Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Platelet-Derived Growth Factor Receptor-α Subunit Targeting Suppresses Metastasis in Advanced Thyroid Cancer In Vitro and In Vivo

  • Lin, Ching-Ling (Department of Internal Medicine, Cathay General Hospital) ;
  • Tsai, Ming-Lin (Department of General Surgery, Cathay General Hospital) ;
  • Chen, Yu-hsin (Department of Internal Medicine, Cathay General Hospital) ;
  • Liu, Wei-Ni (School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University) ;
  • Lin, Chun-Yu (Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University) ;
  • Hsu, Kai-Wen (Institute of New Drug Development, China Medical University) ;
  • Huang, Chien-Yu (Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University) ;
  • Chang, Yu-Jia (Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University) ;
  • Wei, Po-Li (Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University) ;
  • Chen, Shu-Huey (Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University) ;
  • Huang, Li-Chi (Department of Internal Medicine, Cathay General Hospital) ;
  • Lee, Chia-Hwa (School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University)
  • Received : 2020.11.12
  • Accepted : 2021.04.23
  • Published : 2021.09.01
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Abstract

Thyroid cancer is the most common endocrine malignancy. Patients with well-differentiated thyroid cancers, such as papillary and follicular cancers, have a favorable prognosis. However, poorly differentiated thyroid cancers, such as medullary, squamous and anaplastic advanced thyroid cancers, are very aggressive and insensitive to radioiodine treatment. Thus, novel therapies that attenuate metastasis are urgently needed. We found that both PDGFC and PDGFRA are predominantly expressed in thyroid cancers and that the survival rate is significantly lower in patients with high PDGFRA expression. This finding indicates the important role of PDGF/PDGFR signaling in thyroid cancer development. Next, we established a SW579 squamous thyroid cancer cell line with 95.6% PDGFRA gene insertion and deletions (indels) through CRISPR/Cas9. Protein and invasion analysis showed a dramatic loss in EMT marker expression and metastatic ability. Furthermore, xenograft tumors derived from PDGFRA geneedited SW579 cells exhibited a minor decrease in tumor growth. However, distant lung metastasis was completely abolished upon PDGFRA gene editing, implying that PDGFRA could be an effective target to inhibit distant metastasis in advanced thyroid cancers. To translate this finding to the clinic, we used the most relevant multikinase inhibitor, imatinib, to inhibit PDGFRA signaling. The results showed that imatinib significantly suppressed cell growth, induced cell cycle arrest and cell death in SW579 cells. Our developed noninvasive apoptosis detection sensor (NIADS) indicated that imatinib induced cell apoptosis through caspase-3 activation. In conclusion, we believe that developing a specific and selective targeted therapy for PDGFRA would effectively suppress PDGFRA-mediated cancer aggressiveness in advanced thyroid cancers.

Keywords

Acknowledgement

We would like to acknowledge the following for their kind services: Facility Center of Taipei Medical University; Instrument Center and the Laboratory Animal Center at the National Defense Medical Center. This study was also partially supported by "TMU Research Center of Cancer Translational Medicine", "the Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B)" and "Drug Development Center, China Medical University" from The Featured Areas Research Center Program with in the frame work of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. This study was supported by the Ministry of Science and Technology, grant Most-109-2628-B-038-014 for Dr. Lee, grant MOST-109-2314-B-281-007 for Dr. Lin, Cathay General Hospital, by the grant 108-CGH-TMU-04 for both Dr. Lin and Dr. Lee. This work was also financially supported from the Young Scholar Fellowship Program by the Ministry of Science and Technology (MOST) in Taiwan, Grant MOST 109-2636-B-009-007. None of the funding bodies were involved in the design of the study, the collection, analysis, and interpretation of the data, or the writing of the manuscript.

