Skip to main content
Top
Published in: Tumor Biology 12/2015

01-12-2015 | Research Article

BMP-2 induces motility and invasiveness by promoting colon cancer stemness through STAT3 activation

Authors: Bo Ram Kim, Sang Cheul Oh, Dae-Hee Lee, Jung Lim Kim, Suk Young Lee, Myoung Hee Kang, Sun Il Lee, Sanghee Kang, Sung Yup Joung, Byung Wook Min

Published in: Tumor Biology | Issue 12/2015

Login to get access

Abstract

Bone morphogenetic proteins (BMPs) have been involved in metastatic progression and tumorigenesis of many cancer types. However, it remains unclear how BMP-2 contributes to the initiation and development of these cancers. Here, we investigated the role of BMP-2 in colon cancer stem cell (CSC) development from colon cancer cells. We also determined the effects of BMP-2 on CSC development and epithelial-mesenchymal transition (EMT) in human colon cancer cell lines HCT-116 and SW620. We found that BMP-2 enhanced sphere formation of colon cancer cells without serum. Also, BMP-2-induced spheres displayed up-regulation of stemness markers (CD133+ and EpCAM+) and increased drug resistance, hallmarks of CSCs. Importantly, expression of EMT activators p-Smad1/5 and Snail and N-cadherin was increased in the spheres’ cells, indicating that BMP-2 signaling might result in CSC self-renewal and EMT. Furthermore, siRNA-mediated knockdown of signal transducer and activator of transcription 3 (STAT3) in HCT-116 cells reversed BMP-2-induced EMT and stem cell formation. Taken together, our results suggest that the BMP-2 induced STAT3-mediated induction of colon cancer cell metastasis requires an EMT and/or changes in CSC markers.
Literature
2.
go back to reference Lai YL, Lin JK, Liang WY, Huang YC, Chang SC. Surgical resection combined with chemotherapy can help achieve better outcomes in patients with primary colonic lymphoma. J Surg Oncol. 2011;104:265–8.CrossRefPubMed Lai YL, Lin JK, Liang WY, Huang YC, Chang SC. Surgical resection combined with chemotherapy can help achieve better outcomes in patients with primary colonic lymphoma. J Surg Oncol. 2011;104:265–8.CrossRefPubMed
3.
go back to reference Lobo NA, Shimono Y, Qian D, Clarke MF. The biology of cancer stem cells. Annu Rev Cell Dev Biol. 2007;23:675–99.CrossRefPubMed Lobo NA, Shimono Y, Qian D, Clarke MF. The biology of cancer stem cells. Annu Rev Cell Dev Biol. 2007;23:675–99.CrossRefPubMed
4.
go back to reference Smalley MJ, Dale TC. Wnt signalling in mammalian development and cancer. Cancer Metastasis Rev. 1999;18:215–30.CrossRefPubMed Smalley MJ, Dale TC. Wnt signalling in mammalian development and cancer. Cancer Metastasis Rev. 1999;18:215–30.CrossRefPubMed
5.
go back to reference Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, et al. Hedgehog signaling and bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 2006;66:6063–71.CrossRefPubMedPubMedCentral Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, et al. Hedgehog signaling and bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 2006;66:6063–71.CrossRefPubMedPubMedCentral
6.
go back to reference Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS. Role of notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res: BCR. 2004;6:R605–15.CrossRefPubMedPubMedCentral Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS. Role of notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res: BCR. 2004;6:R605–15.CrossRefPubMedPubMedCentral
7.
