Evaluation of BMP-2 as a Differentiating and Radiosensitizing Agent for Colorectal Cancer Stem Cells


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Аннотация

Background:Despite effective clinical responses, a large proportion of patients undergo resistance to radiotherapy. The low response rate to current treatments in different stages of colorectal cancer depends on the prominent role of stem cells in cancer.

Objective:In the present study, the role of BMP-2 as an ionizing radiation-sensitive factor in colorectal cancer cells was investigated.

Methods:A sphere formation assay was used for the enrichment of HCT-116 cancer stem cells (CSCs). The effects of combination therapy (BMP-2+ radiation) on DNA damage response (DDR), proliferation, and apoptosis were evaluated in HCT-116 and CSCs. Gene expressions of CSCs and epithelialmesenchymal transition (EMT) markers were also evaluated.

Results:We found that the sphere formation assay showed a significant increase in the percentage of CSCs. Moreover, expression of CSCs markers, EMT-related genes, and DNA repair proteins significantly decreased in HCT-116 cells compared to the CSCs group after radiation. In addition, BMP-2 promoted the radiosensitivity of HCT-116 cells by decreasing the survival rate of the treated cells at 2, 4, and 6 Gy compared to the control group in HCT-116 cells.

Conclusion:Our findings indicated that BMP-2 could affect numerous signaling pathways involved in radioresistance. Therefore, BMP-2 can be considered an appealing therapeutic target for the treatment of radioresistant human colorectal cancer.

Об авторах

Roghayeh Mahmoudi

Department of Molecular Medicine and Genetics, Hamadan University of Medical Sciences

Email: info@benthamscience.net

Saeid Afshar

Department of Molecular Medicine and Genetics, Hamadan University of Medical Sciences

Email: info@benthamscience.net

Razieh Amini

Department of Molecular Medicine and Genetics, Hamadan University of Medical Sciences,

Email: info@benthamscience.net

Akram Jalali

Research Center for Molecular Medicine, Hamadan University of Medical Sciences

Email: info@benthamscience.net

Massoud Saidijam

Department of Molecular Medicine and Genetics, Hamadan University of Medical Sciences

Email: info@benthamscience.net

Rezvan Najafi

Department of Molecular Medicine and Genetics, Hamadan University of Medical Sciences,

