Innovating Glioma Therapy Using Secretions from Umbilical Cord Mesenchymal Stem Cells to Target Homeobox and Growth Factor Genes
-
Ahmad Faried
,
Achmad Adam
,
Wahyu Widowati
,
Annisa Firdaus Sutendi
,
Faradhina Salfa Nindya
,
William Junino Saputro
,
Dhanar Septyawan Hadiprasetyo
Abstract
Background: Glioblastoma is a prevalent and challenging malignant brain tumor. Secretome therapy using human umbilical cord mesenchymal stem cells (hUCMSCs) appears to be a promising treatment for glioblastoma. This study analyzed the potential of the hUCMSC secretomes (hUCMSCs-sec) for glioma therapy.
Materials and Methods: Characterization of hUCMSCs was performed by examining certain markers, including CD44, CD90, CD105, CD73, CD13, CD19, CD14, CD45, CD34, and HLA-D. The cells' ability to differentiate into adipocytes, chondrocytes, and osteocytes was evaluated. Cytotoxic effect on Glioblastoma (GBM) cells was analyzed using 2-[2-methoxy-4-nitrophenyl]-3-[4-nitrophenyl]-5-[2,4-disulfophenyl]-2H-tetrazolium (WST-8). mRNA relative expression, including homeobox (HOXA5, HOXB1, HOXC9 and HOXC10), insulin-like growth factor binding protein 2 (IGFBP2), Extracellular signal-regulated kinases (ERK), Epidermal growth factor receptor (EGFR), and Caspase 3 (Casp3), were quantified by quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR).
Results: The hUCMSCs-sec was successfully isolated and identified, showing positive markers and its capacity to differentiate into chondrocytes, adipocytes, and osteocytes. hUCMSCs-sec exerted a cytotoxic effect on GBM cells and upregulated the expression of Casp3, whereas it decreased the expression of HOX, IGFBP2, EGFR, and ERK in GBM cells.
Conclusion: The secretomes from hUCMSCs show potential for GBM cell therapy by improving the deregulation of HOX, inducing apoptosis, and inhibiting cell proliferation genes.
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2. Laug D, Glasgow SM, Deneen B. A glial blueprint for gliomagenesis. Nat Rev Neurosci. 2018; 19(7):393-403.
3. Osuka S, Van Meir EG. Overcoming therapeutic resistance in glioblastoma: the way forward. J Clin Invest. 2017; 127(2):415-426.
4. Juratli TA, Schackert G, Krex D. Current status of local therapy for malignant gliomas—a clinical review of three selected approaches. Pharmacol Ther. 2013; 139(3):341-58.
5. Han Y, Wang H. MiR-3918 inhibits tumorigenesis of glioma via targeting EGFR to regulate the PI3K/AKT and ERK pathways. J Mol Neurosci. 2022; 72(2), 433-440.
6. Wei LF, Weng XF, Huang XC, et al. IGFBP2 in cancer: Pathological role and clinical significance (Review). Oncol Rep. 2021; 45(2):427-438.
7. Brotto DB, Siena ÁDD, de Barros II, et al. Contributions of HOX genes to cancer hallmarks: Enrichment pathway analysis and review. Tumour Biol. 2020; 42(5):1010428320918050.
8. Guan Y, He Y, Lv S, et al. Overexpression of HOXC10 promotes glioblastoma cell progression and poor prognosis via the PI3K/AKT signaling pathway. J Drug Target. 2019; 27(1):60-66.
9. Widowati W, Krisanti Jasaputra D, B Sumitro S, et al. Potential of unengineered and engineered wharton’s jelly mesenchymal stem cells as cancer inhibitor agent. Immunol Endocr Metab Agents Med Chem. 2015; 15(2), 128-137.
10. Damayanti RH, Rusdiana T, Wathoni N. Mesenchymal stem cell secretome for dermatology application: a review. Clin Cosmet Investig Dermatol. 2021; 14:1401-1412.
