Dataset Information

Mesenchymal stem cells enhance tumorigenic properties of human glioblastoma cells through independent cell-cell communication mechanisms

ABSTRACT: Mesenchymal stem cells (MSC) display tumor tropism and have been addressed as vehicles for delivery of anti-cancer agents. As cellular components of the tumor microenvironment, MSC also influence tumor progression. However, the contribution of MSC in brain cancer is not well understood since either oncogenic or tumor suppressor effects have been reported for these cells. Here, MSC were found capable of stimulating human Glioblastoma (GBM) cell proliferation through a paracrine effect mediated by TGFB1. Moreover, when in direct cell-cell contact with GBM cells, MSC elicited an increased proliferative and invasive tumor cell behavior under 3D conditions, as well as accelerated tumor development in nude mice, independently of paracrine TGFB1. A secretome profiling of MSC-GBM co-cultures identified 126 differentially expressed proteins and 10 proteins exclusively detected under direct cell-cell contact conditions. Most of these proteins are exosome cargos and are involved in cell motility and tissue development. These results indicate a dynamic interaction between MSC and GBM cells, favoring aggressive tumor cell traits through alternative and independent mechanisms. Overall, these findings indicate that MSC may exert pro-tumorigenic effects when in close contact with tumor cells, which must be carefully considered when employing MSC in targeted cell therapy protocols against cancer

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Mesenchymal Stem Cell Of Wharton's Jelly, Cell Culture

DISEASE(S): Brain Cancer

SUBMITTER: Amanda Assoni

LAB HEAD: Oswaldo Keith Okamoto

PROVIDER: PXD008035 | Pride | 2018-06-13

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

Items per page:

1 - 5 of 46

Publications

Mesenchymal stem cells enhance tumorigenic properties of human glioblastoma through independent cell-cell communication mechanisms.

Rodini Carolina Oliveira CO Gonçalves da Silva Patrícia Benites PB Assoni Amanda Faria AF Carvalho Valdemir Melechco VM Okamoto Oswaldo Keith OK

Oncotarget 20180515 37

Mesenchymal stem cells (MSC) display tumor tropism and have been addressed as vehicles for delivery of anti-cancer agents. As cellular components of the tumor microenvironment, MSC also influence tumor progression. However, the contribution of MSC in brain cancer is not well understood since either oncogenic or tumor suppressor effects have been reported for these cells. Here, MSC were found capable of stimulating human Glioblastoma (GBM) cell proliferation through a paracrine effect mediated by ...[more]

PMID: 29872504

Similar Datasets

Project description:A significant challenge for chimeric antigen receptor (CAR) T cell therapy against glioblastoma (GBM) is its immunosuppressive tumor microenvironment (TME), which is densely populated and supported by protumoral glioma-associated microglia and macrophages (GAMs). Targeting CD47, a don't-eat-me signal overexpressed by tumor cells, disrupts the CD47-SIRPalpha axis and induces GAM phagocytic function. However, antibody-mediated CD47 blockade monotherapy is associated with toxicity and low bioavailability in solid tumors. To overcome these limitations, we combined local CAR T cell therapy with paracrine GAM modulation to effectively eliminate GBM. To this end, we engineered a new CAR T cell against epidermal growth factor receptor variant III (EGFRvIII) that constitutively secretes a signal regulatory protein gamma (SIRPgamma)-related protein (SGRP) with high affinity to CD47. Anti-EGFRvIII-SGRP CAR T cells eliminated EGFRvIII+ GBM in a dose-dependent manner in vitro and eradicated orthotopically xenografted EGFRvIII-mosaic GBM by locoregional application in vivo. This resulted in significant tumor-free long-term survival, followed by partial tumor control upon tumor re-challenge. Combining anti-CD47 antibodies with anti-EGFRvIII CAR T cells failed to achieve a similar therapeutic effect, underscoring the importance of sustained paracrine GAM modulation. Multidimensional brain immunofluorescence microscopy and in-depth spectral flow cytometry on GBM-xenografted brains showed that anti-EGFRvIII-SGRP CAR T cells accelerated GBM clearance, increased CD68+ cell trafficking to tumor scar sites and promoted GAM-mediated tumor cell uptake. In a peripheral lymphoma mouse xenograft model, anti-CD19-SGRP CAR T cells had superior efficacy to conventional anti-CD19 CAR T cells. Validation on human GBM explants revealed that anti-EGFRvIII-SGRP CAR T cells had a similar tumor-killing capacity to anti-EGFRvIII CAR monotherapy but showed a slight improvement in the maintenance of tumor-infiltrated CD14+ cells. Thus, local anti-EGFRvIII-SGRP CAR T cell therapy combines the potent antitumor effect of engineered T cells with the modulation of the surrounding innate immune TME. This results in the additive elimination of bystander EGFRvIII- tumor cells in a manner that overcomes the main mechanisms of CAR T cell therapy resistance, including tumor innate immune suppression and antigen escape.

Project description:Disseminated tumor cells (DTCs) in the bone marrow can be detected in patients with solid tumors early on in disease progression. Via interaction with mesenchymal stromal cells (MSCs) these tumor cells may interfere with hematopoiesis. Using appropriate co-culture models, we investigated whether DTCs can change the bone marrow microenvironment by modulating MSC function with a special emphasis on their chemoattractive activity towards hematopoietic stem and progenitor cells (HSPCs). Human bone marrow derived MSCs as well as an immortalised MSC line (SCP-1) were co-cultured with MCF-7, MDA-MB231 breast carcinoma or MCF-10A non-malignant breast epithelial cells or their conditioned medium. Gene expression analysis of SCP-1 cells cultured with MCF-7 conditioned medium revealed SDF-1/CXCL12 as one of the significantly downregulated genes. Both tumor cell lines caused an inhibited SDF-1 promoter activity in SCP-1 cells, whereby MCF-7 medium decreased it to 77% and MDA-MB231 to 47%. Moreover, the SDF-1 mRNA and protein levels were significantly reduced. As a functional consequence of lower SDF-1 levels, we detected a decreased trans-well migration potential of CD34+ HSPC to MSC/tumor cell co-cultures or conditioned medium. The specificity of this chemokine mediated effect was confirmed by blocking studies with the CXCR4 antagonist AMD3100. Downregulation of SP1 transcription factor and increased miR23a levels in MSCs after contact with tumor cell medium as well as an enhanced TGFb1 expression were identified as potential molecular regulators of SDF-1 activity in MSCs. We propose an additional mechanism by which tumor cells affect the niche environment of HSPCs and therefore negatively impact hematopoiesis. Gene expression of human immortalized mesenchymal stromal cells (SCP-1) was investigated after incubation with conditioned medium of the breast carcinoma cell line MCF-7 for 24, 48, and 72 hours. Three independent experiments were performed at each time.

			Action	DRS
	KOCR01F-14.raw	Raw
	KOCR01F-14_150604170430.raw	Raw
	KOCR01F-14_150606122107.raw	Raw
	KOCR01F-15.raw	Raw
	KOCR01F-15_150604180028.raw	Raw