The Effects of TGF-β Signaling on Cancer Cells and Cancer Stem Cells in the Bone Microenvironment
Abstract
:1. Introduction
2. Results
2.1. Suppression of TGF-β Signaling by a TGF-β Receptor 1 Kinase Inhibitor (R1-Ki) in the Bone Micro-E
2.2. The Effects of TGF-β on Tumor Growth and Cell Proliferation
2.3. The Effect of TGF-β Signaling on the Induction of the Necrotic Area and Apoptosis
2.4. The Effect of TGF-β Signaling on the Induction of CSC in the Bone Micro-E
2.5. The Involvement of ERK1/2, AKT, and BMP Signaling in Tumor Growth within the Bone and subQ Micro-Es
3. Discussion
4. Materials and Methods
4.1. Tumor Cell Lines and Tissue Preparation
4.2. Immunohistochemistry
4.3. Definition of Tumor Bone Micro-E and Tumor subQ’s Micro-E.
4.4. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Buonomo, O.C.; Caredda, E.; Portarena, I.; Vanni, G.; Orlandi, A.; Bagni, C.; Petrella, G.; Palombi, L.; Orsaria, P. New insights into the metastatic behavior after breast cancer surgery, according to well-established clinicopathological variables and molecular subtypes. PLoS ONE 2017, 12, e0184680. [Google Scholar] [CrossRef] [PubMed]
- Kennecke, H.; Yerushalmi, R.; Woods, R.; Cheang, M.C.; Voduc, D.; Speers, C.H.; Nielsen, T.O.; Gelmon, K. Metastatic behavior of breast cancer subtypes. J. Clin. Oncol. 2010, 28, 3271–3277. [Google Scholar] [CrossRef] [PubMed]
- Coleman, R.E. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin. Cancer Res. 2006, 12, 6243s–6249s. [Google Scholar] [CrossRef]
- Weigelt, B.; Peterse, J.L.; van’t Veer, L.J. Breast cancer metastasis: Markers and models. Nat. Rev. Cancer 2005, 5, 591–602. [Google Scholar] [CrossRef]
- Le, M.G.; Arriagada, R.; Spielmann, M.; Guinebretiere, J.M.; Rochard, F. Prognostic factors for death after an isolated local recurrence in patients with early-stage breast carcinoma. Cancer 2002, 94, 2813–2820. [Google Scholar] [CrossRef]
- Guo, B.; Villeneuve, D.J.; Hembruff, S.L.; Kirwan, A.F.; Blais, D.E.; Bonin, M.; Parissenti, A.M. Cross-resistance studies of isogenic drug-resistant breast tumor cell lines support recent clinical evidence suggesting that sensitivity to paclitaxel may be strongly compromised by prior doxorubicin exposure. Breast Cancer Res. Treat. 2004, 85, 31–51. [Google Scholar] [CrossRef]
- Buenrostro, D.; Mulcrone, P.L.; Owens, P.; Sterling, J.A. The Bone Microenvironment: A Fertile Soil for Tumor Growth. Curr. Osteoporos. Rep. 2016, 14, 151–158. [Google Scholar] [CrossRef]
- Paget, S. The distribution of secondary growths in cancer of the breast. Cancer Metastasis Rev. 1989, 8, 98–101. [Google Scholar] [CrossRef]
- Patel, S.A.; Dave, M.A.; Murthy, R.G.; Helmy, K.Y.; Rameshwar, P. Metastatic breast cancer cells in the bone marrow microenvironment: Novel insights into oncoprotection. Oncol. Rev. 2011, 5, 93–102. [Google Scholar] [CrossRef]
- Mundy, G.R. Metastasis to bone: Causes, consequences and therapeutic opportunities. Nat. Rev. Cancer 2002, 2, 584–593. [Google Scholar] [CrossRef] [PubMed]
