Estrogen receptors (ERα and ERβ) in the brain play critical roles in maintaining brain tissue homeostasis and in tissue repair after injury. Growth of cancer metastasis in the brain is a constant damaging process. The role of ERs of the host in the progression of cancer brain metastasis is unknown. To determine the role of ERβ of host in the progression of lung cancer brain metastasis, we used an isogenic murine lung cancer cell line, Lewis lung carcinoma cells (3LL), to produce orthotopic lung cancer brain metastases in wild type and ERβ knockout (ERβ -/- ) mice. In the wild type mice, we found that ERα and ERβ appeared in the tumor associated reactive astrocytes at 24hr after injection of tumor cells, and ERβ remained thereafter while ERα disappeared after 1 week. The metastasis bearing ERβ -/- mice survived significantly longer than the wild type mice. To further test the role of ERβ of reactive astrocytes in the survival of cancer cells, we knocked down ERβ in cultured actrocytes using shRNA and performed 3D co-culture with 3LL cells in the presence/absence of chemotherapeutic agents, oxaliplatin and 5-fluorouracil. We found that loss of ERβ in astrocytes significantly reduced the survivability of 3LL cells co-cultured with astrocytes. It is concluded that ERβ of host, especially ERβ in reactive astrocytes, promotes the progression of lung cancer brain metastasis and ERβ might be a potential therapeutic target for lung cancer brain metastasis.
J. G. Santarelli, V. Sarkissian, L. C. Hou, A. Veeravagu and V. Tse, “Molecular Events of Brain Metastasis,” Neurosurgical Focus, Vol. 22, No. 3, 2007, pp. 1-5. doi:10.3171/foc.2007.22.3.2
E. C. Kaal, C. G. Niel and C. J. Vecht, “Therapeutic Management of Brain Metastasis,” The Lancet Neurology, Vol. 4, No. 5, 2005, pp. 289-298. doi:10.1016/S1474-4422(05)70072-7
G. Bernardo, Q. Cuzzoni, M. R. Strada, A. Bernardo, G. Brunetti, I. Jedrychowska, U. Pozzi and R. Palumbo, “First-Line Chemotherapy with Vinorelbine, Gemcitabine, and Carboplatin in the Treatment of Brain Metastases from Non-Small-Cell Lung Cancer: A Phase II Study,” Cancer Investigation, Vol. 20, No. 3, 2002, pp. 293-302. doi:10.1081/CNV-120001173
W. S. Kamoun, C. D. Ley, C. T. Farrar, A. M. Duyverman, J. Lahdenranta, D. A. Lacorre, T. T. Batchelor, E. di Tomaso, D. G. Duda, L. L. Munn, D. Fukumura, A. G. Sorensen and R. K. Jain, “Edema Control by Cediranib, a Vascular Endothelial Growth Factor Receptor-Targeted Kinase Inhibitor, Prolongs Survival Despite Persistent Brain Tumor Growth in Mice,” Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, Vol. 27, No. 15, 2009, pp. 2542-2552.
M. Zhang and Y. Olsson, “Hematogenous Metastases of the Human Brain—Characteristics of Peritumoral Brain Changes: A Review,” Journal of Neuro-Oncology, Vol. 35, No. 1, 1997, pp. 81-89. doi:10.1023/A:1005799805335
M. D. Laird, J. R. Vender and K. M. Dhandapani, “Opposing Roles for Reactive Astrocytes Following Traumatic Brain Injury,” Neuro-Signals, Vol. 16, No. 2-3, 2008, pp. 154-164. doi:10.1159/000111560
H. F. Dvorak, L. F. Brown, M. Detmar and A. M. Dvorak, “Vascular Permeability Factor/Vascular Endothelial Growth Factor, Microvascular Hyperpermeability, and Angiogenesis,” The American Journal of Pathology, Vol. 146, No. 5, 1995, pp. 1029-1039.
J. Z. Escalone, “Astrocytes in Brain Tumours. Differentiation or Trapping?” Histology and Histopathology, Vol. 9, No. 2, 1994, pp. 325-332.