go back to reference Yeung TM, Gandhi SC, Wilding JL, Muschel R, Bodmer WF. Cancer stem cells from colorectal cancer-derived cell lines. Proc Natl Acad Sci U S A. 2010;107:3722–7.CrossRefPubMedPubMedCentral Yeung TM, Gandhi SC, Wilding JL, Muschel R, Bodmer WF. Cancer stem cells from colorectal cancer-derived cell lines. Proc Natl Acad Sci U S A. 2010;107:3722–7.CrossRefPubMedPubMedCentral
8.
go back to reference Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A. 2007;104:10158–63.CrossRefPubMedPubMedCentral Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A. 2007;104:10158–63.CrossRefPubMedPubMedCentral
9.
go back to reference Hardwick JCH, Van Den Brink GR, Bleuming SA, Ballester I, Van Den Brande JMH, Keller JJ, et al. Bone morphogenetic protein 2 is expressed by, and acts upon, mature epithelial cells in the colon. Gastroenterology. 2004;126:111–21.CrossRefPubMed Hardwick JCH, Van Den Brink GR, Bleuming SA, Ballester I, Van Den Brande JMH, Keller JJ, et al. Bone morphogenetic protein 2 is expressed by, and acts upon, mature epithelial cells in the colon. Gastroenterology. 2004;126:111–21.CrossRefPubMed
10.
go back to reference Miyazono K, Kusanagi K, Inoue H. Divergence and convergence of tgf-beta/bmp signaling. J Cell Physiol. 2001;187:265–76.CrossRefPubMed Miyazono K, Kusanagi K, Inoue H. Divergence and convergence of tgf-beta/bmp signaling. J Cell Physiol. 2001;187:265–76.CrossRefPubMed
11.
go back to reference Miyazawa K, Shinozaki M, Hara T, Furuya T, Miyazono K. Two major smad pathways in tgf-beta superfamily signalling. Genes Cells: Devoted Mol Cell Mech. 2002;7:1191–204.CrossRef Miyazawa K, Shinozaki M, Hara T, Furuya T, Miyazono K. Two major smad pathways in tgf-beta superfamily signalling. Genes Cells: Devoted Mol Cell Mech. 2002;7:1191–204.CrossRef
12.
go back to reference Shirai YT, Ehata S, Yashiro M, Yanagihara K, Hirakawa K, Miyazono K. Bone morphogenetic protein-2 and -4 play tumor suppressive roles in human diffuse-type gastric carcinoma. Am J Pathol. 2011;179:2920–30.CrossRefPubMedPubMedCentral Shirai YT, Ehata S, Yashiro M, Yanagihara K, Hirakawa K, Miyazono K. Bone morphogenetic protein-2 and -4 play tumor suppressive roles in human diffuse-type gastric carcinoma. Am J Pathol. 2011;179:2920–30.CrossRefPubMedPubMedCentral
13.
go back to reference Zhang Y, Chen X, Qiao M, Zhang BQ, Wang N, Zhang Z, et al. Bone morphogenetic protein 2 inhibits the proliferation and growth of human colorectal cancer cells. Oncol Rep. 2014;32:1013–20.PubMedPubMedCentral Zhang Y, Chen X, Qiao M, Zhang BQ, Wang N, Zhang Z, et al. Bone morphogenetic protein 2 inhibits the proliferation and growth of human colorectal cancer cells. Oncol Rep. 2014;32:1013–20.PubMedPubMedCentral
14.
go back to reference Kang MH, Oh SC, Lee HJ, Kang HN, Kim JL, Kim JS, et al. Metastatic function of bmp-2 in gastric cancer cells: the role of pi3k/akt, mapk, the nf-kappab pathway, and mmp-9 expression. Exp Cell Res. 2011;317:1746–62.CrossRefPubMed Kang MH, Oh SC, Lee HJ, Kang HN, Kim JL, Kim JS, et al. Metastatic function of bmp-2 in gastric cancer cells: the role of pi3k/akt, mapk, the nf-kappab pathway, and mmp-9 expression. Exp Cell Res. 2011;317:1746–62.CrossRefPubMed
15.
go back to reference Fong YC, Li TM, Wu CM, Hsu SF, Kao ST, Chen RJ, et al. Bmp-2 increases migration of human chondrosarcoma cells via pi3k/akt pathway. J Cell Physiol. 2008;217:846–55.CrossRefPubMed Fong YC, Li TM, Wu CM, Hsu SF, Kao ST, Chen RJ, et al. Bmp-2 increases migration of human chondrosarcoma cells via pi3k/akt pathway. J Cell Physiol. 2008;217:846–55.CrossRefPubMed
