Top

Published in:

01-03-2015 | Original Paper

Glioma cells escaped from cytotoxicity of temozolomide and vincristine by communicating with human astrocytes

Authors: Weiliang Chen, Donghai Wang, Xinwen Du, Ying He, Songyu Chen, Qianqian Shao, Chao Ma, Bin Huang, Anjing Chen, Peng Zhao, Xun Qu, Xingang Li

Published in: Medical Oncology | Issue 3/2015

Abstract

Resistance to chemotherapeutic drugs remains a great obstacle to successful treatment of gliomas. Understanding the mechanism of glioma chemoresistance is conducive to develop effective strategies to overcome resistance. Astrocytes are the major stromal cells in the brain and have been demonstrated to play a key role in the malignant phenotype of gliomas. However, little is known regarding its role in glioma chemoresistance. In our study, we established a co-culture system of human astrocytes and glioma in vitro to simulate tumor microenvironment. Our results showed that astrocytes significantly reduced glioma cell apoptosis induced by the chemotherapeutic drugs temozolomide and vincristine. This protective effect was dependent on direct contact between astrocytes and glioma cells through Cx43-GJC. Moreover, in human glioma specimens, we found astrocytes infiltrating around the tumor, with a reactive appearance, suggesting that these astrocytes would play the same chemoprotective effect on gliomas in vivo. Our results expand the understanding of the interaction between astrocytes and glioma cells and provide a possible explanation for unsatisfactory clinical outcomes of chemotherapeutic drugs. Cx43-GJC between astrocytes and glioma cells may be a potential target for overcoming chemoresistance in gliomas clinically.

Available only for authorised users

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96. doi:10.1056/NEJMoa043330.CrossRefPubMed

Sarkaria JN, Kitange GJ, James CD, Plummer R, Calvert H, Weller M, et al. Mechanisms of chemoresistance to alkylating agents in malignant glioma. Clin Cancer Res. 2008;14(10):2900–8. doi:10.1158/1078-0432.CCR-07-1719.CrossRefPubMedPubMedCentral

Lu C, Shervington A. Chemoresistance in gliomas. Mol Cell Biochem. 2008;312(1–2):71–80. doi:10.1007/s11010-008-9722-8.CrossRefPubMed

Friedman HS, Kerby T, Calvert H. Temozolomide and treatment of malignant glioma. Clin Cancer Res. 2000;6(7):2585–97.PubMed

Stanton RA, Gernert KM, Nettles JH, Aneja R. Drugs that target dynamic microtubules: a new molecular perspective. Med Res Rev. 2011;31(3):443–81. doi:10.1002/med.20242.CrossRefPubMedPubMedCentral

Nakasone ES, Askautrud HA, Kees T, Park JH, Plaks V, Ewald AJ, et al. Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell. 2012;21(4):488–503. doi:10.1016/j.ccr.2012.02.017.CrossRefPubMedPubMedCentral

Correia AL, Bissell MJ. The tumor microenvironment is a dominant force in multidrug resistance. Drug Resist Updat. 2012;15(1–2):39–49. doi:10.1016/j.drup.2012.01.006.CrossRefPubMedPubMedCentral

Zhang W, Huang P. Cancer-stromal interactions: role in cell survival, metabolism and drug sensitivity. Cancer Biol Ther. 2011;11(2):150–6.CrossRefPubMedPubMedCentral

Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012;487(7408):500–4. doi:10.1038/nature11183.CrossRefPubMedPubMedCentral

10.

Muerkoster S, Wegehenkel K, Arlt A, Witt M, Sipos B, Kruse ML, et al. Tumor stroma interactions induce chemoresistance in pancreatic ductal carcinoma cells involving increased secretion and paracrine effects of nitric oxide and interleukin-1beta. Cancer Res. 2004;64(4):1331–7.CrossRefPubMed

11.

Shekhar MP, Santner S, Carolin KA, Tait L. Direct involvement of breast tumor fibroblasts in the modulation of tamoxifen sensitivity. Am J Pathol. 2007;170(5):1546–60. doi:10.2353/ajpath.2007.061004.CrossRefPubMedPubMedCentral

12.

Farina C, Aloisi F, Meinl E. Astrocytes are active players in cerebral innate immunity. Trends Immunol. 2007;28(3):138–45. doi:10.1016/j.it.2007.01.005.CrossRefPubMed

13.

Charles NA, Holland EC, Gilbertson R, Glass R, Kettenmann H. The brain tumor microenvironment. Glia. 2012;60(3):502–14.CrossRefPubMed

14.

Nagano N, Sasaki H, Aoyagi M, Hirakawa K. Invasion of experimental rat brain tumor: early morphological changes following microinjection of C6 glioma cells. Acta Neuropathol. 1993;86(2):117–25.CrossRefPubMed

15.

Lal PG, Ghirnikar RS, Eng LF. Astrocyte-astrocytoma cell line interactions in culture. J Neurosci Res. 1996;44(3):216–22. doi:10.1002/(SICI)1097-4547(19960501)44:3<216:AID-JNR2>3.0.CO;2-J.CrossRefPubMed

16.

Iadecola C, Nedergaard M. Glial regulation of the cerebral microvasculature. Nat Neurosci. 2007;10(11):1369–76. doi:10.1038/nn2003.CrossRefPubMed

17.

Trendelenburg G, Dirnagl U. Neuroprotective role of astrocytes in cerebral ischemia: focus on ischemic preconditioning. Glia. 2005;50(4):307–20. doi:10.1002/glia.20204.CrossRefPubMed

18.

Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci. 2004;24(9):2143–55. doi:10.1523/JNEUROSCI.3547-03.2004.CrossRefPubMed

19.

Yang C, Rahimpour S, Yu AC, Lonser RR, Zhuang Z. Regulation and dysregulation of astrocyte activation and implications in tumor formation. Cell Mol Life Sci. 2013;. doi:10.1007/s00018-013-1274-8.PubMedCentral

20.

Sofroniew MV. Reactive astrocytes in neural repair and protection. Neurosci. 2005;11(5):400–7. doi:10.1177/1073858405278321.

21.

Mahesh VB, Dhandapani KM, Brann DW. Role of astrocytes in reproduction and neuroprotection. Mol Cell Endocrinol. 2006;246(1–2):1–9. doi:10.1016/j.mce.2005.11.017.CrossRefPubMed

22.

Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT. Angiogenesis in brain tumours. Nat Rev Neurosci. 2007;8(8):610–22. doi:10.1038/nrn2175.CrossRefPubMed

23.

Kim SJ, Kim JS, Park ES, Lee JS, Lin Q, Langley RR, et al. Astrocytes upregulate survival genes in tumor cells and induce protection from chemotherapy. Neoplasia. 2011;13(3):286–98.CrossRefPubMedPubMedCentral

24.

Lin Q, Balasubramanian K, Fan D, Kim SJ, Guo L, Wang H, et al. Reactive astrocytes protect melanoma cells from chemotherapy by sequestering intracellular calcium through gap junction communication channels. Neoplasia. 2010;12(9):748–54.CrossRefPubMedPubMedCentral

25.

Krysko DV, Leybaert L, Vandenabeele P, D’Herde K. Gap junctions and the propagation of cell survival and cell death signals. Apoptosis Int J Progr Cell Death. 2005;10(3):459–69. doi:10.1007/s10495-005-1875-2.CrossRef

26.

Charles AC, Naus CC, Zhu D, Kidder GM, Dirksen ER, Sanderson MJ. Intercellular calcium signaling via gap junctions in glioma cells. J Cell Biol. 1992;118(1):195–201.CrossRefPubMed

27.

Zhang W, Couldwell WT, Simard MF, Song H, Lin JH, Nedergaard M. Direct gap junction communication between malignant glioma cells and astrocytes. Cancer Res. 1999;59(8):1994–2003.PubMed

28.

Orrenius S, Zhivotovsky B, Nicotera P. Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol. 2003;4(7):552–65. doi:10.1038/nrm1150.CrossRefPubMed

29.

Roderick HL, Cook SJ. Ca²⁺ signalling checkpoints in cancer: remodelling Ca²⁺ for cancer cell proliferation and survival. Nat Rev Cancer. 2008;8(5):361–75. doi:10.1038/nrc2374.CrossRefPubMed

30.

Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119(1):7–35. doi:10.1007/s00401-009-0619-8.CrossRefPubMedPubMedCentral

31.

Clavreul A, Etcheverry A, Chassevent A, Quillien V, Avril T, Jourdan ML, et al. Isolation of a new cell population in the glioblastoma microenvironment. J Neurooncol. 2012;106(3):493–504. doi:10.1007/s11060-011-0701-7.CrossRefPubMed

32.

Oliveira R, Christov C, Guillamo JS, de Bouard S, Palfi S, Venance L, et al. Contribution of gap junctional communication between tumor cells and astroglia to the invasion of the brain parenchyma by human glioblastomas. BMC Cell Biol. 2005;6(1):7. doi:10.1186/1471-2121-6-7.CrossRefPubMedPubMedCentral

33.

Sun P, Liu Y, Ying H, Li S. Action of db-cAMP on the bystander effect and chemosensitivity through connexin 43 and Bcl-2-mediated pathways in medulloblastoma cells. Oncol Rep. 2012;28(3):969–76. doi:10.3892/or.2012.1900.PubMed

34.

Carystinos GD, Alaoui-Jamali MA, Phipps J, Yen L, Batist G. Upregulation of gap junctional intercellular communication and connexin 43 expression by cyclic-AMP and all-trans-retinoic acid is associated with glutathione depletion and chemosensitivity in neuroblastoma cells. Cancer Chemother Pharmacol. 2001;47(2):126–32.CrossRefPubMed

35.

Robe PA, Nguyen-Khac M, Jolois O, Rogister B, Merville MP, Bours V. Dexamethasone inhibits the HSV-tk/ganciclovir bystander effect in malignant glioma cells. BMC Cancer. 2005;5:32. doi:10.1186/1471-2407-5-32.CrossRefPubMedPubMedCentral

36.

Chakravarti A, Erkkinen MG, Nestler U, Stupp R, Mehta M, Aldape K, et al. Temozolomide-mediated radiation enhancement in glioblastoma: a report on underlying mechanisms. Clin Cancer Res. 2006;12(15):4738–46. doi:10.1158/1078-0432.CCR-06-0596.CrossRefPubMed

37.

Rouach N, Avignone E, Meme W, Koulakoff A, Venance L, Blomstrand F, et al. Gap junctions and connexin expression in the normal and pathological central nervous system. Biol Cell. 2002;94(7–8):457–75.CrossRefPubMed

38.

Warn-Cramer BJ, Lau AF. Regulation of gap junctions by tyrosine protein kinases. Biochim Biophys Acta. 2004;1662(1–2):81–95. doi:10.1016/j.bbamem.2003.10.018.CrossRefPubMedPubMedCentral

39.

Soroceanu L, Manning TJ Jr, Sontheimer H. Reduced expression of connexin-43 and functional gap junction coupling in human gliomas. Glia. 2001;33(2):107–17.CrossRefPubMed

40.

Huang RP, Hossain MZ, Huang R, Gano J, Fan Y, Boynton AL. Connexin 43 (cx43) enhances chemotherapy-induced apoptosis in human glioblastoma cells. Int J Cancer. 2001;92(1):130–8.CrossRefPubMed

41.

Gielen PR, Aftab Q, Ma N, Chen VC, Hong X, Lozinsky S, et al. Connexin43 confers temozolomide resistance in human glioma cells by modulating the mitochondrial apoptosis pathway. Neuropharmacology. 2013;75:539–48. doi:10.1016/j.neuropharm.2013.05.002.CrossRefPubMed

42.

Munoz JL, Rodriguez-Cruz V, Greco SJ, Ramkissoon SH, Ligon KL, Rameshwar P. Temozolomide resistance in glioblastoma cells occurs partly through epidermal growth factor receptor-mediated induction of connexin 43. Cell Death Dis. 2014;5:e1145. doi:10.1038/cddis.2014.111.CrossRefPubMedPubMedCentral

43.

Decrock E, Krysko DV, Vinken M, Kaczmarek A, Crispino G, Bol M, et al. Transfer of IP(3) through gap junctions is critical, but not sufficient, for the spread of apoptosis. Cell Death Differ. 2012;19(6):947–57. doi:10.1038/cdd.2011.176.CrossRefPubMedPubMedCentral

44.

Gagliano N, Costa F, Cossetti C, Pettinari L, Bassi R, Chiriva-Internati M, et al. Glioma-astrocyte interaction modifies the astrocyte phenotype in a co-culture experimental model. Oncol Rep. 2009;22(6):1349–56.CrossRefPubMed

Title: Glioma cells escaped from cytotoxicity of temozolomide and vincristine by communicating with human astrocytes
Authors: Weiliang Chen
Donghai Wang
Xinwen Du
Ying He
Songyu Chen
Qianqian Shao
Chao Ma
Bin Huang
Anjing Chen
Peng Zhao
Xun Qu
Xingang Li
Publication date: 01-03-2015
Publisher: Springer US
Published in: Medical Oncology / Issue 3/2015
Print ISSN: 1357-0560
Electronic ISSN: 1559-131X
DOI: https://doi.org/10.1007/s12032-015-0487-0

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Glioma cells escaped from cytotoxicity of temozolomide and vincristine by communicating with human astrocytes

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2015

Radiation sensitization with sodium nitrite in patients with brain metastases: a pilot randomized controlled trial

The efficacy of first-line chemotherapy is associated with KRAS mutation status in patients with advanced non-small cell lung cancer: a meta-analysis

Downregulation of UPK1A suppresses proliferation and enhances apoptosis of bladder transitional cell carcinoma cells

VGLL4 inhibits EMT in part through suppressing Wnt/β-catenin signaling pathway in gastric cancer

Aprepitant as prophylaxis of chemotherapy-induced nausea and vomiting in anthracyclines and cyclophosphamide-based regimen for adjuvant breast cancer

Improved health-related quality of life of patients with metastatic renal cell carcinoma treated with a 2 weeks on and 1 week off schedule of sunitinib

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page