99. Zimmers, T. A., et al. Induction of cachexia in mice by systemically administered myostatin. Science 296, 1486-1488 (2002).
100. Saad, F., et al. Pathologic fractures correlate with reduced survival in patients with malignant bone disease. Cancer 110, 1860-1867 (2007).
101. Baud'huin, M., et al. A soluble bone morphogenetic protein type IA receptor increases bone mass and bone strength. Proc. Natl Acad. Sci. USA 109, 12207-12212 (2012).
102. Pearsall, R. S., et al. A soluble activin type IIA receptor induces bone formation and improves skeletal integrity. Proc. Natl Acad. Sci. USA 105, 7082-7087 (2008).
103. Vogt, J., Traynor, R. & Sapkota, G. P. The specificities of small molecule inhibitors of the TGFβ and BMP pathways. Cell. Signal. 23, 1831-1842 (2011).
104. Rangel, M. C., et al. Role of Cripto1 during epithelial-tomesenchymal transition in development and cancer. Am. J. Pathol. 180, 2188-2200 (2012).
105. Akhurst, R. J. & Hata, A. Targeting the TGFβ signalling pathway in disease. Nature Rev. Drug Discov. 11, 790-811 (2012).
106. Alison, M. R., Lin, W. R., Lim, S. M. & Nicholson, L. J. Cancer stem cells: in the line of fire. Cancer Treat. Rev. 38, 589-598 (2012).
107. Lombardo, Y., et al. Bone morphogenetic protein 4 induces differentiation of colorectal cancer stem cells and increases their response to chemotherapy in mice. Gastroenterology 140, 297-309 (2011).
108. Ivanova, T., et al. Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer. Gut 62, 22-33 (2013).
109. Antsiferova, M. & Werner, S. The bright and the dark sides of activin in wound healing and cancer. J. Cell Sci. 125, 3929-3937 (2012).
110. Weigelt, B. & Downward, J. Genomic determinants of PI3K pathway inhibitor response in Cancer. Front. Oncol. 2, 109 (2012).
111. Kodach, L. L., et al. Statins augment the chemosensitivity of colorectal cancer cells inducing epigenetic reprogramming and reducing colorectal cancer cell 'stemness' via the bone morphogenetic protein pathway. Gut 60, 1544-1553 (2011).
112. Kugimiya, F., et al. Mechanism of osteogenic induction by FK506 via BMP/Smad pathways. Biochem. Biophys. Res. Commun. 338, 872-879 (2005).
113. van der Poel, H. G., Hanrahan, C., Zhong, H. & Simons, J. W. Rapamycin induces Smad activity in prostate cancer cell lines. Urol. Res. 30, 380-386 (2003).