11. López de Andrés J, Griñán-Lisón C, Jiménez G, et al. Cancer stem cell secretomes in the tumor microenvironment: a key point for an effective personalized cancer treatment. J Hematol Oncol. 2020; 13(1):136.
12. Gomes ED, de Castro JV, Costa BM, et al. The impact of Mesenchymal Stem Cells and their secretomes as a treatment for gliomas. Biochimie. 2018; 155:59-66.
13. Mirabdollahi M, Haghjooyjavanmard S, Sadeghi-Aliabadi H. Anticancer effects of umbilical cord-derived mesenchymal stem cell secretomes on the breast cancer cell line. Cell Tissue Bank. 2019; 20(3):423-34.
14. Hendijani F, Javanmard SH, Rafiee L, et al. Effects of human Wharton’s jelly mesenchymal stem cell secretomes on proliferation, apoptosis and drug resistance of lung cancer cells. Res Pharm Sci. 2015; 10(2):134-42.
15. Lee YT, Tan YJ, Oon CE. Molecular targeted therapy: Treating cancer with specificity. Eur J Pharmacol. 2018; 834:188-96.
16. Widowati W, Wijaya L, Murti H, et al. Conditioned medium from normoxic (WJMSCs-norCM) and hypoxia-treated WJMSCs (WJMSCs-hypoCM) WJMSCs to inhibit cancer cell proliferation. Biomark Genom Med. 2015; 7(1):8-17.
17. Widowati W, Gunanegara RF, Rizal R, et al. Comparative analysis of Wharton’s Jelly mesenchymal stem cells (WJ-MSCs) isolated using explant and enzymatic methods. In J Phys: Conf Ser. 2019; 1374(1):012024.
18. Widowati W, Jasaputra DK, Kusuma HS, et al. Hypoxic and Normoxic-Human Wharton’s Jelly Mesenchymal Stem Cell-Free Lysate for Anticancer Therapies, Walailak J Sci & Tech. 2021; 18(9):9270.
19. Widowati W, Priyandoko D, Lenny L, et al. Extract Suppresses Inflammation on Acute Respiratory Distress Syndrome Cells Models via Decreasing IL-1ß, IL-6 and COX-2 Expressions. Trends Sci. 2023; 21(1):7010.
20. Maleki M, Ghanbarvand F, Behvarz MR, et al. Comparison of mesenchymal stem cell markers in multiple human adult stem cells. Int J Stem Cells. 2014; 7(2):118-26.
21. Ghaneialvar H, Soltani L, Rahmani HR, et al. Characterization and classification of mesenchymal stem cells from several species using surface markers for cell therapy purposes. Indian J Clin Biochem. 2018; 33(1):46-52.
22. Amidi F, Hoseini MA, Nia KN, et al. Male germ-like cell differentiation potential of human umbilical cord Wharton’s jelly-derived mesenchymal stem cells in co-culture with human placenta cells in presence of BMP4 and retinoic acid. Iran J Basic Med Sci. 2015;18(4):325-33.
23. Ratajczak MZ, Bujko K, Ciechanowicz A, et al. SARS-CoV-2 entry receptor ACE2 is expressed on very small CD45− precursors of hematopoietic and endothelial cells and in response to virus spike protein activates the Nlrp3 inflammasome. Stem Cell Rev Rep. 2021; 1791):266-277.
24. Duan M, Steinfort DP, Smallwood D, et al. CD11b immunophenotyping identifies inflammatory profiles in the mouse and human lungs. Mucosal Immunol. 2016; 9(2):550-63.
25. Erokhina SA, Streltsova MA, Kanevskiy LM, et al. HLA-DR-expressing NK cells: Effective killers suspected for antigen presentation. J Leukoc Biol. 2021; 109(2):327-337.
26. Denu RA, Nemcek S, Bloom DD, et al. Fibroblasts and mesenchymal stromal/stem cells are phenotypically indistinguishable. Acta Haematol. 2016; 136(2):85-97.
