Reactive astrocytes protect melanoma cells from chemotherapy by sequestering intracellular calcium through gap junction communication channels.
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.
Lin
Qingtang
Q
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Balasubramanian
Krishnakumar
K
Fan
Dominic
D
Kim
Sun-Jin
SJ
Guo
Lixia
L
Wang
Hua
H
Bar-Eli
Menashe
M
Aldape
Kenneth D
KD
Fidler
Isaiah J
IJ
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
D000970:Antineoplastic Agents; D017630:Connexins; D002118:Calcium
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