16.
go back to reference Langenfeld EM, Calvano SE, Abou-Nukta F, Lowry SF, Amenta P, Langenfeld J. The mature bone morphogenetic protein-2 is aberrantly expressed in non-small cell lung carcinomas and stimulates tumor growth of a549 cells. Carcinogenesis. 2003;24:1445–54.CrossRefPubMed Langenfeld EM, Calvano SE, Abou-Nukta F, Lowry SF, Amenta P, Langenfeld J. The mature bone morphogenetic protein-2 is aberrantly expressed in non-small cell lung carcinomas and stimulates tumor growth of a549 cells. Carcinogenesis. 2003;24:1445–54.CrossRefPubMed
17.
go back to reference Thiery JP. Epithelial–mesenchymal transitions in development and pathologies. Curr Opin Cell Biol. 2003;15:740–6.CrossRefPubMed Thiery JP. Epithelial–mesenchymal transitions in development and pathologies. Curr Opin Cell Biol. 2003;15:740–6.CrossRefPubMed
18.
go back to reference Bedi S, Vidyasagar A, Djamali A. Epithelial-to-mesenchymal transition and chronic allograft tubulointerstitial fibrosis. Transplant Rev. 2008;22:1–5.CrossRef Bedi S, Vidyasagar A, Djamali A. Epithelial-to-mesenchymal transition and chronic allograft tubulointerstitial fibrosis. Transplant Rev. 2008;22:1–5.CrossRef
19.
go back to reference Moustakas A, Heldin CH. Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci. 2007;98:1512–20.CrossRefPubMed Moustakas A, Heldin CH. Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci. 2007;98:1512–20.CrossRefPubMed
21.
go back to reference Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.CrossRefPubMed Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.CrossRefPubMed
22.
go back to reference Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med. 2009;15:1010–2.CrossRefPubMed Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med. 2009;15:1010–2.CrossRefPubMed
23.
go back to reference Kang MH, Kim JS, Seo JE, Oh SC, Yoo YA. Bmp2 accelerates the motility and invasiveness of gastric cancer cells via activation of the phosphatidylinositol 3-kinase (pi3k)/akt pathway. Exp Cell Res. 2010;316:24–37.CrossRefPubMed Kang MH, Kim JS, Seo JE, Oh SC, Yoo YA. Bmp2 accelerates the motility and invasiveness of gastric cancer cells via activation of the phosphatidylinositol 3-kinase (pi3k)/akt pathway. Exp Cell Res. 2010;316:24–37.CrossRefPubMed
24.
go back to reference Kryczek I, Lin Y, Nagarsheth N, Peng D, Zhao L, Zhao E, et al. Il-22(+)cd4(+) t cells promote colorectal cancer stemness via stat3 transcription factor activation and induction of the methyltransferase dot1l. Immunity. 2014;40:772–84.CrossRefPubMedPubMedCentral Kryczek I, Lin Y, Nagarsheth N, Peng D, Zhao L, Zhao E, et al. Il-22(+)cd4(+) t cells promote colorectal cancer stemness via stat3 transcription factor activation and induction of the methyltransferase dot1l. Immunity. 2014;40:772–84.CrossRefPubMedPubMedCentral
25.
go back to reference Lejeune D, Dumoutier L, Constantinescu S, Kruijer W, Schuringa JJ, Renauld JC. Interleukin-22 (il-22) activates the jak/stat, erk, jnk, and p38 map kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from il-10. J Biol Chem. 2002;277:33676–82.CrossRefPubMed Lejeune D, Dumoutier L, Constantinescu S, Kruijer W, Schuringa JJ, Renauld JC. Interleukin-22 (il-22) activates the jak/stat, erk, jnk, and p38 map kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from il-10. J Biol Chem. 2002;277:33676–82.CrossRefPubMed
26.
