Targetting Interleukins Involved in Glioblastoma – A New Pharmacological Approach
PDF

Keywords

Glioblastoma
Interleukins
Cytokines
, Immunotherapy
Pro-Inflammatory
Anti-Inflammatory

How to Cite

Masood, A., Kayani, M., & Batool, S. (2020). Targetting Interleukins Involved in Glioblastoma – A New Pharmacological Approach. Journal of Life and Bio Sciences Research , 1(3), 82 - 88. https://doi.org/10.38094/jlbsr1330

Abstract

Brain tumor is unchecked growth of brain cells disrupting many of its important functions and, affecting molecular regulatory and signaling networks. Glioblastoma is one of the most deleterious tumors of human brain. Cytokines are secondary messenger molecules in many of the immunological and other biochemical reactions. With glioblastoma progression, various cytokines are secreted that either up-regulate or down-regulate many others with immunological function. Interleukins are a family of cytokines acting mainly as immune-regulatory proteins. They have been implicated in brain tumor initiation, progression and invasion. Due to their multiple and varied regulatory roles at every stage of tumor, they are now becoming an attractive target for study in glioblastoma. This mini review briefly summarizes the types and roles of major interleukins and their regulation and, effects in glioblastoma that have been studied so far. Immunotherapeutic aspects are particularly emphasized as the promising therapeutic targets to control brain tumors. Main types of interleukins which are implicated in brain tumors are discussed here which includes interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), and interleukin-12 (IL-12). Glioblastoma is one of the most invasive tumor and still lack effective control measures clinically. Conventional treatments like chemotherapy and radiation therapy are not only ineffective in controlling the spread of glioblastoma, but also have damaging and unwanted side effects on healthy cells. Immunotherapy by blocking and/or increasing the action of certain interleukins has proven to be effective control measure in laboratory investigations. Future work extending these findings to clinical and human trials is expected to provide effective treatment measures.

https://doi.org/10.38094/jlbsr1330
PDF

References

Albulescu, R., Elena, C., Ionela, D.P., Simona, M., Laura, G.N., Daniel, P., Mihaela, T., Cristiana, P. (2013). Cytokine Patterns in Brain Tumour Progression. Mediators of Inflammation, 2013, 7.

Bloch, O., Courtney, A. C., Rajwant, K., Michael, S., Martin, J.R., Andrew, T.P. (2013). Gliomas promote immunosuppression through induction of B7-H1 expression in tumor-associated macrophages. Clinical Cancer Research, 19(12), 3165-3175.

Cadieux, B., Ching, T.T., VandenBerg, S.R., Costello, J.F. (2006). Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation. Cancer Research, 66(17), 84698476.

Chen, H., Qingdong, Ke., Thomas, K., Yan, Y., Max, C. (2006). Nickel ions increase histone H3 lysine 9 dimethylation and induce transgene silencing. Molecular Cell Biology, 26(10), 3728-3737.

Chiu, T.L., Wang, M.J., Su, C.C. (2012). The treatment of glioblastoma multiforme through activation of microglia and TRAIL induced by rAAV2-mediated IL-12 in a syngeneic rat model. Journal of Biomedical Science, 19(1), 45.

Commins, S.P., Borish, L., Steinke, J.W. (2010). Immunologic messenger molecules: cytokines, interferons, and chemokines. The Journal of Allergy and Clinical Immunology, 125 (2 Suppl 2), S53S72.

Connelly, J.M., Malkin, M.G. (2007). Environmental risk factors for brain tumors. Current Neurology and Neuroscience Reports, 7(3), 208214.

Crump, C., Sundquist, J., Sieh, W., Winkleby, M.A., Sundquist, K. (2015). Perinatal and familial risk factors for brain tumors in childhood through young adulthood. Cancer Research, 75(3), 576583.

Curran, C.S., Michael, D.E., Paul, J.B. (2011). GM-CSF Production by Glioblastoma Cells Has a Functional Role in Eosinophil Survival, Activation, and Growth Factor Production for Enhanced Tumor Cell Proliferation. The Journal of Immunology, 187(3), 1254-1263.