M. Zhang and Y. Olsson, “Reactions of Astrocytes and Microglial Cells around Hematogenous Metastases of the Human Brain Expression of Endothelin-Like Immunoreactivity in Reactive Astrocytes and Activation of Microglial Cells,” Journal of the Neurological Sciences, Vol. 134, No. 1-2, 1995, pp. 26-32. doi:10.1016/0022-510X(95)00227-9
C. Escartin and G. Bonvento, “Targeted Activation of Astrocytes: A Potential Neuroprotective Strategy,” Molecular Neurobiology, Vol. 38, No. 3, 2008, pp. 231-241. doi:10.1007/s12035-008-8043-y
J. L. Ridet, A. Privat, S. K. Malhotra and F. H. Gage, “Reactive Astrocytes: Cellular and Molecular Cues to Biological Function,” Trends in Neurosciences, Vol. 20, No. 12, 1997, pp. 570-577. doi:10.1016/S0166-2236(97)01139-9
D. P. Fitzgerald, D. Palmieri, E. Hua, E. Hargrave, J. M. Herring, Y. Qian, E. Vega-Valle, R. J. Weil, A. M. Stark, A. O. Vortmeyer and P. S. Steeg, “Reactive Glia Are Recruited by Highly Proliferative Brain Metastases of Breast Cancer and Promote Tumor Cell Colonization,” Clinical & Experimental Metastasis, Vol. 25, No. 7, 2008, pp. 799-810. doi:10.1007/s10585-008-9193-z
I. Azcoitia, D. Garcia-Ovejero, J. A. Chowen and L. M. Garcia-Segura, “Astroglia Play a Key Role in the Neuroprotective Actions of Estrogen,” Progress in Brain Research, Vol. 132, 2001, pp. 469-478. doi:10.1016/S0079-6123(01)32096-4
K. M. Dhandapani and D. W. Brann, “Role of Astrocytes in Estrogen-Mediated Neuroprotection,” Experimental Gerontology, Vol. 42, No. 1-2, 2007, pp. 70-75. doi:10.1016/j.exger.2006.06.032
D. Garcia-Ovejero, S. Veiga, L. M. Garcia-Segura and L. L. Doncarlos, “Glial Expression of Estrogen and Androgen Receptors after Rat Brain Injury,” The Journal of Comparative Neurology, Vol. 450, No. 3, 2002, pp. 256-271. doi:10.1002/cne.10325
S. Sakuma, D. Tokuhara, H. Hattori, O. Matsuoka and T. Yamano, “Expression of Estrogen Receptor Alpha and Beta in Reactive Astrocytes at the Male Rat Hippocampus after Status Epilepticus,” Neuropathology: Official Journal of the Japanese Society of Neuropathology, Vol. 29, No. 1, 2009, pp. 55-62.
S. Suzuki, L. M. Gerhold, M. Bottner, S. W. Rau, C. D. Cruz, E. Yang, H. Zhu, J. Yu, A. B. Cashion, M. S. Kindy, I. Merchenthaler, F. H. Gage and P. M. Wise, “Estradiol Enhances Neurogenesis Following Ischemic Stroke through Estrogen Receptors Alpha and Beta,” The Journal of Comparative Neurology, Vol. 500, No. 6, 2007, pp. 1064-1075. doi:10.1002/cne.21240
L. A. Helguero, M. H. Faulds, J. A. Gustafsson and L. A. Haldosen, “Estrogen Receptors Alfa (ERalpha) and Beta (ERbeta) Differentially Regulate Proliferation and Apoptosis of the Normal Murine Mammary Epithelial Cell Line HC11,” Oncogene, Vol. 24, No. 44, 2005, pp. 6605- 6616.
C. Palmieri, G. J. Cheng, S. Saji, M. Zelada-Hedman, A. Warri, Z. Weihua, S. Van Noorden, T. Wahlstrom, R. C. Coombes, M. Warner and J. A. Gustafsson, “Estrogen Receptor Beta in Breast Cancer,” Endocrine-Related Cancer, Vol. 9, No. 1, 2002, pp. 1-13. doi:10.1677/erc.0.0090001
S. Yano, H. Shinohara, R. S. Herbst, H. Kuniyasu, C. D. Bucana, L. M. Ellis, D. W. Davis, D. J. McConkey and I. J. Fidler, “Expression of Vascular Endothelial Growth Factor Is Necessary but Not Sufficient for Production and Growth of Brain Metastasis,” Cancer Research, Vol. 60, No. 17, 2000, pp. 4959-4967.