go back to reference Pickert G, Neufert C, Leppkes M, Zheng Y, Wittkopf N, Warntjen M, et al. Stat3 links il-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med. 2009;206:1465–72.CrossRefPubMedPubMedCentral Pickert G, Neufert C, Leppkes M, Zheng Y, Wittkopf N, Warntjen M, et al. Stat3 links il-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med. 2009;206:1465–72.CrossRefPubMedPubMedCentral
27.
28.
go back to reference Urist MR. Bone: formation by autoinduction. Science (New York, NY). 1965;150:893–9.CrossRef Urist MR. Bone: formation by autoinduction. Science (New York, NY). 1965;150:893–9.CrossRef
30.
go back to reference Liao A, Wang W, Sun D, Jiang Y, Tian S, Li J, Yang X, Shi R. Bone morphogenetic protein 2 mediates epithelial-mesenchymal transition via akt and erk signaling pathways in gastric cancer. Tumour Biol. 2015;36:2773–78. Liao A, Wang W, Sun D, Jiang Y, Tian S, Li J, Yang X, Shi R. Bone morphogenetic protein 2 mediates epithelial-mesenchymal transition via akt and erk signaling pathways in gastric cancer. Tumour Biol. 2015;36:2773–78.
31.
go back to reference Hou CH, Hsiao YC, Fong YC, Tang CH. Bone morphogenetic protein-2 enhances the motility of chondrosarcoma cells via activation of matrix metalloproteinase-13. Bone. 2009;44:233–42.CrossRefPubMed Hou CH, Hsiao YC, Fong YC, Tang CH. Bone morphogenetic protein-2 enhances the motility of chondrosarcoma cells via activation of matrix metalloproteinase-13. Bone. 2009;44:233–42.CrossRefPubMed
32.
go back to reference Kang MH, Kang HN, Kim JL, Kim JS, Oh SC, Yoo YA. Inhibition of pi3 kinase/akt pathway is required for bmp2-induced emt and invasion. Oncol Rep. 2009;22:525–34.PubMed Kang MH, Kang HN, Kim JL, Kim JS, Oh SC, Yoo YA. Inhibition of pi3 kinase/akt pathway is required for bmp2-induced emt and invasion. Oncol Rep. 2009;22:525–34.PubMed
33.
go back to reference Piccirillo SG, Vescovi AL. Bone morphogenetic proteins regulate tumorigenicity in human glioblastoma stem cells. Ernst Schering Found Symp Proc. 2006;5:59–81. Piccirillo SG, Vescovi AL. Bone morphogenetic proteins regulate tumorigenicity in human glioblastoma stem cells. Ernst Schering Found Symp Proc. 2006;5:59–81.
34.
go back to reference Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, Milde T, et al. Cd133 expression is not restricted to stem cells, and both cd133+ and cd133- metastatic colon cancer cells initiate tumors. J Clin Investig. 2008;118:2111–20.PubMedPubMedCentral Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, Milde T, et al. Cd133 expression is not restricted to stem cells, and both cd133+ and cd133- metastatic colon cancer cells initiate tumors. J Clin Investig. 2008;118:2111–20.PubMedPubMedCentral
35.
go back to reference Langan RC, Mullinax JE, Raiji MT, Upham T, Summers T, Stojadinovic A, et al. Colorectal cancer biomarkers and the potential role of cancer stem cells. J Cancer. 2013;4:241–50.CrossRefPubMedPubMedCentral Langan RC, Mullinax JE, Raiji MT, Upham T, Summers T, Stojadinovic A, et al. Colorectal cancer biomarkers and the potential role of cancer stem cells. J Cancer. 2013;4:241–50.CrossRefPubMedPubMedCentral
37.
go back to reference Liao T, Kaufmann AM, Qian X, Sangvatanakul V, Chen C, Kube T, et al. Susceptibility to cytotoxic t cell lysis of cancer stem cells derived from cervical and head and neck tumor cell lines. J Cancer Res Clin Oncol. 2013;139:159–70.CrossRefPubMed Liao T, Kaufmann AM, Qian X, Sangvatanakul V, Chen C, Kube T, et al. Susceptibility to cytotoxic t cell lysis of cancer stem cells derived from cervical and head and neck tumor cell lines. J Cancer Res Clin Oncol. 2013;139:159–70.CrossRefPubMed