Cui, X., Toshifumi W., Yoshio S., Katsuyoshi H., Seishiro H. (2006). Chronic oral exposure to inorganic arsenate interferes with methylation status of p16INK4a and RASSF1A and induces lung cancer in A/J mice. Toxicol Sci, 91(2), 372-381.

Danaila, L., Ghyka, G., Ursaciuc, C. (1993). Interleukin-2 (IL-2) in the treatment of malignant brain tumors (glioblastomas). Romanian Journal of Neurology and Psychiatry, 31(3-4), 195206.

David, J.M., Charli, D., Duane, H.H., Claudia, P. (2016). The IL-8/IL-8 Axis: A double agent in Tumor Immune Resistance. Vaccines (Basel) 4(3),22.

Dennis, K.L., Nichole, R.B., Fotini, G., Khashayarsha, K. (2013). Current status of interleukin-10 and regulatory T-cells in cancer. Current Opinions in Oncology, 25(6), 637-645.

Desbaillets, I., Diserens, A.C., Tribolet, N. de., Hamou, M.F., Meir, E.G.V. (1997). Upregulation of Interleukin 8 by Oxygen-deprived Cells in Glioblastoma Suggests a Role in Leukocyte Activation, Chemotaxis, and Angiogenesis. The Journal of Experimental Medicine, 186(8), 12011212.

Desaknai, S., Katalin, L., Egon, J.H., Hirofumi, H., Geza, S. (2001). Brain tumor treatment with IL-2 and IL-12 producing autologous cancer cell vaccines. Advances in Experimental Medicine and Biology, 495, 369-372.

Di Santo, Adami M., Bertorelli R., Ghezzi P. (1997). Systemic interleukin 10 administration inhibits brain tumor necrosis factor production in mice. Eur J Pharmacol, 336(2-3), 197-202.

Dinarello, C.A. (2007). Historical Review of Cytokines. European Journal of Immunology, 37(Suppl 1), S34S45.

Dwyer, J., Hebda, J.K., Le Guelte, A., Galan-Moya, E.M., Smith, S.S., Azzi, S., Gavard, J. (2012). Glioblastoma Cell-Secreted Interleukin-8 Induces Brain Endothelial Cell Permeability via CXCR2. PLoSONE, 7(9), e45562.

Dudas, J., Alexandra, F., Mario, B., Volker, S., Ilona, K., Georg, M.S., Herbert, R. (2011). Tumor-produced, active Interleukin-1 regulates gene expression in carcinoma-associated fibroblasts. Experimental Cell Research, 317(15), 2222-2229.

Erta, M., Quintana, A., Hidalgo, J. (2012). Interleukin-6, a Major Cytokine in the Central Nervous System. International Journal of Biological Sciences, 8(9), 12541266.

Fabbri, E., Eleonora, B., Giulia, M., Claudio, G., Albino, E., Cinzia, C., Susanna, K., Valentino, B., Lisa P., Nicoletta, B., Alessia, F., Monica, B., Giuseppe, M., Marco, C., Giulio, C., Roberto, G. (2015). Regulation of IL-8 gene expression in gliomas by microRNA miR-93. BMC Cancer, 15(1), 661.

Feuerstein, G.Z., Liu, T., Barone, F.C. (1994). Cytokines, inflammation, and brain injury: role of tumor necrosis factor-alpha. Cerebrovascular and Brain Metabolism Reviews, 6(4), 341360.

Guo, Y., Feng, X., TianJian, L., Zhenfeng, D., Zhan, Z. (2012). Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treatment Reviews, 38(7), 904-910.

Haarmann, A., Nowak, E., Dei߬ A., van der Pol, S., Monoranu, C.M., Kooij, G., Buttmann, M. (2015). Soluble VCAM-1 impairs human brain endothelial barrier integrity via integrin -4-transduced outside-in signalling. Acta Neuropathologica, 129(5), 639652.