Автор, ответственный за переписку.
Email: info@benthamscience.net

Список литературы

  1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 can-cers in 185 countries. CA Cancer J Clin 2021; 71(3): 209-49. doi: 10.3322/caac.21660 PMID: 33538338
  2. Hasan Abdali M, Afshar S, Sedighi Pashaki A, et al. Investigating the effect of radiosensitizer for ursolic acid and kamolonol acetate on HCT-116 cell line. Bioorg Med Chem 2020; 28(1): 115152. doi: 10.1016/j.bmc.2019.115152 PMID: 31771799
  3. Geng L, Wang J. Molecular effectors of radiation resistance in colorectal cancer. Precis Radiat Oncol 2017; 1(1): 27-33. doi: 10.1002/pro6.5
  4. Afshar S, Sedighi Pashaki A, Najafi R, et al. Cross-resistance of acquired radioresistant colorectal cancer cell line to gefitinib and regoraf-enib. Iran J Med Sci 2020; 45(1): 50-8. PMID: 32038059
  5. Duldulao MP, Lee W, Streja L, et al. Distribution of residual cancer cells in the bowel wall after neoadjuvant chemoradiation in patients with rectal cancer. Dis Colon Rectum 2013; 56(2): 142-9. doi: 10.1097/DCR.0b013e31827541e2 PMID: 23303141
  6. Mladenov E, Magin S, Soni A, Iliakis G. DNA double-strand break repair as determinant of cellular radiosensitivity to killing and target in radiation therapy. Front Oncol 2013; 3: 113. doi: 10.3389/fonc.2013.00113 PMID: 23675572
  7. Morgan MA, Lawrence TS. Molecular pathways: overcoming radiation resistance by targeting DNA damage response pathways. Clin Cancer Res 2015; 21(13): 2898-904. doi: 10.1158/1078-0432.CCR-13-3229 PMID: 26133775
  8. Eriksson D, Stigbrand T. Radiation-induced cell death mechanisms. Tumour Biol 2010; 31(4): 363-72. doi: 10.1007/s13277-010-0042-8 PMID: 20490962
  9. Sun Z, Liu C, Jiang WG, Ye L. Deregulated bone morphogenetic proteins and their receptors are associated with disease progression of gastric cancer. Comput Struct Biotechnol J 2020; 18: 177-88. doi: 10.1016/j.csbj.2019.12.014 PMID: 31988704
  10. Mitra A, Mishra L, Li S. EMT, CTCs and CSCs in tumor relapse and drug-resistance. Oncotarget 2015; 6(13): 10697-711. doi: 10.18632/oncotarget.4037 PMID: 25986923
  11. Kozovska Z, Gabrisova V, Kucerova L. Colon cancer: Cancer stem cells markers, drug resistance and treatment. Biomed Pharmacother 2014; 68(8): 911-6. doi: 10.1016/j.biopha.2014.10.019 PMID: 25458789
  12. Zhang Y, Chen X, Qiao M, et al. Bone morphogenetic protein 2 inhibits the proliferation and growth of human colorectal cancer cells. Oncol Rep 2014; 32(3): 1013-20. doi: 10.3892/or.2014.3308 PMID: 24993644
  13. Shirai Y, 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(6): 2920-30. doi: 10.1016/j.ajpath.2011.08.022 PMID: 21996676
  14. Ruiu R, Rolih V, Bolli E, et al. Fighting breast cancer stem cells through the immune-targeting of the xCT cystine–glutamate antiporter. Cancer Immunol Immunother 2019; 68(1): 131-41. doi: 10.1007/s00262-018-2185-1 PMID: 29947961
  15. Rahimi A, Amiri I, Roushandeh AM, et al. Sublethal concentration of H2O2 enhances the protective effect of mesenchymal stem cells in rat model of spinal cord injury. Biotechnol Lett 2018; 40(3): 609-15. doi: 10.1007/s10529-017-2499-7 PMID: 29288352
  16. Karkhane M, et al. Cancer stem cells: cell heterogeneity in cancer and nanotechnology approaches for their treatment. J Mazandaran Univ Med Sci 2016; 25(133): 361-75.
  17. Das PK, Islam F, Lam AK. The roles of cancer stem cells and therapy resistance in colorectal carcinoma. Cells 2020; 9(6): 1392. doi: 10.3390/cells9061392 PMID: 32503256
  18. Krause M, Dubrovska A, Linge A, Baumann M. Cancer stem cells: Radioresistance, prediction of radiotherapy outcome and specific tar-gets for combined treatments. Adv Drug Deliv Rev 2017; 109: 63-73. doi: 10.1016/j.addr.2016.02.002 PMID: 26877102
  19. Jing N, Gao WQ, Fang YX. Regulation of formation, stemness and therapeutic resistance of cancer stem cells. Front Cell Dev Biol 2021; 9: 641498. doi: 10.3389/fcell.2021.641498 PMID: 33898430
  20. Vermeulen L. de Sousa e Melo F, Richel DJ, Medema JP. The developing cancer stem-cell model: Clinical challenges and opportunities. Lancet Oncol 2012; 13(2): e83-9. doi: 10.1016/S1470-2045(11)70257-1 PMID: 22300863
  21. Ren F, Sheng W-Q, Du X. CD133: A cancer stem cells marker, is used in colorectal cancers. World J Gastroenterol 2013; 19(17): 2603-11. doi: 10.3748/wjg.v19.i17.2603 PMID: 23674867
  22. Dalerba P, Dylla SJ, Park IK, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA 2007; 104(24): 10158-63. doi: 10.1073/pnas.0703478104 PMID: 17548814
