Aim: To study effects of recombinant human growth hormone (rhGH) on growth hormone-insulin-like growth factor axis (GH-IGFs) of human gastric cancer cell in vivo in order to reveal part mechanism of growth effects of rhGH on gastric cancer. Methods: Nude mice were randomly divided into control group, cisplatin (DDP) group, rhGH group and DDP + rhGH group after human gastric cancer xenograft model of node mice was successfully founded and drugs were used for 6 days. We investigated volume of tumor, inhibitory rate of tumor and cell cycle by slide gauge and flow cytometry. In addition, We also respectively investigated insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) of blood serum of nude mice, IGF-ImRNA, insulin-like growth factor-I receptor (IGF-IR) mRNA and IGFBP-3 mRNA of xenograft of nude mice by enzyme linked immunosorbent assay (ELISA) and semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) on the first day of completing use of drugs later. Results: Tumor grew obviously slowly and tumor inhibitory rate obviously rose in DDP group and DDP + rhGH group compared with control group and rhGH group (p < 0.05), but they were not remarkably different between DDP group and DDP + rhGH group or between control group and rhGH group. Cells of gastric cancer xenograft in S phase distinctly diminished in DDP group and DDP + rhGH group compared with control group and rhGH group (p < 0.05), but they were not statistically significant between DDP group and DDP + rhGH group or between control group and rhGH group. IGF-I and IGFBP-3 of blood serum of nude mice obviously rose, but ratio of IGF-I and IGFBP-3 obviously lowered in rhGH group and DDP + rhGH group compared with control group and DDP group (p < 0.05). Expressions of IGF-I mRNA and IGF-IR mRNA were not obviously different in all groups. But expression of IGFBP-3 mRNA obviously increased in rhGH group, DDP group and DDP + rhGH group compared with control group; meanwhile, expression of IGFBP-3 mRNA also obviously increased in DDP + rhGH group compared with control group, DDP group and rhGH group. Conclusion: Our results indicated rhGH in short-time use did not improve proliferation of human gastric cancer cells and its mechanism was possible that rhGH in short-time use raised simultaneously IGF-I and IGFBP-3 of blood serum and increased IGFBP-3 mRNA, but degraded ratio of IGF-I and IGFBP-3 of blood serum in human gastric cancer cells.
References
[1]
Smith, G.D., Gunnell, D. and Holly, J. (2000) Cancer and Insulin-Like Growth Factor-I. A Potential Mechanism Linking the Environment with Cancer Risk. BMJ, 321, 847-848. http://dx.doi.org/10.1136/bmj.321.7265.847
[2]
Samani, A.A., Yakar, S., LeRoith, D. and Brodt, P. (2007) The Role of the IGF System in Cancer Growth and Metastasis: Overview and Recent Insights. Endocrine Reviews, 28, 20-47. http://dx.doi.org/10.1210/er.2006-0001
[3]
Bogarin, R. and Steinbok, P. (2009) Growth Hormone Treatment and Risk of Recurrence or Progression of Brain Tumors in Children: A Review. Child’s Nervous System, 25, 273-279. http://dx.doi.org/10.1007/s00381-008-0790-6
[4]
Losa, M., Gatti, E., Rossini, A. and Lanzi, R. (2008) Replacement Therapy with Growth Hormone and Pituitary Tumor Recurrence: The Relevance of the Problem. Journal of Endocrinological Investigation, 31, 75-78.
[5]
Arnold, J.R., Arnold, D.F., Marland, A., Karavitaki, N. and Wass, J.A. (2009) GH Replacement in Patients with Non-Functioning Pituitary Adenoma (NFA) Treated Solely by Surgery Is Not Associated with Increased Risk of Tumor Recurrence. Clinical Endocrinology, 70, 435-438. http://dx.doi.org/10.1111/j.1365-2265.2008.03391.x
[6]
Rohrer, T.R., Langer, T., Grabenbauer, G.G., Buchfelder, M., Glowatzki, M. and Dörr, H.G. (2010) Growth Hormone Therapy and the Risk of Tumor Recurrence after Brain Tumor Treatment in Children. Journal of Pediatric Endocrinology and Metabolism, 23, 935-942. http://dx.doi.org/10.1515/jpem.2010.150
[7]
Chen, J.Y., Zhang, J., Tan, J., Gan, P., Sun, M. and Chen, X.Z. (1999) Evaluation of Human Growth Hormone on Gastric and Gastric Cancer Patients after Surgery. Chinese Journal of Base and Clinics in General Surgery, 6, 365-367.