Hirohata, S. (1999). Human Th1 responses driven by IL-12 are associated with enhanced expression of CD40 ligand. Clinical and Experimental Immunology, 115(1), 7885.

Holland, E.C. (2000). Glioblastoma multiforme: the terminator. Proceedings of the National Academy of Sciences of the United States of America, 97(12), 6242-6244.

Huang, A.Y., Golumbek, P., Ahmadzadeh, M., Jaffee, E., Pardoll, D., Levitsky, H. (1994). Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science, 264(5161), 961965.

Huang, S., Ullrich, S.E., Bar-Eli, M. (1999). Regulation of tumor growth and metastasis by interleukin-10: the melanoma experience. J Interferon Cytokine Research, 19(7), 697-703.

Huettner, C., Paulus, W., Roggendorf, W. (1995). Messenger RNA expression of the immunosuppressive cytokine IL-10 in human gliomas. The American Journal of Pathology, 146(2), 317-322.

Iglesia, N., Genevieve, K., Kah-Leong, L., Catherine, L.N., Jacqueline, F.B., David, A.F., Paul, S.M., David, N.L., Azad, B. (2008). Deregulation of a STAT3Interleukin 8 Signaling Pathway Promotes Human Glioblastoma Cell Proliferation and Invasiveness. The Journal of Neuroscience, 28(23), 5870.

Ines, C., Ana, L.V., Marí¡¬ G.T., Marí¡¬ C.P., Alvaro, O., Marí¡¬ C.L., Catarina, O., Patricia, D., Alberto, O., Maria, D.T. (2015). Molecular and Genomic Alterations in Glioblastoma Multiforme. The American Journal of Pathology, 185(7), 1820-1833.

Jack, C.S., Nathalie, A., Joshua, M., Vivianne, M., Manon, B., Ellie, M., Aaron, S., Jack, P.A. (2005). TLR signaling tailors innate immune responses in human microglia and astrocytes. The Journal of Immunology, 175(7), 4320-4330.

Janson, K., Nedzi, L.A., David, O., Schorin, M., Walsh, J.W., Bhattacharjee, M., Biegel, J.A. (2006). Predisposition to atypical teratoid/rhabdoid tumor due to an inheritedINI1 mutation. Pediatric Blood and Cancer, 47(3), 279284.

Kawakami, M., Kawakami K., Puri, R. (2003). Interleukin-4-Pseudomonas Exotoxin Chimeric Fusion Protein for Malignant Glioma Therapy. Journal of Neuro-Oncology, 65(1), 15-25.

Kazuya, S., Jan, V.D., Mark, Y.S., Sally, R.S., Richard, T.C., Ralph, A.T., Charles, C., Frederick, W.Q., Tetsuya, N., Dario, A.A. Vignali, P.C. Doherty, G.G., Paul, W.E., Ihle, J.N. (1996). Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted State6 gene. Nature, 380, 630-633.

Ke, Q., Qin, L., Thomas, P. E., Hong, S., Max, C. (2008). Nickel compounds induce phosphorylation of histone H3 at serine 10 by activating JNK-MAPK pathway. Carcinogenesis, 29(6), 1276-1281.

Kleihues, P.C. (1997) In: Pathology and Genetics of Tumors of the Nervous System. Kleihues, P., Cavenee, W.K., editors. International Agency for Research on Cancer; Lyon, France.

Kore, R.A., Abraham, E.C. (2014). Inflammatory cytokines, interleukin-1 beta and tumor necrosis factor-alpha, upregulated in glioblastoma multiforme, raise the levels of CRYAB in exosomes secreted by U373 glioma cells. Biochemical and Biophysical Research Communications, 453(3), 326331.

Lapointe, S., Perry, A., Butowski, N.A. (2018). Primary Brain Tumours in Adults. The Lancet, 392 (10145), 432-446.