  23. Kim BR, Oh SC, Lee DH, et al. BMP-2 induces motility and invasiveness by promoting colon cancer stemness through STAT3 activation. Tumour Biol 2015; 36(12): 9475-86. doi: 10.1007/s13277-015-3681-y PMID: 26124007
  24. Nickel J, Mueller TD. Specification of BMP Signaling. Cells 2019; 8(12): 1579. doi: 10.3390/cells8121579 PMID: 31817503
  25. Farnsworth RH, Karnezis T, Shayan R, et al. A role for bone morphogenetic protein-4 in lymph node vascular remodeling and primary tumor growth. Cancer Res 2011; 71(20): 6547-57. doi: 10.1158/0008-5472.CAN-11-0200 PMID: 21868759
  26. Irshad S, Bansal M, Guarnieri P, et al. Bone morphogenetic protein and Notch signalling crosstalk in poor-prognosis, mesenchymal-subtype colorectal cancer. J Pathol 2017; 242(2): 178-92. doi: 10.1002/path.4891 PMID: 28299802
  27. Davis H, Raja E, Miyazono K, Tsubakihara Y, Moustakas A. Mechanisms of action of bone morphogenetic proteins in cancer. Cytokine Growth Factor Rev 2016; 27: 81-92. doi: 10.1016/j.cytogfr.2015.11.009 PMID: 26678814
  28. Wakefield LM, Hill CS. Beyond TGFβ: roles of other TGFβ superfamily members in cancer. Nat Rev Cancer 2013; 13(5): 328-41. doi: 10.1038/nrc3500 PMID: 23612460
  29. Brunen D, Willems S, Kellner U, Midgley R, Simon I, Bernards R. TGF-β: An emerging player in drug resistance. Cell Cycle 2013; 12(18): 2960-8. doi: 10.4161/cc.26034 PMID: 23974105
  30. Wang Z, Shen Z, Li Z, et al. Activation of the BMP-BMPR pathway conferred resistance to EGFR-TKIs in lung squamous cell carcinoma patients with EGFR mutations. Proc Natl Acad Sci USA 2015; 112(32): 9990-5. doi: 10.1073/pnas.1510837112 PMID: 26216950
  31. Fukuda T, Fukuda R, Koinuma D, Moustakas A, Miyazono K, Heldin CH. BMP2-induction of FN14 promotes protumorigenic signaling in gynecologic cancer cells. Cell Signal 2021; 87: 110146. doi: 10.1016/j.cellsig.2021.110146 PMID: 34517088
  32. Olivares-Urbano MA, Griñán-Lisón C, Marchal JA, Núñez MI. CSC radioresistance: A therapeutic challenge to improve radiotherapy ef-fectiveness in cancer. Cells 2020; 9(7): 1651. doi: 10.3390/cells9071651 PMID: 32660072
  33. Schulz A, Meyer F, Dubrovska A, Borgmann K. Cancer stem cells and radioresistance: DNA repair and beyond. Cancers 2019; 11(6): 862. doi: 10.3390/cancers11060862 PMID: 31234336
  34. de Jesús K-AA, Xu X. Mechanisms of radioresistance in hepatocellular carcinoma. Oncology 2017; 3(4): 165-70.
  35. Samadi P, Soleimani M, Nouri F, Rahbarizadeh F, Najafi R, Jalali A. An integrative transcriptome analysis reveals potential predictive, prognostic biomarkers and therapeutic targets in colorectal cancer. BMC Cancer 2022; 22(1): 835. doi: 10.1186/s12885-022-09931-4 PMID: 35907803
  36. Bach DH, Park HJ, Lee SK. The dual role of bone morphogenetic proteins in cancer. Mol Ther Oncolytics 2018; 8: 1-13. doi: 10.1016/j.omto.2017.10.002 PMID: 29234727
  37. Zabkiewicz C, Resaul J, Hargest R, Jiang WG, Ye L. Bone morphogenetic proteins, breast cancer, and bone metastases: Striking the right balance. Endocr Relat Cancer 2017; 24(10): R349-66. doi: 10.1530/ERC-17-0139 PMID: 28733469
  38. Wang X, Zhang F, Yang J, et al. The chemotherapeutic effect of docetaxel, cisplatin and fluorouracil regimen on gastric cancer stem cells. J Nanosci Nanotechnol 2017; 17(2): 983-9. doi: 10.1166/jnn.2017.12591 PMID: 29671949
  39. Wang L, Park P, Zhang H, et al. BMP-2 inhibits the tumorigenicity of cancer stem cells in human osteosarcoma OS99-1 cell line. Cancer Biol Ther 2011; 11(5): 457-63. doi: 10.4161/cbt.11.5.14372 PMID: 21178508
  40. Wang L, Park P, La Marca F, Than KD, Lin CY. BMP-2 inhibits tumor-initiating ability in human renal cancer stem cells and induces bone formation. J Cancer Res Clin Oncol 2015; 141(6): 1013-24. doi: 10.1007/s00432-014-1883-0 PMID: 25431339
  41. Pretzsch E, et al. Mechanisms of metastasis in colorectal cancer and metastatic organotropism: Hematogenous versus peritoneal spread. J Oncol 2019. doi: 10.1155/2019/7407190
  42. 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(1): 24-37. doi: 10.1016/j.yexcr.2009.10.010 PMID: 19835871
  43. Cai Z, Cao Y, Luo Y, Hu H, Ling H. Signalling mechanism(s) of epithelial–mesenchymal transition and cancer stem cells in tumour thera-peutic resistance. Clin Chim Acta 2018; 483: 156-63. doi: 10.1016/j.cca.2018.04.033 PMID: 29709449