References

  1. Agaimy, A., Terracciano, L. M., Dirnhofer, S., Tornillo, L., Foerster, A., Hartmann, A. and Bihl, M. P. (2009) V600E BRAF mutations are alternative early molecular events in a subset of KIT/PDGFRA wild-type gastrointestinal stromal tumours. J. Clin. Pathol. 62, 613-616. https://doi.org/10.1136/jcp.2009.064550
  2. Ahmad, A., Wang, Z., Kong, D., Ali, R., Ali, S., Banerjee, S. and Sarkar, F. H. (2011) Platelet-derived growth factor-D contributes to aggressiveness of breast cancer cells by up-regulating Notch and NF-kappaB signaling pathways. Breast Cancer Res. Treat. 126, 15-25. https://doi.org/10.1007/s10549-010-0883-2
  3. Allen, T. M. (2002) Ligand-targeted therapeutics in anticancer therapy. Nat. Rev. Cancer 2, 750-763. https://doi.org/10.1038/nrc903
  4. Barretina, J., Caponigro, G., Stransky, N., Venkatesan, K., Margolin, A. A., Kim, S., Wilson, C. J., Lehar, J., Kryukov, G. V., Sonkin, D., Reddy, A., Liu, M., Murray, L., Berger, M. F., Monahan, J. E., Morais, P., Meltzer, J., Korejwa, A., Jane-Valbuena, J., Mapa, F. A., Thibault, J., Bric-Furlong, E., Raman, P., Shipway, A., Engels, I. H., Cheng, J., Yu, G. K., Yu, J., Aspesi, P., Jr., de Silva, M., Jagtap, K., Jones, M. D., Wang, L., Hatton, C., Palescandolo, E., Gupta, S., Mahan, S., Sougnez, C., Onofrio, R. C., Liefeld, T., MacConaill, L., Winckler, W., Reich, M., Li, N., Mesirov, J. P., Gabriel, S. B., Getz, G., Ardlie, K., Chan, V., Myer, V. E., Weber, B. L., Porter, J., Warmuth, M., Finan, P., Harris, J. L., Meyerson, M., Golub, T. R., Morrissey, M. P., Sellers, W. R., Schlegel, R. and Garraway, L. A. (2012) The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603-607. https://doi.org/10.1038/nature11003
  5. Bayot, M. L. and Limaiem, F. (2021) Biosafety guidelines. In Statpearls. Treasure Island (FL).
  6. Beckham, T. H., Romesser, P. B., Groen, A. H., Sabol, C., Shaha, A. R., Sabra, M., Brinkman, T., Spielsinger, D., McBride, S., Tsai, C. J., Riaz, N., Tuttle, R. M., Fagin, J. A., Sherman, E. J., Wong, R. J. and Lee, N. Y. (2018) Intensity-modulated radiation therapy with or without concurrent chemotherapy in nonanaplastic thyroid cancer with unresectable or gross residual disease. Thyroid 28, 1180-1189. https://doi.org/10.1089/thy.2018.0214
  7. Brill, A., Elinav, H. and Varon, D. (2004) Differential role of platelet granular mediators in angiogenesis. Cardiovasc. Res. 63, 226-235. https://doi.org/10.1016/j.cardiores.2004.04.012
  8. Capp, C., Wajner, S. M., Siqueira, D. R., Brasil, B. A., Meurer, L. and Maia, A. L. (2010) Increased expression of vascular endothelial growth factor and its receptors, VEGFR-1 and VEGFR-2, in medullary thyroid carcinoma. Thyroid 20, 863-871. https://doi.org/10.1089/thy.2009.0417
  9. Chaudhry, A., Papanicolaou, V., Oberg, K., Heldin, C. H. and Funa, K. (1992) Expression of platelet-derived growth factor and its receptors in neuroendocrine tumors of the digestive system. Cancer Res. 52, 1006-1012.
  10. Chen, P. H., Chen, X. and He, X. (2013) Platelet-derived growth factors and their receptors: structural and functional perspectives. Biochim. Biophys. Acta 1834, 2176-2186. https://doi.org/10.1016/j.bbapap.2012.10.015
  11. Chen, S. H., Chow, J. M., Hsieh, Y. Y., Lin, C. Y., Hsu, K. W., Hsieh, W. S., Chi, W. M., Shabangu, B. M. and Lee, C. H. (2019) HDAC1,2 knock-out and HDACi induced cell apoptosis in imatinib-resistant K562 cells. Int. J. Mol. Sci. 20, 2271. https://doi.org/10.3390/ijms20092271
  12. Chen, S. H., Hsieh, Y. Y., Tzeng, H. E., Lin, C. Y., Hsu, K. W., Chiang, Y. S., Lin, S. M., Su, M. J., Hsieh, W. S. and Lee, C. H. (2020) ABL genomic editing sufficiently abolishes oncogenesis of human chronic myeloid leukemia cells in vitro and in vivo. Cancers (Basel) 12, 1399. https://doi.org/10.3390/cancers12061399
  13. Chu, J. S., Ge, F. J., Zhang, B., Wang, Y., Silvestris, N., Liu, L. J., Zhao, C. H., Lin, L., Brunetti, A. E., Fu, Y. L., Wang, J., Paradiso, A. and Xu, J. M. (2013) Expression and prognostic value of VEGFR-2, PDGFR-beta, and c-Met in advanced hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 32, 16. https://doi.org/10.1186/1756-9966-32-16
  14. Clark, R. A., Folkvord, J. M., Hart, C. E., Murray, M. J. and McPherson, J. M. (1989) Platelet isoforms of platelet-derived growth factor stimulate fibroblasts to contract collagen matrices. J. Clin. Invest. 84, 1036-1040. https://doi.org/10.1172/JCI114227
  15. Corey, D. M., Rinkevich, Y. and Weissman, I. L. (2016) Dynamic patterns of clonal evolution in tumor vasculature underlie alterations in lymphocyte-endothelial recognition to foster tumor immune escape. Cancer Res. 76, 1348-1353. https://doi.org/10.1158/0008-5472.CAN-15-1150
  16. Ding, J., Li, X. M., Liu, S. L., Zhang, Y. and Li, T. (2014) Overexpression of platelet-derived growth factor-D as a poor prognosticator in endometrial cancer. Asian Pac. J. Cancer Prev. 15, 3741-3745. https://doi.org/10.7314/APJCP.2014.15.8.3741
  17. Hagglof, C., Hammarsten, P., Josefsson, A., Stattin, P., Paulsson, J., Bergh, A. and Ostman, A. (2010) Stromal PDGFRbeta expression in prostate tumors and non-malignant prostate tissue predicts prostate cancer survival. PLoS ONE 5, e10747. https://doi.org/10.1371/journal.pone.0010747
  18. Hayat, M. J., Howlader, N., Reichman, M. E. and Edwards, B. K. (2007) Cancer statistics, trends, and multiple primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) Program. Oncologist 12, 20-37. https://doi.org/10.1634/theoncologist.12-1-20
  19. Hsu, K. W., Huang, C. Y., Tam, K. W., Lin, C. Y., Huang, L. C., Lin, C. L., Hsieh, W. S., Chi, W. M., Chang, Y. J., Wei, P. L., Chen, S. T. and Lee, C. H. (2018) The application of non-invasive apoptosis detection sensor (NIADS) on histone deacetylation inhibitor (HDACi)-induced breast cancer cell death. Int. J. Mol. Sci. 19, 452. https://doi.org/10.3390/ijms19020452
  20. Huang, L. C., Tam, K. W., Liu, W. N., Lin, C. Y., Hsu, K. W., Hsieh, W. S., Chi, W. M., Lee, A. W., Yang, J. M., Lin, C. L. and Lee, C. H. (2018) CRISPR/Cas9 genome editing of epidermal growth factor receptor sufficiently abolished oncogenicity in anaplastic thyroid cancer. Dis. Markers 2018, 3835783. https://doi.org/10.1155/2018/3835783
  21. Huang, W., Fridman, Y., Bonfil, R. D., Ustach, C. V., Conley-LaComb, M. K., Wiesner, C., Saliganan, A., Cher, M. L. and Kim, H. R. (2012) A novel function for platelet-derived growth factor D: induction of osteoclastic differentiation for intraosseous tumor growth. Oncogene 31, 4527-4535. https://doi.org/10.1038/onc.2011.573
  22. Jechlinger, M., Sommer, A., Moriggl, R., Seither, P., Kraut, N., Capodiecci, P., Donovan, M., Cordon-Cardo, C., Beug, H. and Grunert, S. (2006) Autocrine PDGFR signaling promotes mammary cancer metastasis. J. Clin. Invest. 116, 1561-1570. https://doi.org/10.1172/JCI24652
  23. Kanaan, R. and Strange, C. (2017) Use of multitarget tyrosine kinase inhibitors to attenuate platelet-derived growth factor signalling in lung disease. Eur. Respir. Rev. 26, 170061. https://doi.org/10.1183/16000617.0061-2017
  24. Kim, M. J., Kim, S. K., Park, H. J., Chung, D. H., Park, H. K., Lee, J. S., Kwon, K. H. and Chung, J. H. (2012) PDGFRA promoter polymorphisms are associated with the risk of papillary thyroid cancer. Mol. Med. Rep. 5, 1267-1270. https://doi.org/10.3892/mmr.2012.784
  25. Kim, W. W., Ha, T. K. and Bae, S. K. (2018) Clinical implications of the BRAF mutation in papillary thyroid carcinoma and chronic lymphocytic thyroiditis. J. Otolaryngol. Head Neck Surg. 47, 4. https://doi.org/10.1186/s40463-017-0247-6
  26. Kunadharaju, R., Goyal, G., Rudraraju, A. and Silberstein, P. T. (2015) New treatment options for metastatic thyroid cancer. Fed. Pract. 32, 21S-26S.
  27. Lee, C. H., Huang, C. S., Chen, C. S., Tu, S. H., Wang, Y. J., Chang, Y. J., Tam, K. W., Wei, P. L., Cheng, T. C., Chu, J. S., Chen, L. C., Wu, C. H. and Ho, Y. S. (2010) Overexpression and activation of the alpha9-nicotinic receptor during tumorigenesis in human breast epithelial cells. J. Natl. Cancer Inst. 102, 1322-1335. https://doi.org/10.1093/jnci/djq300
  28. Lin, C. L., Tsai, M. L., Lin, C. Y., Hsu, K. W., Hsieh, W. S., Chi, W. M., Huang, L. C. and Lee, C. H. (2019) HDAC1 and HDAC2 double knockout triggers cell apoptosis in advanced thyroid cancer. Int. J. Mol. Sci. 20, 454. https://doi.org/10.3390/ijms20020454
  29. Lin, J. D. and Chao, T. C. (2005) Vascular endothelial growth factor in thyroid cancers. Cancer Biother. Radiopharm. 20, 648-661. https://doi.org/10.1089/cbr.2005.20.648
  30. Lindmark, G., Sundberg, C., Glimelius, B., Pahlman, L., Rubin, K. and Gerdin, B. (1993) Stromal expression of platelet-derived growth factor beta-receptor and platelet-derived growth factor b-chain in colorectal cancer. Lab. Invest. 69, 682-689.
  31. Liu, D., Hu, S., Hou, P., Jiang, D., Condouris, S. and Xing, M. (2007) Suppression of BRAF/MEK/MAP kinase pathway restores expression of iodide-metabolizing genes in thyroid cells expressing the V600E BRAF mutant. Clin. Cancer Res. 13, 1341-1349. https://doi.org/10.1158/1078-0432.CCR-06-1753
  32. Matei, D., Kelich, S., Cao, L., Menning, N., Emerson, R. E., Rao, J., Jeng, M. H. and Sledge, G. W. (2007) PDGF BB induces VEGF secretion in ovarian cancer. Cancer Biol. Ther. 6, 1951-1959. https://doi.org/10.4161/cbt.6.12.4976
  33. Medarametla, V., Festin, S., Sugarragchaa, C., Eng, A., Naqwi, A., Wiedmann, T. and Zisman, L. S. (2014) PK10453, a nonselective platelet-derived growth factor receptor inhibitor, prevents the progression of pulmonary arterial hypertension. Pulm. Circ. 4, 82-102. https://doi.org/10.1086/674881
  34. Peterson, J. E., Zurakowski, D., Italiano, J. E., Jr., Michel, L. V., Connors, S., Oenick, M., D'Amato, R. J., Klement, G. L. and Folkman, J. (2012) VEGF, PF4 and PDGF are elevated in platelets of colorectal cancer patients. Angiogenesis 15, 265-273. https://doi.org/10.1007/s10456-012-9259-z
  35. Sethi, S., Macoska, J., Chen, W. and Sarkar, F. H. (2010) Molecular signature of epithelial-mesenchymal transition (EMT) in human prostate cancer bone metastasis. Am. J. Transl. Res. 3, 90-99.