38.
go back to reference Lu Y, Zhu H, Shan H, Lu J, Chang X, Li X, et al. Knockdown of oct4 and nanog expression inhibits the stemness of pancreatic cancer cells. Cancer Lett. 2013;340:113–23.CrossRefPubMed Lu Y, Zhu H, Shan H, Lu J, Chang X, Li X, et al. Knockdown of oct4 and nanog expression inhibits the stemness of pancreatic cancer cells. Cancer Lett. 2013;340:113–23.CrossRefPubMed
39.
go back to reference Ma L, Lu MF, Schwartz RJ, Martin JF. Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning. Development. 2005;132:5601–11.CrossRefPubMed Ma L, Lu MF, Schwartz RJ, Martin JF. Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning. Development. 2005;132:5601–11.CrossRefPubMed
40.
go back to reference Ghosh-Choudhury N, Mandal CC, Choudhury GG. Statin-induced ras activation integrates the phosphatidylinositol 3-kinase signal to akt and mapk for bone morphogenetic protein-2 expression in osteoblast differentiation. J Biol Chem. 2007;282:4983–93.CrossRefPubMed Ghosh-Choudhury N, Mandal CC, Choudhury GG. Statin-induced ras activation integrates the phosphatidylinositol 3-kinase signal to akt and mapk for bone morphogenetic protein-2 expression in osteoblast differentiation. J Biol Chem. 2007;282:4983–93.CrossRefPubMed
41.
go back to reference Ghosh-Choudhury N, Abboud SL, Nishimura R, Celeste A, Mahimainathan L, Choudhury GG. Requirement of bmp-2-induced phosphatidylinositol 3-kinase and akt serine/threonine kinase in osteoblast differentiation and smad-dependent bmp-2 gene transcription. J Biol Chem. 2002;277:33361–8.CrossRefPubMed Ghosh-Choudhury N, Abboud SL, Nishimura R, Celeste A, Mahimainathan L, Choudhury GG. Requirement of bmp-2-induced phosphatidylinositol 3-kinase and akt serine/threonine kinase in osteoblast differentiation and smad-dependent bmp-2 gene transcription. J Biol Chem. 2002;277:33361–8.CrossRefPubMed
42.
go back to reference Kashyap V, Rezende NC, Scotland KB, Shaffer SM, Persson JL, Gudas LJ, et al. Regulation of stem cell pluripotency and differentiation involves a mutual regulatory circuit of the nanog, oct4, and sox2 pluripotency transcription factors with polycomb repressive complexes and stem cell micrornas. Stem Cells Dev. 2009;18:1093–108.CrossRefPubMedPubMedCentral Kashyap V, Rezende NC, Scotland KB, Shaffer SM, Persson JL, Gudas LJ, et al. Regulation of stem cell pluripotency and differentiation involves a mutual regulatory circuit of the nanog, oct4, and sox2 pluripotency transcription factors with polycomb repressive complexes and stem cell micrornas. Stem Cells Dev. 2009;18:1093–108.CrossRefPubMedPubMedCentral
43.
go back to reference Kim D, Kim CH, Moon JI, Chung YG, Chang MY, Han BS, et al. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell. 2009;4:472–6.CrossRefPubMedPubMedCentral Kim D, Kim CH, Moon JI, Chung YG, Chang MY, Han BS, et al. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell. 2009;4:472–6.CrossRefPubMedPubMedCentral
Metadata
Title
BMP-2 induces motility and invasiveness by promoting colon cancer stemness through STAT3 activation
Authors
Bo Ram Kim
Sang Cheul Oh
Dae-Hee Lee
Jung Lim Kim
Suk Young Lee
Myoung Hee Kang
Sun Il Lee
Sanghee Kang
Sung Yup Joung
Byung Wook Min
Publication date
01-12-2015
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 12/2015
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-3681-y

Other articles of this Issue 12/2015

Tumor Biology 12/2015 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine