title: Reactive astrocytes protect melanoma cells from chemotherapy by sequestering intracellular calcium through gap junction communication channels.
abstract: Brain metastases are highly resistant to chemotherapy. Metastatic tumor cells are known to exploit the host microenvironment for their growth and survival. We report here that melanoma brain metastases are surrounded and infiltrated by activated astrocytes, and we hypothesized that these astrocytes can play a role similar to their established ability to protect neurons from apoptosis. In coculture experiments, astrocytes, but not fibroblasts, reduced apoptosis in human melanoma cells treated with various chemotherapeutic drugs. This chemoprotective effect was dependent on physical contact and gap junctional communication between astrocytes and tumor cells. Moreover, the protective effect of astrocytes resulted from their sequestering calcium from the cytoplasm of tumor cells. These data suggest that brain tumors can, in principle, harness the neuroprotective effects of reactive astrocytes for their own survival and implicate a heretofore unrecognized mechanism for resistance in brain metastasis that might be of relevance in the clinic.
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Qingtang
authors.initials: Q
authors.lastname: Lin
authors.forename: Krishnakumar
authors.initials: K
authors.lastname: Balasubramanian
authors.forename: Dominic
authors.initials: D
authors.lastname: Fan
authors.forename: Sun-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Lixia
authors.initials: L
authors.lastname: Guo
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Menashe
authors.initials: M
authors.lastname: Bar-Eli
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.forename: Isaiah J
authors.initials: IJ
authors.lastname: Fidler
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001253:Astrocytes / Q000378:metabolism / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D002450:Cell Communication / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D017630:Connexins / Q000378:metabolism / Q000502:physiology*; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D008954:Models, Biological; D041681:NIH 3T3 Cells
chemical_list: D000970:Antineoplastic Agents; D017630:Connexins; D002118:Calcium
references.citation: Neoplasia. 2011 Mar;13(3):286-98
references.pmid: 21390191
references.citation: Science. 2005 May 6;308(5723):778-81
references.pmid: 15879185
references.citation: Acta Neurol Belg. 2004 Jun;104(2):51-6
references.pmid: 15508267
references.citation: AJNR Am J Neuroradiol. 2008 Oct;29(9):1684-91
references.pmid: 18599575
references.citation: Cancer Res. 2005 Apr 1;65(7):2705-11
references.pmid: 15805269
references.citation: Int J Cancer. 1988 Apr 15;41(4):589-94
references.pmid: 3356491
references.citation: J Neurooncol. 1994;20(2):121-39
references.pmid: 7807190
references.citation: Expert Rev Anticancer Ther. 2005 Oct;5(5):809-20
references.pmid: 16221051
references.citation: Int J Oncol. 2009 Oct;35(4):665-72
references.pmid: 19724901
references.citation: Lancet Oncol. 2002 Jan;3(1):53-7
references.pmid: 11905606
references.citation: Biol Cell. 2002 Nov;94(7-8):457-75
references.pmid: 12566220
references.citation: Mol Carcinog. 1996 Jul;16(3):157-64
references.pmid: 8688151
references.citation: Cancer. 2002 May 15;94(10):2698-705
references.pmid: 12173339
references.citation: Science. 2005 Nov 4;310(5749):791-3
references.pmid: 16272104
references.citation: Nat Rev Cancer. 2003 Jun;3(6):453-8
references.pmid: 12778135
references.citation: Science. 2002 Oct 18;298(5593):556-62
references.pmid: 12386325
references.citation: Am J Pathol. 1992 Nov;141(5):1115-24
references.pmid: 1443046
references.citation: Nat Rev Neurosci. 2006 Jan;7(1):41-53
references.pmid: 16371949
references.citation: Mol Cell Endocrinol. 2006 Feb 26;246(1-2):1-9
references.pmid: 16388890
references.citation: Cancer Cell. 2008 May;13(5):385-93
references.pmid: 18455122
references.citation: Neuroscientist. 2005 Oct;11(5):400-7
references.pmid: 16151042
references.citation: Nat Rev Cancer. 2008 May;8(5):361-75
references.pmid: 18432251
references.citation: FASEB J. 2008 Apr;22(4):1193-203
references.pmid: 18029447
references.citation: J Neurol. 2002 Oct;249(10):1357-69
references.pmid: 12382150
references.citation: J Biol Chem. 2007 Jun 22;282(25):18357-18364
references.pmid: 17470427
references.citation: Clin Exp Metastasis. 2009;26(5):403-14
references.pmid: 19277878
references.citation: Exp Cell Res. 1996 Jan 10;222(1):48-53
references.pmid: 8549672
references.citation: J Neurosci. 2006 Feb 8;26(6):1739-48
references.pmid: 16467522
references.citation: Nat Neurosci. 1998 Oct;1(6):494-500
references.pmid: 10196547
references.citation: Cytometry A. 2006 Jun;69(6):487-93
references.pmid: 16646046
references.citation: Neuropathol Appl Neurobiol. 1991 Oct;17(5):407-14
references.pmid: 1758571
references.citation: Apoptosis. 2005 May;10(3):459-69
references.pmid: 15909108
references.citation: Curr Drug Targets. 2005 Nov;6(7):821-33
references.pmid: 16305461
references.citation: Cancer Res. 2008 Nov 1;68(21):9078-86
references.pmid: 18974154
references.citation: Anticancer Res. 1999 Sep-Oct;19(5C):4413-20
references.pmid: 10650785
references.citation: Nature. 2009 Feb 5;457(7230):675-7
references.pmid: 19194443
references.citation: Cancer Res. 1991 Apr 15;51(8):2029-35
references.pmid: 1826230
references.citation: Cancer Res. 2004 Dec 15;64(24):9086-92
references.pmid: 15604277
references.citation: Cancer Res. 1995 Jun 15;55(12):2620-6
references.pmid: 7780978