27. Kornicka K, Marycz K, Tomaszewski KA, et al. The effect of age on osteogenic and adipogenic differentiation potential of human adipose-derived stromal stem cells (hASCs) and the impact of stress factors in the course of the differentiation process. Oxid Med Cell Longev. 2015:2015:309169.
28. Han SM, Han SH, Coh YR, et al. Enhanced proliferation and differentiation of Oct4- and Sox2-overexpressing human adipose tissue mesenchymal stem cells. Exp Mol Med. 2014; 46(6):e101.
29. Sadri M, Abdolmaleki P, Abrun S, et al. Static magnetic field effect on cell alignment, growth, and differentiation in human cord-derived mesenchymal stem cells. Cell Mol Bioeng. 2017; 10(3):249-262.
30. Nakayama N, Pothiawala A, Lee JY, et al. Human pluripotent stem cell-derived chondroprogenitor for cartilage tissue engineering. Cell Mol Life Sci. 2020; 77(13):2543-2563.
31. Kuntjoro M, Agustono B, Prasetyo EP, et al. The effect of Advanced Glycation End products (AGEs) on human Umbilical Cord Mesenchymal Stem Cells (hUCMSCS) about osteogenesis and calcification. Res J Pharm Tech. 2021; 14(8):4019-4024.
32. Lin Z, Wu Y, Xu Y, et al. Mesenchymal stem cell-derived exosome for cancer therapy resistance: recent advances and therapeutic potential. Mol Cancer. 2022;21(1):179.
33. Karaoz E, Sun E, Demir CS. Mesenchymal stem cell-derived exosome do not promote cancer cell proliferation in vitro. Int J Physiol, Pathophysiol Pharmacol. 2019; 11(4):177-189.
34. Widowati W, Murti H, Widyastuti H, et al. Decreased inhibition of proliferation and induction of apoptosis in breast cancer cell lines (T47D and MCF7) following treatment with conditioned medium derived from hypoxia-treated Whiterton’s jelly msc compared with normoxia-treated MSCs. Int J Hematol Oncol Stem Cell Res. 2021; 15(2):77-89.
35. Zhuang WZ, Lin YH, Su LJ, et al. Mesenchymal stem/stromal cell-based therapy: Mechanism, systemic safety, and biodistribution for precision clinical applications. J Biomed Sci. 2021; 28(1):28.
36. Bhatlekar S, Fields JZ, Boman BM. HOX genes and their role in the development of human cancers. J Mol Med (Berl). 2014; 92(8):811-23.
37. Cimino PJ, Kim Y, Wu HJ, et al. Increased HOXA5 expression provides a selective advantage for gain of whole chromosome 7 in IDH wild-type glioblastoma. Genes Dev. 2018; 32(7-8):512-523.
38. Sugiura R, Satoh R, Takasaki T. ERK: a double-edged sword in cancer. ERK-dependent apoptosis as a potential therapeutic strategy for cancer. Cells. 2021; 10(10):2509.
39. Fong Y, Wu CY, Chang KF, et al. Dual roles of extracellular signal-regulated kinase (ERK) in quinoline compound BPIQ-induced apoptosis and anti-migration of human non-small cell lung cancer cells. Cancer Cell Int. 2017; 17:37.
40. Ebadi Zavieh S, Safari F. The antitumor activity of hAMSC secretomes in HT-29 colon cancer cells through downregulation of EGFR/c-Src/IRTKS expression and p38/ERK1/2 phosphorylation. Cell Biochem Biophys. 2022; 80(2):395-402.
41. Phillips LM, Zhou X, Cogdell DE, et al. Glioma progression is mediated by an addiction to aberrant IGFBP2 expression, which can be blocked using anti‐IGFBP2 strategies. J Pathol. 2016; 239(3):355-64.
