Stromal Modulators of TGF-β in Cancer

Costanza, Brunella; Umelo, Ijeoma Adaku; Bellier, Justine; Castronovo, Vincent; Turtoï, Andrei

doi:10.3390/jcm6010007

Cited by 149 publications

(121 citation statements)

References 187 publications

(223 reference statements)

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“…However, it is important to note that MSCs can either support or suppress tumorigenesis (reviewed in ). In contrast to their anti‐apoptotic and anti‐inflammatory functions, MSCs have been shown to interact with tumor cells via paracrine signaling and possibly increase the risk for metastasis by mediating epithelial‐to‐mesenchymal transition in addition to augmenting angiogenesis . This less‐desirable effect imparted by MSC immunomodulatory activities at tumor microenvironments warrants some caution in their use in circumstances of pre‐existing tumor conditions.…”

Section: Multifaceted Characterization Of Mscsmentioning

confidence: 99%

Concise Review: Multifaceted Characterization of Human Mesenchymal Stem Cells for Use in Regenerative Medicine

Samsonraj

Raghunath

Nurcombe

et al. 2017

Stem Cells Translational Medicine

574

474

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Mesenchymal stem cells (MSC) hold great potential for regenerative medicine because of their ability for self‐renewal and differentiation into tissue‐specific cells such as osteoblasts, chondrocytes, and adipocytes. MSCs orchestrate tissue development, maintenance and repair, and are useful for musculoskeletal regenerative therapies to treat age‐related orthopedic degenerative diseases and other clinical conditions. Importantly, MSCs produce secretory factors that play critical roles in tissue repair that support both engraftment and trophic functions (autocrine and paracrine). The development of uniform protocols for both preparation and characterization of MSCs, including standardized functional assays for evaluation of their biological potential, are critical factors contributing to their clinical utility. Quality control and release criteria for MSCs should include cell surface markers, differentiation potential, and other essential cell parameters. For example, cell surface marker profiles (surfactome), bone‐forming capacities in ectopic and orthotopic models, as well as cell size and granularity, telomere length, senescence status, trophic factor secretion (secretome), and immunomodulation, should be thoroughly assessed to predict MSC utility for regenerative medicine. We propose that these and other functionalities of MSCs should be characterized prior to use in clinical applications as part of comprehensive and uniform guidelines and release criteria for their clinical‐grade production to achieve predictably favorable treatment outcomes for stem cell therapy. Stem Cells Translational Medicine 2017;6:2173–2185

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Section: Multifaceted Characterization Of Mscsmentioning

confidence: 99%

Concise Review: Multifaceted Characterization of Human Mesenchymal Stem Cells for Use in Regenerative Medicine

Samsonraj

Raghunath

Nurcombe

et al. 2017

Stem Cells Translational Medicine

574

474

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“…Of note, many TGF-b signaling genes were significantly upregulated in EL08-1D2 cells in response to AZA ( Figure 5C; supplemental Table 4). Because TGF-b is epigenetically regulated and plays a role in regulation of stromal cell function and HSPC support in various diseases including MDS, [17][18][19][20][21] we selected TGF-b as a gene of interest for further expression analysis in our primary MSC samples. To this end, we analyzed 8 healthy and 7 MDS MSC samples by RT-PCR.…”

Section: Aza Targets Stromal Pathways With Diverse Biological Functionmentioning

confidence: 99%

Direct modulation of the bone marrow mesenchymal stromal cell compartment by azacitidine enhances healthy hematopoiesis