Ledeboer, A., John, J.P.B., Anne, W., Saskia, V.J., Adrian, F.B., Jos饬 E.L., Fred, J.H.T., Anne-Marie, V.D. (2002). Expression and regulation of interleukin-10 and interleukin-10 receptor in rat astroglial and microglial cells. European Journal of Neuroscience, 16(7), 1175-1185.

Leonard, S.S., Bower, J.J., Shi, X. (2004). Metal-induced toxicity, carcinogenesis, mechanisms and cellular responses. Molecular and Cellular Biochemistry, 255(1-2), 3-10.

Lewis, C.E., Pollard, J.W. (2006). Distinct Role of Macrophages in Different Tumor Microenvironments. Cancer Research 66(2), 605-612.

Li, Z., Chen, L., Qin, Z. (2009). Paradoxical roles of IL-4 in tumor immunity. Cellular and Molecular Immunology, 6(6), 415-422.

Lichtor, T., Roberta, P.G., Katherine, T., Shannon, M., Elizabeth, M., Edward, P. C. (2002). Application of interleukin-2-secreting syngeneic/allogeneic fibroblasts in the treatment of primary and metastatic brain tumors. Cancer Gene Therapy, 9(5), 464-469.

Liu, Q., Gang, L., Ronghui, Li., Jie, S., Qiaowei, H., Lin, D., Cai, Z., Jian, Z. (2010). IL-6 promotion of glioblastoma cell invasion and angiogenesis in U251 and T98G cell lines. Journal of Neuro-Oncology, 100(2), 165-176.

Lobo-Silva, D., Guilhermina M. Carriche, A. Gil, C., Susana R., Margarida, S. (2016). Balancing the immune response in the brain: IL-10 and its regulation. Journal of Neuroinflammation, 13(1), 297.

Macmillan Cancer Support. Types of brain tumors. Available from http://www.macmillan.org.uk.

Martinez-Maza, O., Berek, J.S. (1991). Interleukin 6 and cancer treatment. In Vivo, 5(6), 583-588.

Meir, E.V., Sawamura, Y., Diserens, A.C., Hamou, M.F., Tribolet, N. (1990). Human Glioblastoma Cells Release Interleukin 6 in vivo and in vitro. Cancer Research, 50, 6683-6688.

Reilly, K.M. (2009). Brain tumor susceptibility: the role of genetic factors and uses of mouse models to unravel risk. Brain pathology (Zurich, Switzerland), 19(1), 121131.

Romani, M., Pistillo, M.P., Banelli, B. (2018). Epigenetic Targeting of Glioblastoma. Frontiers in Oncology, 8, 448.

Rutledge, W.C., Kong, J., Gao, J., Gutman, D.A., Cooper, L.A., Appin, C., Park, Y., Scarpace, L., Mikkelsen, T., Cohen, M.L., Aldape, K.D., McLendon, R.E., Lehman, N.L., Miller, C.R., Schniederjan, M.J., Brennan, C.W., Saltz, J. H., Moreno, C.S., Brat, D.J. (2013). Tumor-infiltrating lymphocytes in glioblastoma are associated with specific genomic alterations and related to transcriptional class. Clinical Cancer Research, 19(18), 4951-60.

Saleh, M., Davis, I.D., Wikis, A.F. (1997). The paracrine role of tumour-derived mIL-4 on tumour-associated endothelium. International Journal of Cancer, 72(4), 664-672.

Segal, B.M., Deborah, D.G., Ethan, M.S. (2002). IL-10 Producing CD4+ T cells Mediate Tumor Rejection. The journal of Immunology, 168, 1-4.

Seiichi, Y., Ryuichi, T., Nobuyuki, T. (1988). Immunological study of Interleukin-2 in Patients with Malignant Brain Tumors. Neurologia Medico-Chirurgica (Tokyo), 28, 631-634.

Shimamura, T., Hussain, S.R., Puri, R.K. (2006). The IL-4 and IL-13 pseudomonas exotoxins: new hope for brain tumor therapy." Neurosurgical Focus, 20(4), E11.