42. Eskandari E, Eaves CJ. Paradoxical roles of caspase-3 in the regulation of cell survival, proliferation, and tumorigenesis. J Cell Biol. 2022; 221(6):e202201159.
43. Rezaei-Tazangi F, Alidadi H, Samimi A, et al. Effects of Wharton’s jelly mesenchymal stem cells-derived secretomes on colon carcinoma HT-29 cells. Tissue Cell. 2020; 67:101413.
44. Said YM, El-Gamel NE, Ali SA, et al. Evaluation of Human Whartons Jelly-Derived Mesenchymal Stem Cell Conditioning Medium (hWJ-MSCs-CM) and Scorpion Venom Breast Cancer Cell Line In Vitro. J Gastrointest Cancer. 2022;53(4):888-901.
2. Laug D, Glasgow SM, Deneen B. A glial blueprint for gliomagenesis. Nat Rev Neurosci. 2018; 19(7):393-403.
3. Osuka S, Van Meir EG. Overcoming therapeutic resistance in glioblastoma: the way forward. J Clin Invest. 2017; 127(2):415-426.
4. Juratli TA, Schackert G, Krex D. Current status of local therapy for malignant gliomas—a clinical review of three selected approaches. Pharmacol Ther. 2013; 139(3):341-58.
5. Han Y, Wang H. MiR-3918 inhibits tumorigenesis of glioma via targeting EGFR to regulate the PI3K/AKT and ERK pathways. J Mol Neurosci. 2022; 72(2), 433-440.
6. Wei LF, Weng XF, Huang XC, et al. IGFBP2 in cancer: Pathological role and clinical significance (Review). Oncol Rep. 2021; 45(2):427-438.
7. Brotto DB, Siena ÁDD, de Barros II, et al. Contributions of HOX genes to cancer hallmarks: Enrichment pathway analysis and review. Tumour Biol. 2020; 42(5):1010428320918050.
8. Guan Y, He Y, Lv S, et al. Overexpression of HOXC10 promotes glioblastoma cell progression and poor prognosis via the PI3K/AKT signaling pathway. J Drug Target. 2019; 27(1):60-66.
9. Widowati W, Krisanti Jasaputra D, B Sumitro S, et al. Potential of unengineered and engineered wharton’s jelly mesenchymal stem cells as cancer inhibitor agent. Immunol Endocr Metab Agents Med Chem. 2015; 15(2), 128-137.
10. Damayanti RH, Rusdiana T, Wathoni N. Mesenchymal stem cell secretome for dermatology application: a review. Clin Cosmet Investig Dermatol. 2021; 14:1401-1412.
11. López de Andrés J, Griñán-Lisón C, Jiménez G, et al. Cancer stem cell secretomes in the tumor microenvironment: a key point for an effective personalized cancer treatment. J Hematol Oncol. 2020; 13(1):136.
12. Gomes ED, de Castro JV, Costa BM, et al. The impact of Mesenchymal Stem Cells and their secretomes as a treatment for gliomas. Biochimie. 2018; 155:59-66.
13. Mirabdollahi M, Haghjooyjavanmard S, Sadeghi-Aliabadi H. Anticancer effects of umbilical cord-derived mesenchymal stem cell secretomes on the breast cancer cell line. Cell Tissue Bank. 2019; 20(3):423-34.
14. Hendijani F, Javanmard SH, Rafiee L, et al. Effects of human Wharton’s jelly mesenchymal stem cell secretomes on proliferation, apoptosis and drug resistance of lung cancer cells. Res Pharm Sci. 2015; 10(2):134-42.
15. Lee YT, Tan YJ, Oon CE. Molecular targeted therapy: Treating cancer with specificity. Eur J Pharmacol. 2018; 834:188-96.
16. Widowati W, Wijaya L, Murti H, et al. Conditioned medium from normoxic (WJMSCs-norCM) and hypoxia-treated WJMSCs (WJMSCs-hypoCM) WJMSCs to inhibit cancer cell proliferation. Biomark Genom Med. 2015; 7(1):8-17.