et al. 2018

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Key Points• AZA treatment of MSCs in MDS leads to preferential expansion of healthy over malignant hematopoiesis.• AZA regulates key MSC genes crucial for support of hematopoiesis, providing proof of concept for epigenetic therapy of MSCs in MDS. Mesenchymal stromal cells (MSCs) are crucial components of the bone marrow (BM) microenvironment essential for regulating self-renewal, survival, and differentiation of hematopoietic stem/progenitor cells (HSPCs) in the stem cell niche. MSCs are functionally altered in myelodysplastic syndromes (MDS) and exhibit an altered methylome compared with MSCs from healthy controls, thus contributing to disease progression. To determine whether MSCs are amenable to epigenetic therapy and if this affects their function, we examined growth, differentiation, and HSPC-supporting capacity of ex vivo-expanded MSCs from MDS patients in comparison with age-matched healthy controls after direct treatment in vitro with the hypomethylating agent azacitidine (AZA). Strikingly, we find that AZA exerts a direct effect on healthy as well as MDS-derived MSCs such that they favor support of healthy over malignant clonal HSPC expansion in coculture experiments. RNA-sequencing analyses of MSCs identified stromal networks regulated by AZA. Notably, these comprise distinct molecular pathways crucial for HSPC support, foremost extracellular matrix molecules (including collagens) and interferon pathway components. Our study demonstrates that the hypomethylating agent AZA exerts its antileukemic activity in part through a direct effect on the HSPC-supporting BM niche and provides proof of concept for the therapeutic potential of epigenetic treatment of diseased MSCs. In addition, our comprehensive data set of AZA-sensitive gene networks represents a valuable framework to guide future development of targeted epigenetic niche therapy in myeloid malignancies such as MDS and acute myeloid leukemia.

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“…TGF-β can be secreted by cell types such as macrophages and T cells, which further acts on neighboring tumor and immune cells [3-6]. Besides the pro-apoptotic and pro-metastatic effects TGF-β has on tumor cells, its main effects are to induce immunosuppression by promoting Treg cell differentiation, inhibition of B cell proliferation, and inhibition of inflammation mainly by blocking the activation of NF-κB[7]. Recently, several studies have revealed that TGF-β also regulates thrombosis by promoting the expression of plasminogen activator inhibitor-1 (PAI-1) [8, 9].…”

Section: Introductionmentioning

confidence: 99%

Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Β1 Expression in Macrophage

Zhu¹,

Shen²,

Zhu³

et al. 2017

Cell Physiol Biochem

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Background: Plasminogen activator inhibitor-1 (PAI-1) has been regarded as a risk factor for thrombosis and atherosclerosis. Since it has been shown that PAI-1 can activate macrophages through Toll-like receptor-4, we sought to investigate the role of PAI-1 in the tumor microenvironment. Methods: The expression and distribution patterns of PAI-1 and transforming growth factor beta (TGF-β) were measured in 60 non-small cell lung cancer (NSCLC) tumors. A statistical correlation analysis was performed between PAI-1 and TGF-β expression and distribution in each tumor. The distribution of tumor-associated macrophages (TAMs) was also measured and its correlation to PAI-1 levels was analyzed. Levels of secreted CCL-17, CCL-22, IL-6 and TGF-β were measured in cell cultures of human macrophage cell lines THP-1 and U937 treated with PAI-1. Levels of secreted PAI-1 were monitored in cell cultures of human NSCLCs cell lines 95D and A549 treated with TGF-β. Secreted proteins were measured in cell culture supernatants using ELISA. Changes in downstream signaling pathways were investigated using western blot. Results: PAI-1 and TGF-β were found to be overexpressed in human NSCLCs. PAI-1 expression was tightly correlated to TGF-β expression as well as the percentage of TAMs. PAI-1 treatment increased the expression of TAM-associated cytokines and chemokines, including CCL-17, CCL-22, and IL-6. PAI-1 treatment was also observed to enhance TGF-β expression in macrophage cell lines through an IL-6 autocrine/paracrine manner. The effects on TGF-β expression were blocked by NF-κB and STAT3 inhibition. Interestingly, TGF-β also increased levels of secreted PAI-1 in NSCLC cells through SMAD3-dependent signaling, therefore resulting in a feed-forward loop. However, this loop could be blocked by NF-κB, STAT3 and SMAD3 signaling inhibition, as well as treatment with a high concentration of TGF-β. Conclusion: PAI-1 and TGF-β promote NSCLC tumor cells and TAMs and might be valuable targets for cancer immunosuppression.

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Stromal Modulators of TGF-β in Cancer

Cited by 149 publications

References 187 publications

Concise Review: Multifaceted Characterization of Human Mesenchymal Stem Cells for Use in Regenerative Medicine

Concise Review: Multifaceted Characterization of Human Mesenchymal Stem Cells for Use in Regenerative Medicine

Direct modulation of the bone marrow mesenchymal stromal cell compartment by azacitidine enhances healthy hematopoiesis

Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Β1 Expression in Macrophage

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