Abstract 932: Wnt antagonist, secreted frizzled-related protein 4 (SFRP4) and peptides from its associated domains, increases chemotherapeutic response of cancer stem cells of malignant mesothelioma cell lines
Authors: Vanathi Perumal, Senthil Kumar, Frank Arfuso, Simon Fox, Arunasalam Dharmarajan
Journal: Cancer Research (2017)

Abstract Malignant mesothelioma (MM) is a highly aggressive cancer associated with past asbestos exposure that is characterized by rapid progression, late metastases and poor prognosis. There is a need for much improved and novel therapies for this cancer through improved biological understanding of the disease.Previous studies have shown that SFRPs in general and SFRP4 in particular are down regulated in mesothelioma tissue and cell lines 1-4. Based on our own study and previously demonstrated a role for sFRP4 in making chemoresistant tumours amenable to chemotherapeutics 5-16. We have now progressed our work into the effects of peptides derived from the cysteine-rich domain and the netrin-like domain of sFRP4 on tumour initiating cells derived from MM cell lines.We examined the effect of secreted frizzled-related protein 4 (sFRP4), a Wnt signaling antagonist and its associated peptides, in chemosensitizing the MM cell line ONE 58 and JU77 and MM cancer stem cells (CSCs) enriched from these two cell lines to chemotherapeutics.We found tumorspheres exposed to sFRP4 and peptides alone and in combination with cisplatin induced cell death and decreased CD133 and ALDH1 expression.We thus identified for the first time that sFRP4 and associated peptides could help to sensitise to chemotherapeutics and destroy cancer stem cells of MM cell line, which would lead to effective treatment regimen to combat malignant mesothelioma. Our initial in vitro data exemplify the ability of these peptides in diminishing the numbers of therapy-resistant Tumor initiating cells (TICs). References: 1. Lee et al, 2004, Oncogene, 23(39), 6672-6676. 2. He et al, 2005 Cancer research, 65(3), 743-748. 3. Kohnoe et al 2010; Oncology reports, 24(2), 423 4. S.A. Fox et al., 2013 Biochem Biophys Res Commun. 2013 Oct 11;440(1):82-7 5. Perumal V et al., 2015 Int J Biochem Cell Biol, Mar 21;64:91-96 6. Wolf V et al., FEBS Lett 1997. 385-9 7. Hsieh M, et al., Endocrinology 2003, 144:4597-4606 8. Drake JM, et al., Apoptosis 2003, 8:389-397 9. Constantinou T, et al., J Mol Signal 2008, 3:10 10. White L, et al., Reprod Biomed Online 2009, 18:104-110 11. Muley A et al., Am J Pathol 2010, 176: 1505-1516 12. Longman D,et al., Oncology Research 2012, 20: 1-6 13. Uttara S, et al., BMC Cell Biology 2012,13: 25 14. Warrier A, et al., Cancer Gene Therapy 2014, 21: 381-388 15. Warrier S, et al., Oncology Research 2014 21: 9 16. Perumal V, et al, Exp Cell Res. 2016 Feb 15;341(2):218-24. Citation Format: Vanathi Perumal, Senthil Kumar, Frank Arfuso, Simon Fox, Arunasalam Dharmarajan. Wnt antagonist, secreted frizzled-related protein 4 (SFRP4) and peptides from its associated domains, increases chemotherapeutic response of cancer stem cells of malignant mesothelioma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 932. doi:10.1158/1538-7445.AM2017-932