  44. Bastos LGR, de Marcondes PG, de-Freitas-Junior JCM, et al. Progeny from irradiated colorectal cancer cells acquire an EMT-like pheno-type and activate Wnt/β-catenin pathway. J Cell Biochem 2014; 115(12): 2175-87. doi: 10.1002/jcb.24896 PMID: 25103643
  45. Chang L, Graham PH, Hao J, et al. Emerging roles of radioresistance in prostate cancer metastasis and radiation therapy. Cancer Metastasis Rev 2014; 33(2-3): 469-96. doi: 10.1007/s10555-014-9493-5 PMID: 24445654
  46. Takahashi H, Nakamura K, Usami A, et al. Possible role of nuclear β-catenin in resistance to preoperative chemoradiotherapy in locally advanced rectal cancer. Histopathology 2017; 71(2): 227-37. doi: 10.1111/his.13227 PMID: 28370249
  47. Zhao Y, Yi J, Tao L, et al. Wnt signaling induces radioresistance through upregulating HMGB1 in esophageal squamous cell carcinoma. Cell Death Dis 2018; 9(4): 433. doi: 10.1038/s41419-018-0466-4 PMID: 29567990
  48. Zhao Y, Tao L, Yi J, Song H, Chen L. The role of canonical Wnt signaling in regulating Radioresistance. Cell Physiol Biochem 2018; 48(2): 419-32. doi: 10.1159/000491774 PMID: 30021193
  49. Shrivastav M, Miller CA, De Haro LP, et al. DNA-PKcs and ATM co-regulate DNA double-strand break repair. DNA Repair 2009; 8(8): 920-9. doi: 10.1016/j.dnarep.2009.05.006 PMID: 19535303
  50. Wang W, et al. XRRA1 targets ATM/CHK1/2-mediated DNA repair in colorectal cancer. BioMed Res Int 2017; 5718968: 2017.
  51. Carruthers R, Ahmed SU, Strathdee K, et al. Abrogation of radioresistance in glioblastoma stem-like cells by inhibition of ATM kinase. Mol Oncol 2015; 9(1): 192-203. doi: 10.1016/j.molonc.2014.08.003 PMID: 25205037
  52. Skvortsov S, et al. Crosstalk between DNA repair and cancer stem cell (CSC) associated intracellular pathways. In: Seminars in cancer biology. Elsevier 2015.
  53. Hermann PC, Huber SL, Herrler T, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in hu-man pancreatic cancer. Cell Stem Cell 2007; 1(3): 313-23. doi: 10.1016/j.stem.2007.06.002 PMID: 18371365
  54. Simeone DM. Pancreatic cancer stem cells: implications for the treatment of pancreatic cancer. Clin Cancer Res 2008; 14(18): 5646-8. doi: 10.1158/1078-0432.CCR-08-0584 PMID: 18794070
  55. Bao S, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. nature 2006; 444(1): 756-60. doi: 10.1038/nature05236
  56. Hardee ME, Marciscano AE, Medina-Ramirez CM, et al. Resistance of glioblastoma-initiating cells to radiation mediated by the tumor microenvironment can be abolished by inhibiting transforming growth factor-β. Cancer Res 2012; 72(16): 4119-29. doi: 10.1158/0008-5472.CAN-12-0546 PMID: 22693253
  57. Bouquet F, Pal A, Pilones KA, et al. TGFβ1 inhibition increases the radiosensitivity of breast cancer cells in vitro and promotes tumor control by radiation in vivo. Clin Cancer Res 2011; 17(21): 6754-65. doi: 10.1158/1078-0432.CCR-11-0544 PMID: 22028490
  58. Zuo ZQ, Chen KG, Yu XY, et al. Promoting tumor penetration of nanoparticles for cancer stem cell therapy by TGF-β signaling pathway inhibition. Biomaterials 2016; 82: 48-59. doi: 10.1016/j.biomaterials.2015.12.014 PMID: 26751819
  59. Sachdeva R, Wu M, Johnson K, et al. BMP signaling mediates glioma stem cell quiescence and confers treatment resistance in glioblasto-ma. Sci Rep 2019; 9(1): 14569. doi: 10.1038/s41598-019-51270-1 PMID: 31602000
  60. Centurione L, Aiello FB. DNA repair and cytokines: TGF-β, IL-6, and thrombopoietin as different biomarkers of radioresistance. Front Oncol 2016; 6: 175. doi: 10.3389/fonc.2016.00175 PMID: 27500125
  61. Sun X, He Z, Guo L, et al. ALG3 contributes to stemness and radioresistance through regulating glycosylation of TGF-β receptor II in breast cancer. J Exp Clin Cancer Res 2021; 40(1): 149. doi: 10.1186/s13046-021-01932-8 PMID: 33931075
  62. Zhang Z, Fan Y, Xie F, et al. Breast cancer metastasis suppressor OTUD1 deubiquitinates SMAD7. Nat Commun 2017; 8(1): 2116. doi: 10.1038/s41467-017-02029-7 PMID: 29235476
  63. Yang T, Huang T, Zhang D, et al. TGF-β receptor inhibitor LY2109761 enhances the radiosensitivity of gastric cancer by inactivating the TGF-β/SMAD4 signaling pathway. Aging 2019; 11(20): 8892-910. doi: 10.18632/aging.102329 PMID: 31631064
  64. Du S, et al. Attenuation of the DNA damage response by transforming growth factor-Beta inhibitors enhances radiation sensitivity of non–small-cell lung Cancer cells in vitro and in vivo. Int J Rad Oncol Biol Phy 2015; 91(1): 91-9. doi: 10.1016/j.ijrobp.2014.09.026

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