- Siclari, V.A.; Guise, T.A.; Chirgwin, J.M. Molecular interactions between breast cancer cells and the bone microenvironment drive skeletal metastases. Cancer Metastasis Rev. 2006, 25, 621–633. [Google Scholar] [CrossRef] [PubMed]
- Sosnoski, D.M.; Krishnan, V.; Kraemer, W.J.; Dunn-Lewis, C.; Mastro, A.M. Changes in Cytokines of the Bone Microenvironment during Breast Cancer Metastasis. Int. J. Breast Cancer 2012, 2012, 160265. [Google Scholar] [CrossRef] [PubMed]
- Futakuchi, M.; Nitanda, T.; Ando, S.; Matsumoto, H.; Yoshimoto, E.; Fukamachi, K.; Suzui, M. Therapeutic and Preventive Effects of Osteoclastogenesis Inhibitory Factor on Osteolysis, Proliferation of Mammary Tumor Cell and Induction of Cancer Stem Cells in the Bone Microenvironment. Int. J. Mol. Sci. 2018, 19, 888. [Google Scholar] [CrossRef]
- Li, F.; Tiede, B.; Massague, J.; Kang, Y. Beyond tumorigenesis: Cancer stem cells in metastasis. Cell Res. 2007, 17, 3–14. [Google Scholar] [CrossRef]
- Sato, S.; Futakuchi, M.; Ogawa, K.; Asamoto, M.; Nakao, K.; Asai, K.; Shirai, T. Transforming growth factor β derived from bone matrix promotes cell proliferation of prostate cancer and osteoclast activation-associated osteolysis in the bone microenvironment. Cancer Sci. 2008, 99, 316–323. [Google Scholar] [CrossRef]
- Futakuchi, M.; Nannuru, K.C.; Varney, M.L.; Sadanandam, A.; Nakao, K.; Asai, K.; Shirai, T.; Sato, S.Y.; Singh, R.K. Transforming growth factor-β signaling at the tumor-bone interface promotes mammary tumor growth and osteoclast activation. Cancer Sci. 2009, 100, 71–81. [Google Scholar] [CrossRef]
- Lynch, C.C.; Hikosaka, A.; Acuff, H.B.; Martin, M.D.; Kawai, N.; Singh, R.K.; Vargo-Gogola, T.C.; Begtrup, J.L.; Peterson, T.E.; Fingleton, B.; et al. MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell 2005, 7, 485–496. [Google Scholar] [CrossRef] [Green Version]
- Futakuchi, M.; Singh, R.K. Animal model for mammary tumor growth in the bone microenvironment. Breast Cancer (Tokyo Jpn.) 2013, 20, 195–203. [Google Scholar] [CrossRef]
- Futakuchi, M.; Fukamachi, K.; Suzui, M. Heterogeneity of tumor cells in the bone microenvironment: Mechanisms and therapeutic targets for bone metastasis of prostate or breast cancer. Adv. Drug Deliv. Rev. 2016, 99, 206–211. [Google Scholar] [CrossRef]
- Talmadge, J.E.; Fidler, I.J. AACR centennial series: The biology of cancer metastasis: Historical perspective. Cancer Res. 2010, 70, 5649–5669. [Google Scholar] [CrossRef] [PubMed]
- Iguchi, H.; Tanaka, S.; Ozawa, Y.; Kashiwakuma, T.; Kimura, T.; Hiraga, T.; Ozawa, H.; Kono, A. An experimental model of bone metastasis by human lung cancer cells: The role of parathyroid hormone-related protein in bone metastasis. Cancer Res. 1996, 56, 4040–4043. [Google Scholar] [PubMed]
- Yonou, H.; Yokose, T.; Kamijo, T.; Kanomata, N.; Hasebe, T.; Nagai, K.; Hatano, T.; Ogawa, Y.; Ochiai, A. Establishment of a novel species- and tissue-specific metastasis model of human prostate cancer in humanized non-obese diabetic/severe combined immunodeficient mice engrafted with human adult lung and bone. Cancer Res. 2001, 61, 2177–2182. [Google Scholar] [PubMed]
- Murphy, B.O.; Joshi, S.; Kessinger, A.; Reed, E.; Sharp, J.G. A murine model of bone marrow micrometastasis in breast cancer. Clin. Exp. Metastasis 2002, 19, 561–569. [Google Scholar] [CrossRef]
- Sells Galvin, R.J.; Gatlin, C.L.; Horn, J.W.; Fuson, T.R. TGF-β enhances osteoclast differentiation in hematopoietic cell cultures stimulated with RANKL and M-CSF. Biochem. Biophys. Res. Commun. 1999, 265, 233–239. [Google Scholar] [CrossRef]
- Houde, N.; Chamoux, E.; Bisson, M.; Roux, S. Transforming growth factor-β1 (TGF-β1) induces human osteoclast apoptosis by up-regulating Bim. J. Biol. Chem. 2009, 284, 23397–23404. [Google Scholar] [CrossRef]
- Nakano, M.; Kikushige, Y.; Miyawaki, K.; Kunisaki, Y.; Mizuno, S.; Takenaka, K.; Tamura, S.; Okumura, Y.; Ito, M.; Ariyama, H.; et al. Dedifferentiation process driven by TGF-β signaling enhances stem cell properties in human colorectal cancer. Oncogene 2019, 38, 780–793. [Google Scholar] [CrossRef]
- Carmona-Fontaine, C.; Deforet, M.; Akkari, L.; Thompson, C.B.; Joyce, J.A.; Xavier, J.B. Metabolic origins of spatial organization in the tumor microenvironment. Proc. Natl. Acad. Sci. USA 2017, 114, 2934–2939. [Google Scholar] [CrossRef] [Green Version]
- Yuan, Y. Spatial Heterogeneity in the Tumor Microenvironment. Cold Spring Harb. Perspect. Med. 2016, 6, a026583. [Google Scholar] [CrossRef] [Green Version]
- Dai, Z.; Locasale, J.W. Metabolic pattern formation in the tumor microenvironment. Mol. Syst. Biol. 2017, 13, 915. [Google Scholar] [CrossRef]
- Li, L.; Neaves, W.B. Normal stem cells and cancer stem cells: The niche matters. Cancer Res. 2006, 66, 4553–4557. [Google Scholar] [CrossRef] [PubMed]
- Bottinger, E.P.; Jakubczak, J.L.; Haines, D.C.; Bagnall, K.; Wakefield, L.M. Transgenic mice overexpressing a dominant-negative mutant type II transforming growth factor β receptor show enhanced tumorigenesis in the mammary gland and lung in response to the carcinogen 7,12-dimethylbenz-[a]-anthracene. Cancer Res. 1997, 57, 5564–5570. [Google Scholar] [PubMed]
- Tang, B.; Bottinger, E.P.; Jakowlew, S.B.; Bagnall, K.M.; Mariano, J.; Anver, M.R.; Letterio, J.J.; Wakefield, L.M. Transforming growth factor-β1 is a new form of tumor suppressor with true haploid insufficiency. Nat. Med. 1998, 4, 802–807. [Google Scholar] [CrossRef] [PubMed]
- Daroqui, M.C.; Vazquez, P.; Bal de Kier Joffe, E.; Bakin, A.V.; Puricelli, L.I. TGF-β autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression. Oncol. Rep. 2012, 28, 567–575. [Google Scholar] [CrossRef]
- Oft, M.; Peli, J.; Rudaz, C.; Schwarz, H.; Beug, H.; Reichmann, E. TGF-β1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev. 1996, 10, 2462–2477. [Google Scholar] [CrossRef]
- Yu, Q.; Stamenkovic, I. Transforming growth factor-β facilitates breast carcinoma metastasis by promoting tumor cell survival. Clin. Exp. Metastasis 2004, 21, 235–242. [Google Scholar] [CrossRef]
- Connolly, E.C.; Freimuth, J.; Akhurst, R.J. Complexities of TGF-β targeted cancer therapy. Int. J. Biol. Sci. 2012, 8, 964–978. [Google Scholar] [CrossRef]
- Roberts, A.B.; Wakefield, L.M. The two faces of transforming growth factor β in carcinogenesis. Proc. Natl. Acad. Sci. USA 2003, 100, 8621–8623. [Google Scholar] [CrossRef]
- Biswas, S.; Guix, M.; Rinehart, C.; Dugger, T.C.; Chytil, A.; Moses, H.L.; Freeman, M.L.; Arteaga, C.L. Inhibition of TGF-β with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression. J. Clin. Invest. 2007, 117, 1305–1313. [Google Scholar] [CrossRef]
- Mohammad, K.S.; Javelaud, D.; Fournier, P.G.; Niewolna, M.; McKenna, C.R.; Peng, X.H.; Duong, V.; Dunn, L.K.; Mauviel, A.; Guise, T.A. TGF-β-RI kinase inhibitor SD-208 reduces the development and progression of melanoma bone metastases. Cancer Res. 2011, 71, 175–184. [Google Scholar] [CrossRef]
- Berry, D.A. Biomarker studies and other difficult inferential problems: Statistical caveats. Semin. Oncol. 2007, 34, S17–S22. [Google Scholar] [CrossRef] [PubMed]
- Garraway, I.P. Targeting the RANKL pathway: Putting the brakes on prostate cancer progression in bone. J. Clin. Oncol. 2013, 31, 3838–3840. [Google Scholar] [CrossRef] [PubMed]
- Saad, F.; Eastham, J. Zoledronic Acid improves clinical outcomes when administered before onset of bone pain in patients with prostate cancer. Urology 2010, 76, 1175–1181. [Google Scholar] [CrossRef] [PubMed]
- Piva, M.; Domenici, G.; Iriondo, O.; Rabano, M.; Simoes, B.M.; Comaills, V.; Barredo, I.; Lopez-Ruiz, J.A.; Zabalza, I.; Kypta, R.; et al. Sox2 promotes tamoxifen resistance in breast cancer cells. Embo. Mol. Med. 2014, 6, 66–79. [Google Scholar] [CrossRef]
- Lengerke, C.; Fehm, T.; Kurth, R.; Neubauer, H.; Scheble, V.; Muller, F.; Schneider, F.; Petersen, K.; Wallwiener, D.; Kanz, L.; et al. Expression of the embryonic stem cell marker SOX2 in early-stage breast carcinoma. BMC Cancer 2011, 11, 42. [Google Scholar] [CrossRef]
- Leis, O.; Eguiara, A.; Lopez-Arribillaga, E.; Alberdi, M.J.; Hernandez-Garcia, S.; Elorriaga, K.; Pandiella, A.; Rezola, R.; Martin, A.G. Sox2 expression in breast tumours and activation in breast cancer stem cells. Oncogene 2012, 31, 1354–1365. [Google Scholar] [CrossRef]
- Jia, X.; Li, X.; Xu, Y.; Zhang, S.; Mou, W.; Liu, Y.; Liu, Y.; Lv, D.; Liu, C.H.; Tan, X.; et al. SOX2 promotes tumorigenesis and increases the anti-apoptotic property of human prostate cancer cell. J. Mol. Cell Biol. 2011, 3, 230–238. [Google Scholar] [CrossRef]
- Xiang, R.; Liao, D.; Cheng, T.; Zhou, H.; Shi, Q.; Chuang, T.S.; Markowitz, D.; Reisfeld, R.A.; Luo, Y. Downregulation of transcription factor SOX2 in cancer stem cells suppresses growth and metastasis of lung cancer. Br. J. Cancer 2011, 104, 1410–1417. [Google Scholar] [CrossRef]
- Liu, X.F.; Yang, W.T.; Xu, R.; Liu, J.T.; Zheng, P.S. Cervical cancer cells with positive Sox2 expression exhibit the properties of cancer stem cells. PLoS ONE 2014, 9, e87092. [Google Scholar] [CrossRef]
- Wen, Y.; Hou, Y.; Huang, Z.; Cai, J.; Wang, Z. SOX2 is required to maintain cancer stem cells in ovarian cancer. Cancer Sci. 2017, 108, 719–731. [Google Scholar] [CrossRef] [Green Version]
- Zhu, F.; Qian, W.; Zhang, H.; Liang, Y.; Wu, M.; Zhang, Y.; Zhang, X.; Gao, Q.; Li, Y. SOX2 Is a Marker for Stem-like Tumor Cells in Bladder Cancer. Stem. Cell Rep. 2017, 9, 429–437. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yan, M.; Yang, X.; Wang, L.; Clark, D.; Zuo, H.; Ye, D.; Chen, W.; Zhang, P. Plasma membrane proteomics of tumor spheres identify CD166 as a novel marker for cancer stem-like cells in head and neck squamous cell carcinoma. Mol. Cell Proteom. 2013, 12, 3271–3284. [Google Scholar] [CrossRef] [PubMed]
- Dalerba, P.; Dylla, S.J.; Park, I.K.; Liu, R.; Wang, X.; Cho, R.W.; Hoey, T.; Gurney, A.; Huang, E.H.; Simeone, D.M.; et al. Phenotypic characterization of human colorectal cancer stem cells. Proc. Natl. Acad. Sci. USA 2007, 104, 10158–10163. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Barcellos-de-Souza, P.; Comito, G.; Pons-Segura, C.; Taddei, M.L.; Gori, V.; Becherucci, V.; Bambi, F.; Margheri, F.; Laurenzana, A.; Del Rosso, M.; et al. Mesenchymal Stem Cells are Recruited and Activated into Carcinoma-Associated Fibroblasts by Prostate Cancer Microenvironment-Derived TGF-β1. Stem Cells 2016, 34, 2536–2547. [Google Scholar] [CrossRef]
- Wang, Y.; Yu, Y.; Tsuyada, A.; Ren, X.; Wu, X.; Stubblefield, K.; Rankin-Gee, E.K.; Wang, S.E. Transforming growth factor-β regulates the sphere-initiating stem cell-like feature in breast cancer through miRNA-181 and ATM. Oncogene 2011, 30, 1470–1480. [Google Scholar] [CrossRef]
- Pang, R.W.; Poon, R.T. Cancer stem cell as a potential therapeutic target in hepatocellular carcinoma. Curr. Cancer Drug Targets 2012, 12, 1081–1094. [Google Scholar]
- Yu, D.; Shin, H.S.; Lee, Y.S.; Lee, Y.C. miR-106b modulates cancer stem cell characteristics through TGF-β/Smad signaling in CD44-positive gastric cancer cells. Lab. Invest. 2014, 94, 1370–1381. [Google Scholar] [CrossRef]
- Jiang, F.; Mu, J.; Wang, X.; Ye, X.; Si, L.; Ning, S.; Li, Z.; Li, Y. The repressive effect of miR-148a on TGF β-SMADs signal pathway is involved in the glabridin-induced inhibition of the cancer stem cells-like properties in hepatocellular carcinoma cells. PLoS ONE 2014, 9, e96698. [Google Scholar] [CrossRef]
- Wu, L.; Han, L.; Zhou, C.; Wei, W.; Chen, X.; Yi, H.; Wu, X.; Bai, X.; Guo, S.; Yu, Y.; et al. TGF-β1-induced CK17 enhances cancer stem cell-like properties rather than EMT in promoting cervical cancer metastasis via the ERK1/2-MZF1 signaling pathway. Febs J. 2017, 284, 3000–3017. [Google Scholar] [CrossRef]
- Kohno, M.; Pouyssegur, J. Targeting the ERK signaling pathway in cancer therapy. Ann. Med. 2006, 38, 200–211. [Google Scholar] [CrossRef]
- Dong, F.; Tian, H.; Yan, S.; Li, L.; Dong, X.; Wang, F.; Li, J.; Li, C.; Cao, Z.; Liu, X.; et al. Dihydroartemisinin inhibits endothelial cell proliferation through the suppression of the ERK signaling pathway. Int. J. Mol. Med. 2015, 35, 1381–1387. [Google Scholar] [CrossRef] [PubMed]
- Ramos, J.W. The regulation of extracellular signal-regulated kinase (ERK) in mammalian cells. Int. J. Biochem. Cell Biol. 2008, 40, 2707–2719. [Google Scholar] [CrossRef] [PubMed]
- Xiao, L.; Du, Y.; Shen, Y.; He, Y.; Zhao, H.; Li, Z. TGF-β 1 induced fibroblast proliferation is mediated by the FGF-2/ERK pathway. Front. Biosci. (Landmark Ed.) 2012, 17, 2667–2674. [Google Scholar] [CrossRef] [PubMed]
- Lee, M.K.; Pardoux, C.; Hall, M.C.; Lee, P.S.; Warburton, D.; Qing, J.; Smith, S.M.; Derynck, R. TGF-β activates Erk MAP kinase signalling through direct phosphorylation of ShcA. Embo. J. 2007, 26, 3957–3967. [Google Scholar] [CrossRef] [PubMed]
- Mulder, K.M. Role of Ras and Mapks in TGFβ signaling. Cytokine Growth Factor Rev. 2000, 11, 23–35. [Google Scholar] [CrossRef]
- Zhu, B.; Zhai, J.; Zhu, H.; Kyprianou, N. Prohibitin regulates TGF-β induced apoptosis as a downstream effector of Smad-dependent and -independent signaling. Prostate 2010, 70, 17–26. [Google Scholar] [CrossRef]
- Cheung, M.; Testa, J.R. Diverse mechanisms of AKT pathway activation in human malignancy. Curr Cancer Drug Targets 2013, 13, 234–244. [Google Scholar] [CrossRef]
- Testa, J.R.; Bellacosa, A. AKT plays a central role in tumorigenesis. Proc. Natl. Acad. Sci. USA 2001, 98, 10983–10985. [Google Scholar] [CrossRef] [Green Version]
- Cardone, M.H.; Roy, N.; Stennicke, H.R.; Salvesen, G.S.; Franke, T.F.; Stanbridge, E.; Frisch, S.; Reed, J.C. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998, 282, 1318–1321. [Google Scholar] [CrossRef]
- Hamidi, A.; Song, J.; Thakur, N.; Itoh, S.; Marcusson, A.; Bergh, A.; Heldin, C.H.; Landstrom, M. TGF-β promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85α. Sci. Signal 2017, 10, eaal4186. [Google Scholar] [CrossRef]
- Jung, S.A.; Lee, H.K.; Yoon, J.S.; Kim, S.J.; Kim, C.Y.; Song, H.; Hwang, K.C.; Lee, J.B.; Lee, J.H. Upregulation of TGF-β-induced tissue transglutaminase expression by PI3K-Akt pathway activation in human subconjunctival fibroblasts. Invest. Ophthalmol. Vis. Sci. 2007, 48, 1952–1958. [Google Scholar] [CrossRef] [PubMed]
- Runyan, C.E.; Schnaper, H.W.; Poncelet, A.C. The phosphatidylinositol 3-kinase/Akt pathway enhances Smad3-stimulated mesangial cell collagen I expression in response to transforming growth factor-β1. J. Biol. Chem. 2004, 279, 2632–2639. [Google Scholar] [CrossRef] [PubMed]
- Vo, B.T.; Morton, D., Jr.; Komaragiri, S.; Millena, A.C.; Leath, C.; Khan, S.A. TGF-β effects on prostate cancer cell migration and invasion are mediated by PGE2 through activation of PI3K/AKT/mTOR pathway. Endocrinology 2013, 154, 1768–1779. [Google Scholar] [CrossRef]
- Tang, Y.; Pan, J.; Huang, S.; Peng, X.; Zou, X.; Luo, Y.; Ren, D.; Zhang, X.; Li, R.; He, P.; et al. Downregulation of miR-133a-3p promotes prostate cancer bone metastasis via activating PI3K/AKT signaling. J. Exp. Clin. Cancer Res. 2018, 37, 160. [Google Scholar] [CrossRef] [PubMed]
- Haber, T.; Jockel, E.; Roos, F.C.; Junker, K.; Prawitt, D.; Hampel, C.; Thuroff, J.W.; Brenner, W.; German Renal Cell Tumor, N. Bone Metastasis in Renal Cell Carcinoma is Preprogrammed in the Primary Tumor and Caused by AKT and Integrin α5 Signaling. J. Urol. 2015, 194, 539–546. [Google Scholar] [CrossRef] [PubMed]
- Wu, K.; Fan, J.; Zhang, L.; Ning, Z.; Zeng, J.; Zhou, J.; Li, L.; Chen, Y.; Zhang, T.; Wang, X.; et al. PI3K/Akt to GSK3β/β-catenin signaling cascade coordinates cell colonization for bladder cancer bone metastasis through regulating ZEB1 transcription. Cell Signal 2012, 24, 2273–2282. [Google Scholar] [CrossRef]
- Dai, J.; Keller, J.; Zhang, J.; Lu, Y.; Yao, Z.; Keller, E.T. Bone morphogenetic protein-6 promotes osteoblastic prostate cancer bone metastases through a dual mechanism. Cancer Res. 2005, 65, 8274–8285. [Google Scholar] [CrossRef]
- Sakai, H.; Furihata, M.; Matsuda, C.; Takahashi, M.; Miyazaki, H.; Konakahara, T.; Imamura, T.; Okada, T. Augmented autocrine bone morphogenic protein (BMP) 7 signaling increases the metastatic potential of mouse breast cancer cells. Clin. Exp. Metastasis 2012, 29, 327–338. [Google Scholar] [CrossRef]
- Wang, R.N.; Green, J.; Wang, Z.; Deng, Y.; Qiao, M.; Peabody, M.; Zhang, Q.; Ye, J.; Yan, Z.; Denduluri, S.; et al. Bone Morphogenetic Protein (BMP) signaling in development and human diseases. Genes Dis. 2014, 1, 87–105. [Google Scholar] [CrossRef] [Green Version]
- Ye, L.; Mason, M.D.; Jiang, W.G. Bone morphogenetic protein and bone metastasis, implication and therapeutic potential. Front. Biosci. (Landmark Ed.) 2011, 16, 865–897. [Google Scholar] [CrossRef]
- Aslakson, C.J.; Miller, F.R. Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res. 1992, 52, 1399–1405. [Google Scholar] [PubMed]
- Heppner, G.H.; Miller, F.R.; Shekhar, P.M. Nontransgenic models of breast cancer. Breast Cancer Res. 2000, 2, 331–334. [Google Scholar] [CrossRef] [PubMed]
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Futakuchi, M.; Lami, K.; Tachibana, Y.; Yamamoto, Y.; Furukawa, M.; Fukuoka, J. The Effects of TGF-β Signaling on Cancer Cells and Cancer Stem Cells in the Bone Microenvironment. Int. J. Mol. Sci. 2019, 20, 5117. https://doi.org/10.3390/ijms20205117
Futakuchi M, Lami K, Tachibana Y, Yamamoto Y, Furukawa M, Fukuoka J. The Effects of TGF-β Signaling on Cancer Cells and Cancer Stem Cells in the Bone Microenvironment. International Journal of Molecular Sciences. 2019; 20(20):5117. https://doi.org/10.3390/ijms20205117
Chicago/Turabian StyleFutakuchi, Mitsuru, Kris Lami, Yuri Tachibana, Yukari Yamamoto, Masahiro Furukawa, and Junya Fukuoka. 2019. "The Effects of TGF-β Signaling on Cancer Cells and Cancer Stem Cells in the Bone Microenvironment" International Journal of Molecular Sciences 20, no. 20: 5117. https://doi.org/10.3390/ijms20205117