Tanabe, S., Yamashita, Y. (2018). The role of immune cells in brain development and neurodevelopmental diseases. International Immunology, 30(10), 437-444.

Tugues, S., Burkhard, S.H., Ohs, I., Vrohlings, M., Nussbaum, K., Vom Berg, J., Kulig, P., Becher, B. (2015). New insights into IL-12-mediated tumor suppression. Cell Death and Differentiation, 22(2), 237-246.

Voronov, E., Shouval, D.S., Krelin, Y., Cagnano, E., Benharroch, D., Iwakura, Y., Dinarello, C.A. Apte, R.N. (2003). IL-1 is required for tumor invasiveness and angiogenesis. Proceedings of National Academy of Sciences 100(5), 26452650

Vida, S., Richardson, L., Cardis, E., Krewski, D., McBride, M., Parent, M. E., Abrahamowicz, M., Leffondré¬ K., Siemiatycki, J. (2014). Brain tumours and cigarette smoking: analysis of the INTERPHONE Canada case-control study. Environmental Health, 13, 55.

Volpert, O.V., Fong, T., Koch, A.E., Peterson, J.D., Waltenbaugh, C., Tepper, R.I., Bouck, N.P. (1998). Inhibition of angiogenesis by interleukin 4. The Journal of experimental medicine, 188(6), 10391046.

Vom Berg, J., Vrohlings, M., Haller, S., Haimovici, A., Kulig, P., Sledzinska, A., Weller, M., Becher, B. (2013). Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection. The Journal of Experimental Medicine, 210(13), 28032811.

Wainwright, D.A., Dey, M., Chang, A., Lesniak, M.S. (2013). Targeting Tregs in Malignant Brain Cancer: Overcoming IDO. Frontiers Immunology, 4, 116.

Wang, H., Lathia, J.D., Wu, Q., Wang, J., Li, Z., Heddleston, J.M., Rich, J.N. (2009). Targeting Interleukin 6 Signaling Suppresses Glioma Stem Cell Survival and Tumor Growth. Stem Cells (Dayton, Ohio), 27(10), 23932404.

Wang, L., Liu, Z., Balivada, S., Shrestha, T., Bossmann, S., Pyle, M., Pappan, L., Shi, J., Troyer, D. (2012). Interleukin-1 and transforming growth factor- cooperate to induce neurosphere formation and increase tumorigenicity of adherent LN-229 glioma cells. Stem Cell Research and Therapy, 3(1), 5.

Watters, J.J., Schartner, J.M., Badie, B. (2005). Microglia function in brain tumors. Journal of Neuroscience Research, 81(3), 447455.

Weiss, J.M., Subleski, J.J., Wigginton, J.M., Wiltrout, R.H. (2007). Immunotherapy of Cancer by IL-12-based Cytokine Combinations. Expert Opinion on Biological Therapy, 7(11), 17051721 (2007).

White, M. K., Gordon, J., Reiss, K., Del Valle, L., Croul, S., Giordano, A., Darbinyan, A., Khalili, K. (2005). Human polyomaviruses and brain tumors. Brain Research Reviews, 50(1), 6985.

Yeung, Y. T., McDonald, K. L., Grewal, T., Munoz, L. (2013). Interleukins in glioblastoma pathophysiology: implications for therapy. British Journal of Pharmacology, 168(3), 591606.

Zhang, J.M., An, J. (2007). Cytokines, Inflammation and Pain. International Anesthesiology Clinics, 45(2), 2737.

Zurolo, E., Marjolein, G., Anand, I., Jasper, A., Erwin, A. van V., Jan, J.H., Jaap, C., Reijneveld, Jan,. Gorter, A., Eleonora A. (2012). Regulation of Kir4.1 expression in astrocytes and astrocytic tumors: a role for interleukin-1 . Journal of Neuroinflammation, 9(1), 280.

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Copyright (c) 2020 Array