[8]
Chen, J.Y., Gan, P., Xu, P.Y., Zhang, J., Tan, J. and Sun, M. (2000) Effects of Growth Hormone on Protein Catabolism and Immunologic Function of Postoperative Old Age Patients with Digestive Tract Tumor. Chinese Journal of Gerontology, 20, 162-163.
[9]
Harrison, L.E., Blumberg, D., Berman, R., Ng, B., Hochwald, S., Brennan, M.F. and Burt, M. (1996) Effect of Human Growth Hormone on Human Pancreatic Carcinoma Growth, Protein and Cell Cycle Kinetic. Journal of Surgical Research, 61, 317-322. http://dx.doi.org/10.1006/jsre.1996.0123
[10]
Tacke, J., Bolder, U., Herrmann, A., Berger, G. and Jauch, K.W. (2000) Long-Term Risk of Gastrointestinal Tumor Recurrence after Postoperative Treatment with Recombinant Human Growth Hormone. JPEN, 24, 140-144. http://dx.doi.org/10.1177/0148607100024003140
[11]
Bartlett, D.L.T., Stein, P., Torosian, M.H., Philadelphia, P.A. and Camden, N.J. (1995) Effect of Growth Hormone and Protein Intake on Tumor Growth and Host Cachexia. Surgery, 117, 260-267. http://dx.doi.org/10.1016/S0039-6060(05)80199-0
[12]
Beentjes, J.A., van Gorkom, B.A., Sluiter, W.J., de Vries, E.G., Kleibeuker, J.H. and Dullaart, R.P. (2000) One Year Growth Hormone Replacement Therapy Does Not Alter Colonic Epithelial Cell Proliferation in Growth Hormone Deficient Adults. Clinical Endocrinology, 52, 457-462. http://dx.doi.org/10.1046/j.1365-2265.2000.00993.x
[13]
Blethen, S.L., Allen, D.B., Graves, D., August, G., Moshang, T. and Rosenfeld, R. (1996) Safety of Recombinant Deoxyribonucleic Acid-Derived Growth Hormone: The National Cooperative Growth Study Experience. Journal of Clinical Endocrinology and Metabolism, 81, 1704-1710.
[14]
Chen, J.Y., Liang, D.M., Gan, P., Zhang, Y. and Lin, J. (2004) In Vitro Effects of Recombinant Human Growth Hormone on Growth of Human Gastric Cancer Cell Line BGC823 Cells. World Journal of Gastroenterology, 10, 1132-1136.
[15]
Liang, D.M., Chen, J.Y., Zhang, Y., Gan, P., Lin, J. and Chen, A.B. (2006) Effects of Recombinant Human Growth Hormone on Growth of a Human Gastric Carcinoma Xenograft Model in Nude Mice. World Journal of Gastroenterology, 12, 3810-3813.
[16]
Osieka, R., Houchens, D.P., Goldin, A. and Johnson, R.K. (1977) Chemotherapy of Human Colon Cancer Xenografts in Athymic Nude Mice. Cancer, 40, 2640-2650.
[17]
Lin, Y., Li, S., Cao, P., Cheng, L., Quan, M. and Jiang, S. (2011) The Effects of Recombinant Human GH on Promoting Tumor Growth Depend on the Expression of GH Receptor in Vivo. Journal of Endocrinology, 211, 249-256. http://dx.doi.org/10.1530/JOE-11-0100
[18]
Heemskerk, V.H., Daemen, M.A. and Buurman, W.A. (1999) Insulin-Like Growth Factor-I (IGF-I) and Growth Hormone (GH) in Immunity and Inflammation. Cytokine & Growth Factor Reviews, 10, 5-14.
[19]
Berneis, K. and Keller, U. (1996) Metabolic Actions of Growth Hormone: Direct and Indirect. Baillière’s Clinical Endocrinology and Metabolism, 10, 337-352. http://dx.doi.org/10.1016/S0950-351X(96)80470-8
[20]
LeRoith, D. and Yakar, S. (2007) Mechanisms of Disease: Metabolic Effects of Growth Hormone and Insulin-Like Growth Factor I. Nature Clinical Practice. Endocrinology & Metabolism, 3, 302-310.
[21]
Hayes, V.Y., Urban, R.J., Jiang, J., Marcell, T.J., Helgeson, K. and Mauras, N. (2001) Recombinant Human Growth Hormone and Recombinant Human Insulin-Like Growth Factor I Diminish the Catabolic Effects of Hypogonadism in Man: Metabolic and Molecular Effects. Journal of Clinical Endocrinology & Metabolism, 86, 2211-2219.
[22]
Mauras, N. and Haymond, M.W. (2005) Are the Metabolic Effects of GH and IGF-I Separable? Growth Hormone & IGF Research, 15, 19-27.
[23]
Mauras, N., Martinez, V., Rini, A. and Guevara-Aguirre, J. (2000) Recombinant Human Insulin-Like Growth Factor Has Significant Anabolic Effects in Adults with Growth Hormone Receptor Deficiency: Studies on Protein, Glucose, and Lipid Metabolism. Journal of Clinical Endocrinology & Metabolism, 85, 3036-3042.
[24]
Shimoda, N., Tashiro, T., Yamamori, H., Takagi, K., Nakajima, N. and Ito, I. (1997) Effects of Growth Hormone and Insulin-Like Growth Factor I on Protein Metabolism, Gut Morphology, and Cell-Mediated Immunity in Burned Rats. Nutrition, 13, 540-516.
[25]
Shaneyfelt, T., Husein, R., Bubley, G. and Mantzoros, C.S. (2000) Hormonal Predictors of Prostate Cancer: A Meta-Analysis. Journal of Clinical Oncology, 18, 847-853.
[26]
Toniolo, P., Bruning, P.F., Akhmedkhanov, A., Bonfrer, J.M., Koenig, K.L., Lukanova, A., Shore, R.E. and Zeleniuch-Jacquotte, A. (2000) Serum Insulin-Like Growth Factor-I and Breast Cancer. International Journal of Cancer, 88, 828-832. http://dx.doi.org/10.1002/1097-0215(20001201)88:5<828::AID-IJC22>3.0.CO;2-8
[27]
Ibrahim, Y.H. and Yee, D. (2004) Insulin-Like Growth Factor-I and Cancer Risk. Growth Hormone & IGF Research, 14, 261-269. http://dx.doi.org/10.1016/j.ghir.2004.01.005
[28]
Tomizawa, M., Shinozaki, F., Sugiyama, T., Yamamoto, S., Sueishi, M. and Yoshida, T. (2010) Insulin-Like Growth Factor-I Receptor in Proliferation and Motility of Pancreatic Cancer. World Journal of Gastroenterology, 16, 1854-1858. http://dx.doi.org/10.3748/wjg.v16.i15.1854
[29]
Koenuma, M., Yamori, T. and Tsuruo, T. (1989) Insulin and Insulin-Like Growth Factor I Stimulate Proliferation of Metastatic Variants of Colon Carcinoma 26. Cancer Science, 80, 51-58. http://dx.doi.org/10.1111/j.1349-7006.1989.tb02244.x
[30]
Lippman, M.E. (1985) Growth Regulation of Human Breast Cancer. Clinical Research, 33, 375-382.
[31]
Li, S.L., Liang, S.J., Guo, N., Wu, A.M. and Fujita-Yamaguchi, Y. (2000) Single-Chain Antibodies against Human Insulin-Like Growth Factor I Receptor: Expression, Purification, and Effect on Tumor Growth. Cancer Immunology, Immunotherapy, 49, 243-252. http://dx.doi.org/10.1007/s002620000115
[32]
Reinmuth, N., Liu, W., Fan, F., Jung, Y.D., Ahmad, S.A., Stoeltzing, O., Bucana, C.D., Radinsky, R. and Ellis, L.M. (2002) Blockade of Insulin-Like Growth Factor I Receptor Function Inhibits Growth and Angiogenesis of Colon Cancer. Clinical Cancer Research, 8, 3259-3569.