S. J. Kim, J. S. Kim, E. S. Park, J. S. Lee, Q. Lin, R. R. Langley, M. Maya, J. He, S. W. Kim, Z. Weihua, K. Balasubramanian, D. Fan, G. B. Mills, M. C. Hung and I. J. Fidler, “Astrocytes Upregulate Survival Genes in Tumor Cells and Induce Protection from Chemotherapy,” Neoplasia, Vol. 13, No. 3, 2011, pp. 286-298.
Q. Lin, K. Balasubramanian, D. Fan, S. J. Kim, L. Guo, H. Wang, M. Bar-Eli, K. D. Aldape and I. J. Fidler, “Reactive Astrocytes Protect Melanoma Cells from Chemotherapy by Sequestering Intracellular Calcium through gap Junction Communication Channels,” Neoplasia, Vol. 12, No. 9, 2010, pp. 748-754.
I. J. Fidler, “The Role of the Organ Microenvironment in Brain Metastasis,” Seminars in Cancer Biology, Vol. 21, No. 2, 2011, pp. 107-112. doi:10.1016/j.semcancer.2010.12.009
V. B. Mahesh, K. M. Dhandapani and D. W. Brann, “Role of Astrocytes in Reproduction and Neuroprotection,” Molecular and Cellular Endocrinology, Vol. 246, No. 1-2, 2006, pp. 1-9. doi:10.1016/j.mce.2005.11.017
M. V. Sofroniew, “Reactive Astrocytes in Neural Repair and Protection,” The Neuroscientist: A Review Journal Bringing Neurobiology, Neurology and Psychiatry, Vol. 11, No. 5, 2005, pp. 400-407.
P. J. Albrecht, J. P. Dahl, O. K. Stoltzfus, R. Levenson and S. W. Levison, “Ciliary Neurotrophic Factor Activates Spinal Cord Astrocytes, Stimulating Their Production and Release of Fibroblast Growth Factor-2, to Increase Motor Neuron Survival,” Experimental Neurology, Vol. 173, No. 1, 2002, pp. 46-62. doi:10.1006/exnr.2001.7834
M. Pehar, M. R. Vargas, P. Cassina, A. G. Barbeito, J. S. Beckman and L. Barbeito, “Complexity of Astrocyte-Motor Neuron Interactions in Amyotrophic Lateral Sclerosis,” Neuro-Degenerative Diseases, Vol. 2, No. 3-4, 2005, pp. 139-146. doi:10.1159/000089619
C. Escartin, K. Pierre, A. Colin, E. Brouillet, T. Delzescaux, M. Guillermier, M. Dhenain, N. Déglon, P. Hantraye, L. Pellerin and G. Bonvento, “Activation of Astrocytes by CNTF Induces Metabolic Plasticity and Increases Resistance to Metabolic Insults,” The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, Vol. 27, No. 27, 2007, pp. 7094-7104.
M. Gavillet, I. Allaman and P. J. Magistretti, “Modulation of Astrocytic Metabolic Phenotype by Proinflammatory Cytokines,” Glia, Vol. 56, No. 9, 2008, pp. 975-989. doi:10.1002/glia.20671
M. M. Froes, A. H. Correia, J. Garcia-Abreu, D. C. Spray, A. C. Campos de Carvalho and M. V. Neto, “Gap-Junctional Coupling between Neurons and Astrocytes in Primary Central Nervous System Cultures,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 13, 1999, pp. 7541-7546. doi:10.1073/pnas.96.13.7541
W. Lieberthal, S. A. Menza and J. S. Levine, “Graded ATP Depletion Can Cause Necrosis or Apoptosis of Cultured Mouse Proximal Tubular Cells,” The American Journal of Physiology, Vol. 274, No. 2, 1998, pp. F315-F327.