17. Widowati W, Gunanegara RF, Rizal R, et al. Comparative analysis of Wharton’s Jelly mesenchymal stem cells (WJ-MSCs) isolated using explant and enzymatic methods. In J Phys: Conf Ser. 2019; 1374(1):012024.
18. Widowati W, Jasaputra DK, Kusuma HS, et al. Hypoxic and Normoxic-Human Wharton’s Jelly Mesenchymal Stem Cell-Free Lysate for Anticancer Therapies, Walailak J Sci & Tech. 2021; 18(9):9270.
19. Widowati W, Priyandoko D, Lenny L, et al. Extract Suppresses Inflammation on Acute Respiratory Distress Syndrome Cells Models via Decreasing IL-1ß, IL-6 and COX-2 Expressions. Trends Sci. 2023; 21(1):7010.
20. Maleki M, Ghanbarvand F, Behvarz MR, et al. Comparison of mesenchymal stem cell markers in multiple human adult stem cells. Int J Stem Cells. 2014; 7(2):118-26.
21. Ghaneialvar H, Soltani L, Rahmani HR, et al. Characterization and classification of mesenchymal stem cells from several species using surface markers for cell therapy purposes. Indian J Clin Biochem. 2018; 33(1):46-52.
22. Amidi F, Hoseini MA, Nia KN, et al. Male germ-like cell differentiation potential of human umbilical cord Wharton’s jelly-derived mesenchymal stem cells in co-culture with human placenta cells in presence of BMP4 and retinoic acid. Iran J Basic Med Sci. 2015;18(4):325-33.
23. Ratajczak MZ, Bujko K, Ciechanowicz A, et al. SARS-CoV-2 entry receptor ACE2 is expressed on very small CD45− precursors of hematopoietic and endothelial cells and in response to virus spike protein activates the Nlrp3 inflammasome. Stem Cell Rev Rep. 2021; 1791):266-277.
24. Duan M, Steinfort DP, Smallwood D, et al. CD11b immunophenotyping identifies inflammatory profiles in the mouse and human lungs. Mucosal Immunol. 2016; 9(2):550-63.
25. Erokhina SA, Streltsova MA, Kanevskiy LM, et al. HLA-DR-expressing NK cells: Effective killers suspected for antigen presentation. J Leukoc Biol. 2021; 109(2):327-337.
26. Denu RA, Nemcek S, Bloom DD, et al. Fibroblasts and mesenchymal stromal/stem cells are phenotypically indistinguishable. Acta Haematol. 2016; 136(2):85-97.
27. Kornicka K, Marycz K, Tomaszewski KA, et al. The effect of age on osteogenic and adipogenic differentiation potential of human adipose-derived stromal stem cells (hASCs) and the impact of stress factors in the course of the differentiation process. Oxid Med Cell Longev. 2015:2015:309169.
28. Han SM, Han SH, Coh YR, et al. Enhanced proliferation and differentiation of Oct4- and Sox2-overexpressing human adipose tissue mesenchymal stem cells. Exp Mol Med. 2014; 46(6):e101.
29. Sadri M, Abdolmaleki P, Abrun S, et al. Static magnetic field effect on cell alignment, growth, and differentiation in human cord-derived mesenchymal stem cells. Cell Mol Bioeng. 2017; 10(3):249-262.
30. Nakayama N, Pothiawala A, Lee JY, et al. Human pluripotent stem cell-derived chondroprogenitor for cartilage tissue engineering. Cell Mol Life Sci. 2020; 77(13):2543-2563.
31. Kuntjoro M, Agustono B, Prasetyo EP, et al. The effect of Advanced Glycation End products (AGEs) on human Umbilical Cord Mesenchymal Stem Cells (hUCMSCS) about osteogenesis and calcification. Res J Pharm Tech. 2021; 14(8):4019-4024.