[33]
Key, T.J., Appleby, G.N., Reeves, G.K. and Roddam, A.W. (2010) Insulin-Like Growth Factor I (IGF1), IGF Binding Protein 3 (IGFBP3), and Breast Cancer Risk: Pooled Individual Data Analysis of 17 Prospective Studies. Lancet Oncology, 11, 530-542. http://dx.doi.org/10.1016/S1470-2045(10)70095-4
[34]
Ma, J., Pollak, M.N., Giovannucci, E., Chan, J.M., Tao, Y., Hennekens, C.H. and Stampfer, M.J. (1999) Prospective Study of Colorectal Cancer Risk in Men and Plasma Levels of Insulin-Like Growth Factor (IGF)-I and IGF-Binding Protein-3. Journal of the National Cancer Institute, 91, 620-625. http://dx.doi.org/10.1093/jnci/91.7.620
[35]
Cleveland, R.J., Gammon, M.D., Edmiston, S.N., Teitelbaum, S.L., Britton, J.A., Terry, M.B., Eng, S.M., Neugut, A.I., Santella, R.M. and Conway, K. (2006) IGF1 CA Repeat Polymorphisms, Lifestyle Factors and Breast Cancer Risk in the Long Island Breast Cancer Study Project. Carcinogenesis, 27, 758-765. http://dx.doi.org/10.1093/carcin/bgi294
[36]
Zecevic, M., Amos, C.I., Gu, X., Campos, I.M., Jones, J.S., Lynch, P.M., Rodriguez-Bigas, M.A. and Frazier, M.L. (2006) IGF1 Gene Polymorphism and Risk for Hereditary Nonpolyposis Colorectal Cancer. Journal of the National Cancer Institute, 98, 139-143. http://dx.doi.org/10.1093/jnci/djj016
[37]
McGrath, M., Lee, I.M., Buring, J. and De Vivo, I. (2011) Common Genetic Variation within IGFI, IGFII, IGFBP-1, and IGFBP-3 and Endometrial Cancer Risk. Gynecologic Oncology, 120, 174-178. http://dx.doi.org/10.1016/j.ygyno.2010.10.012
[38]
Shitara, K., Ito, S., Misawa, K., Ito, Y., Ito, H., Hosono, S., Watanabe, M., Tajima, K., Tanaka, H., Muro, K. and Matsuo, K. (2012) Genetic Polymorphism of IGF-I Predicts Recurrence in Patients with Gastric Cancer Who Have Undergone Curative Gastrectomy. Annals of Oncology, 23, 659-664. http://dx.doi.org/10.1093/annonc/mdr293
[39]
Felice, D.L., El-Shennawy, L., Zhao, S., Lantvit, D.L., Shen, Q., Unterman, T.G., Swanson, S.M. and Frasor, J. (2013) Growth Hormone Potentiates 17β-Estradiol-Dependent Breast Cancer Cell Proliferation Independently of IGF-I Receptor Signaling. Endocrinology, 154, 3219-3227. http://dx.doi.org/10.1210/en.2012-2208
[40]
Wang, W., Iresjö, B.M., Karlsson, L. and Svanberg, E. (2000) Provision of rhIGF-I/IGFBP-3 Complex Attenuated Development of Cancer Cachexia in an Experimental Tumor Model. Clinical Nutrition, 19, 127-132. http://dx.doi.org/10.1054/clnu.1999.0090
[41]
Cohen, P., Clemmons, D.R. and Rosenfeld, R.G. (2000) Does the GH-IGF Axis Play a Role in Cancer Pathogenesis? Growth Hormone & IGF Research, 10, 297-305. http://dx.doi.org/10.1054/ghir.2000.0171
[42]
Izzo, L., Meggiorini, M.L., Nofroni, I., Pala, A., De Felice, C., Meloni, P., Simari, T., Izzo, S., Pugliese, F., Impara, L., Merlini, G., Di Cello, P., Cipolla, V., Forcione, A.R., Paliotta, A., Domenici, L. and Bolognese, A. (2012) Insulin-Like Growth Factor-I (IGF-1), IGF-Binding Protein-3 (IGFBP-3) and Mammographic Features. Il Giornale di Chirurgia, 33, 153-162.
[43]
Justová, V., Lacinová, Z., Melenovsky, V., Marek, J., Holly, J.M. and Hass, T. (2001) The Changes of IGF Binding Proteins after rhGH Administration to Patients Totally Dependent on Parenteral Nutrition. Growth Hormone & IGF Research, 11, 407-415. http://dx.doi.org/10.1054/ghir.2001.0257
