Impact of mesenchymal stem cells’ secretome on glioblastoma pathophysiology

Journal of Translational Medicine, Oct 2017

Glioblastoma (GBM) is a highly aggressive primary brain cancer, for which curative therapies are not available. An emerging therapeutic approach suggested to have potential to target malignant gliomas has been based on the use of multipotent mesenchymal stem cells (MSCs), either unmodified or engineered to deliver anticancer therapeutic agents, as these cells present an intrinsic capacity to migrate towards malignant tumors. Nevertheless, it is still controversial whether this innate tropism of MSCs towards the tumor area is associated with cancer promotion or suppression. Considering that one of the major mechanisms by which MSCs interact with and modulate tumor cells is via secreted factors, we studied how the secretome of MSCs modulates critical hallmark features of GBM cells. The effect of conditioned media (CM) from human umbilical cord perivascular cells (HUCPVCs, a MSC population present in the Wharton’s jelly of the umbilical cord) on GBM cell viability, migration, proliferation and sensitivity to temozolomide treatment of U251 and SNB-19 GBM cells was evaluated. The in vivo chicken chorioallantoic membrane (CAM) assay was used to evaluate the effect of HUCPVCs CM on tumor growth and angiogenesis. The secretome of HUCPVCs was characterized by proteomic analyses. We found that both tested GBM cell lines exposed to HUCPVCs CM presented significantly higher cellular viability, proliferation and migration. In contrast, resistance of GBM cells to temozolomide chemotherapy was not significantly affected by HUCPVCs CM. In the in vivo CAM assay, CM from HUCPVCs promoted U251 and SNB-19 tumor cells growth. Proteomic analysis to characterize the secretome of HUCPVCs identified several proteins involved in promotion of cell survival, proliferation and migration, revealing novel putative molecular mediators for the effects observed in GBM cells exposed to HUCPVCs CM. These findings provide novel insights to better understand the interplay between GBM cells and MSCs, raising awareness to potential safety issues regarding the use of MSCs as stem-cell based therapies for GBM.

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Impact of mesenchymal stem cells’ secretome on glioblastoma pathophysiology

Vieira de Castro et al. J Transl Med Impact of mesenchymal stem cells' secretome on glioblastoma pathophysiology Joana Vieira de Castro 1 3 Eduardo D. Gomes 1 3 Sara Granja 1 3 Sandra I. Anjo 2 4 Fátima Baltazar 1 3 Bruno Manadas 2 António J. Salgado 0 1 3 Bruno M. Costa 0 1 3 0 António J. Salgado and Bruno M. Costa share senior authorship 1 Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar , 4710-057 Braga , Portugal 2 CNC-Center for Neuroscience and Cell Biology, University of Coimbra , 3004-517 Coimbra , Portugal 3 ICVS/3B's-PT Government Associate Laboratory, University of Minho, Braga/Guimarães, Campus de Gualtar , 4710-057 Braga , Portugal 4 Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra , 3004-517 Coimbra , Portugal Background: Glioblastoma (GBM) is a highly aggressive primary brain cancer, for which curative therapies are not available. An emerging therapeutic approach suggested to have potential to target malignant gliomas has been based on the use of multipotent mesenchymal stem cells (MSCs), either unmodified or engineered to deliver anticancer therapeutic agents, as these cells present an intrinsic capacity to migrate towards malignant tumors. Nevertheless, it is still controversial whether this innate tropism of MSCs towards the tumor area is associated with cancer promotion or suppression. Considering that one of the major mechanisms by which MSCs interact with and modulate tumor cells is via secreted factors, we studied how the secretome of MSCs modulates critical hallmark features of GBM cells. Methods: The effect of conditioned media (CM) from human umbilical cord perivascular cells (HUCPVCs, a MSC population present in the Wharton's jelly of the umbilical cord) on GBM cell viability, migration, proliferation and sensitivity to temozolomide treatment of U251 and SNB-19 GBM cells was evaluated. The in vivo chicken chorioallantoic membrane (CAM) assay was used to evaluate the effect of HUCPVCs CM on tumor growth and angiogenesis. The secretome of HUCPVCs was characterized by proteomic analyses. Results: We found that both tested GBM cell lines exposed to HUCPVCs CM presented significantly higher cellular viability, proliferation and migration. In contrast, resistance of GBM cells to temozolomide chemotherapy was not significantly affected by HUCPVCs CM. In the in vivo CAM assay, CM from HUCPVCs promoted U251 and SNB-19 tumor cells growth. Proteomic analysis to characterize the secretome of HUCPVCs identified several proteins involved in promotion of cell survival, proliferation and migration, revealing novel putative molecular mediators for the effects observed in GBM cells exposed to HUCPVCs CM. Conclusions: These findings provide novel insights to better understand the interplay between GBM cells and MSCs, raising awareness to potential safety issues regarding the use of MSCs as stem-cell based therapies for GBM. Glioblastoma; Mesenchymal stem cells; Human umbilical cord perivascular cells; Conditioned media; Secretome; Viability; Proliferation; Migration; Proteomics Background Gliomas are the most common primary malignancies in the central nervous system (CNS), accounting for approximately 80% of all primary brain tumors [ 1 ]. Glioblastoma (GBM, grade IV) is the most common and malignant type of glioma in adults, presenting a high mortality rate and very poor patient outcomes. In fact, despite multimodal therapeutic approaches consisting of surgery, chemotherapy and radiotherapy, virtually all GBMs recur and lead to death, presenting a median overall survival of  ~  15  months [ 2 ]. This poor outcome has not changed significantly in the last decades, stressing the need for novel therapeutic strategies that may, more efficiently, overcome the highly resistance nature of these tumors. A novel therapeutic approach currently being investigated for a variety of cancer types is based on the use of tumor-trophic stem cells, such as mesenchymal stem cells (MSCs) [ 3–17 ]. These are multipotent progenitor cells that are defined according to 3 main characteristics: (i) expression of CD105, CD73 and CD90 (MSCs markers), and lack of expression of CD45, CD34, CD14 (hematopoietic markers); (ii) ability to adhere to plastic surfaces; and (iii) differentiation capacity into adipocytes, osteoblasts and chondrocytes (multipotency) [ 18, 19 ]. Additionally, MSCs are also characterized by their proliferative and self-renewal abilities, and can be isolated from bone marrow (BM-MSCs) [20], adipose tissue (ASCs) [ 21 ], umbilical cord (e.g., human umbilical cord perivascular cells; HUCPVCs) [ 22–24 ], among other sources [ 25–30 ]. The use of MSCs is relatively promising since these cells: (i) can be easily isolated and subsequently expanded in  vitro; (ii) show multi-lineage differentiation ability; (iii) have an immune privileged nature; (iv) present capacity to home for site of injury, (...truncated)


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Joana Vieira de Castro, Eduardo D. Gomes, Sara Granja, Sandra I. Anjo, Fátima Baltazar, Bruno Manadas, António J. Salgado, Bruno M. Costa. Impact of mesenchymal stem cells’ secretome on glioblastoma pathophysiology, Journal of Translational Medicine, 2017, pp. 200, DOI: 10.1186/s12967-017-1303-8