  36. Shalem, O., Sanjana, N. E., Hartenian, E., Shi, X., Scott, D. A., Mikkelsen, T. S., Heckl, D., Ebert, B. L., Root, D. E., Doench, J. G. and Zhang, F. (2014) Genome-scale CRISPR-Cas9 knockout screening in human cells. Science 343, 84-87. https://doi.org/10.1126/science.1247005
  37. Shao, Z. M., Nguyen, M. and Barsky, S. H. (2000) Human breast carcinoma desmoplasia is PDGF initiated. Oncogene 19, 4337-4345. https://doi.org/10.1038/sj.onc.1203785
  38. Sherman, S. I. (2010) Cytotoxic chemotherapy for differentiated thyroid carcinoma. Clin. Oncol. 22, 464-468. https://doi.org/10.1016/j.clon.2010.03.014
  39. Tang, K. T. and Lee, C. H. (2010) BRAF mutation in papillary thyroid carcinoma: pathogenic role and clinical implications. J. Chin. Med. Assoc. 73, 113-128. https://doi.org/10.1016/S1726-4901(10)70025-3
  40. Uhlen, M., Fagerberg, L., Hallstrom, B. M., Lindskog, C., Oksvold, P., Mardinoglu, A., Sivertsson, A., Kampf, C., Sjostedt, E., Asplund, A., Olsson, I., Edlund, K., Lundberg, E., Navani, S., Szigyarto, C. A., Odeberg, J., Djureinovic, D., Takanen, J. O., Hober, S., Alm, T., Edqvist, P. H., Berling, H., Tegel, H., Mulder, J., Rockberg, J., Nilsson, P., Schwenk, J. M., Hamsten, M., von Feilitzen, K., Forsberg, M., Persson, L., Johansson, F., Zwahlen, M., von Heijne, G., Nielsen, J. and Ponten, F. (2015) Proteomics. Tissue-based map of the human proteome. Science 347, 1260419. https://doi.org/10.1126/science.1260419
  41. Ustach, C. V., Huang, W., Conley-LaComb, M. K., Lin, C. Y., Che, M., Abrams, J. and Kim, H. R. (2010) A novel signaling axis of matriptase/PDGF-D/ss-PDGFR in human prostate cancer. Cancer Res. 70, 9631-9640. https://doi.org/10.1158/0008-5472.CAN-10-0511
  42. Villanueva, J., Vultur, A. and Herlyn, M. (2011) Resistance to BRAF inhibitors: unraveling mechanisms and future treatment options. Cancer Res. 71, 7137-7140. https://doi.org/10.1158/0008-5472.CAN-11-1243
  43. Wu, Q., Wang, R., Yang, Q., Hou, X., Chen, S., Hou, Y., Chen, C., Yang, Y., Miele, L., Sarkar, F. H., Chen, Y. and Wang, Z. (2013) Chemoresistance to gemcitabine in hepatoma cells induces epithelial-mesenchymal transition and involves activation of PDGF-D pathway. Oncotarget 4, 1999-2009. https://doi.org/10.18632/oncotarget.1471
  44. Xing, M. (2005) BRAF mutation in thyroid cancer. Endocr. Relat. Cancer 12, 245-262. https://doi.org/10.1677/erc.1.0978