32. Lin Z, Wu Y, Xu Y, et al. Mesenchymal stem cell-derived exosome for cancer therapy resistance: recent advances and therapeutic potential. Mol Cancer. 2022;21(1):179.
33. Karaoz E, Sun E, Demir CS. Mesenchymal stem cell-derived exosome do not promote cancer cell proliferation in vitro. Int J Physiol, Pathophysiol Pharmacol. 2019; 11(4):177-189.
34. Widowati W, Murti H, Widyastuti H, et al. Decreased inhibition of proliferation and induction of apoptosis in breast cancer cell lines (T47D and MCF7) following treatment with conditioned medium derived from hypoxia-treated Whiterton’s jelly msc compared with normoxia-treated MSCs. Int J Hematol Oncol Stem Cell Res. 2021; 15(2):77-89.
35. Zhuang WZ, Lin YH, Su LJ, et al. Mesenchymal stem/stromal cell-based therapy: Mechanism, systemic safety, and biodistribution for precision clinical applications. J Biomed Sci. 2021; 28(1):28.
36. Bhatlekar S, Fields JZ, Boman BM. HOX genes and their role in the development of human cancers. J Mol Med (Berl). 2014; 92(8):811-23.
37. Cimino PJ, Kim Y, Wu HJ, et al. Increased HOXA5 expression provides a selective advantage for gain of whole chromosome 7 in IDH wild-type glioblastoma. Genes Dev. 2018; 32(7-8):512-523.
38. Sugiura R, Satoh R, Takasaki T. ERK: a double-edged sword in cancer. ERK-dependent apoptosis as a potential therapeutic strategy for cancer. Cells. 2021; 10(10):2509.
39. Fong Y, Wu CY, Chang KF, et al. Dual roles of extracellular signal-regulated kinase (ERK) in quinoline compound BPIQ-induced apoptosis and anti-migration of human non-small cell lung cancer cells. Cancer Cell Int. 2017; 17:37.
40. Ebadi Zavieh S, Safari F. The antitumor activity of hAMSC secretomes in HT-29 colon cancer cells through downregulation of EGFR/c-Src/IRTKS expression and p38/ERK1/2 phosphorylation. Cell Biochem Biophys. 2022; 80(2):395-402.
41. Phillips LM, Zhou X, Cogdell DE, et al. Glioma progression is mediated by an addiction to aberrant IGFBP2 expression, which can be blocked using anti‐IGFBP2 strategies. J Pathol. 2016; 239(3):355-64.
42. Eskandari E, Eaves CJ. Paradoxical roles of caspase-3 in the regulation of cell survival, proliferation, and tumorigenesis. J Cell Biol. 2022; 221(6):e202201159.
43. Rezaei-Tazangi F, Alidadi H, Samimi A, et al. Effects of Wharton’s jelly mesenchymal stem cells-derived secretomes on colon carcinoma HT-29 cells. Tissue Cell. 2020; 67:101413.
44. Said YM, El-Gamel NE, Ali SA, et al. Evaluation of Human Whartons Jelly-Derived Mesenchymal Stem Cell Conditioning Medium (hWJ-MSCs-CM) and Scorpion Venom Breast Cancer Cell Line In Vitro. J Gastrointest Cancer. 2022;53(4):888-901.
| Files | ||
| Issue | Vol 19 No 1 (2025) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijhoscr.v19i1.17820 | |
| Keywords | ||
| Cytotoxic; mRNA expression; Glioblastoma therapy; human umbilical cord mesenchymal stem cells (hUCMSCs); Secretome | ||
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How to Cite
1.
Faried A, Adam A, Widowati W, Sutendi A, Nindya F, Saputro W, Hadiprasetyo D. Innovating Glioma Therapy Using Secretions from Umbilical Cord Mesenchymal Stem Cells to Target Homeobox and Growth Factor Genes. Int J Hematol Oncol Stem Cell Res. 2025;19(1):17-28.
