Inhibition of TGF‐β/Smad Signaling by BAMBI Blocks Differentiation of Human Mesenchymal Stem Cells to Carcinoma‐Associated Fibroblasts and Abolishes their Protumor Effects

Shangguan, Lei; Ti, Xinyu; Krause, U.; Bai, Hai; Zhao, Yanli; Yang, Zhenhua; Liu, Fei

doi:10.1002/stem.1251

Cited by 128 publications

(100 citation statements)

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“…In vivo experiment showed that BAMBI transduction abolished protumor effects of an orthotopic breast cancer xenograft model (43) and modulated the effects of diabetes via inhibiting TGF-β signaling (44). Our study found that BAMBI overex pression and β-sitosterol suppressed tumor growth in NSCLC xenografts, revealing the antitumor effect of BAMBI overexpression and β-sitosterol.…”

Section: Discussionmentioning

confidence: 54%

BAMBI overexpression together with β-sitosterol ameliorates NSCLC via inhibiting autophagy and inactivating TGF-β/Smad2/3 pathway

Wang

et al. 2017

Oncology Reports

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Abstract. Non-small cell lung cancer (NSCLC) has the highest mortality rate among all solid tumors with a poor prognosis. The BMP and activin receptor membrane bound inhibitor (BAMBI) has been identified as a hallmark of NSCLC and β-sitosterol possesses antitumor potentiality. This study explores the effect of BAMBI overexpression and β-sitosterol in the context of NSCLC. The results revealed that the transfection of pcDNA-BAMBI and β-sitosterol treatment significantly reduced the levels of autophagy markers light chain 3 (LC3) II and Beclin 1, whereas the levels of LC3 I and p62 were promoted. The reduced punctate accumulations of GFP-LC3 were detected in pcDNA-BAMBI and β-sitosterol groups, especially in pcDNA-BAMBI + β-sitosterol group. BAMBI overexpression and β-sitosterol induced G0/G1 cell cycle arrest and inhibted cell proliferation in A549 cells. In addition, the levels of transforming growth factor-β (TGF-β)/p-Smad2/3/c-Myc pathway proteins were decreased. The TGF-β overexpression further confirmed that BAMBI overexpression and β-sitosterol treatment suppre ssed autohagy and viability of A549 cells was through TGF-β/Smad2/3/c-Myc pathway. Finally, the tumor growth was suppressed in NSCLC xenografts, and the inhibitory effect was stronger under treatment of pcDNA-BAMBI together with β-sitosterol. These results indicate that BAMBI overexpression and β-sitosterol may serve as novel targets for the treatment of NSCLC. IntroductionLung cancer is the leading cause of deaths with the most rapidly increasing incidence worldwide. Non-small cell lung cancer (NSCLC) has the highest mortality rate among all solid tumors with a poor prognosis (1). More than half of lung carcinomas are detected in a progressed or already metastasized state with a 5-year survival, for lacking of characteristic early symptoms (2). The general therapy treating the majority of patients is chemotherapy, which often induces resistance (3). It is necessary to develop novel therapeutic approaches to better understand the lung cancer progression.Autophagy is a fundamental cellular homeostatic process that cells use to degrade and recycle cellular proteins (4). This process can be induced in response to either intracellular or extracellular factors, such as hypoxia, low cellular energy state and organelle damage (5). The microtubule-associated protein 1 light chain 3 (LC3), functions as a structural component in the formation of autophagosomes. The conversion of the cytosolic form of LC3 (LC3 I) to lipidated form (LC3 II) indicates autophagosome formation (6). Beclin 1, is required for the initiation and in the process of autophagosome formation (7). p62 acts as a receptor or adaptor for autophagic degradation of ubiquitinated proteins, the upregulation of p62 is commonly detected in human tumors and contributes dire ctly to tumorigenesis (8). Thus, LC3, Beclin 1 and p62 were considered as autophagy markers in many studies (9,10).Transforming growth factor-β (TGF-β) has a crucial role in homeostasis, fibrosis angiogenesis, carcinogenesis and d...

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Section: Discussionmentioning

confidence: 54%

BAMBI overexpression together with β-sitosterol ameliorates NSCLC via inhibiting autophagy and inactivating TGF-β/Smad2/3 pathway

Wang

et al. 2017

Oncology Reports

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“…Published reports indicate that prolonged stimulation of BM-derived human MSCs with breast tumor-derived factors (Tumor CM) has led to conversion of MSCs into functional CAFs that promoted tumor growth [11-14]. We began this study by determining the influence of such tumor-derived factors on the inflammatory traits of CAFs generated by MSCs exposed to Tumor CM, using the expression of the inflammatory/pro-malignancy chemokines CCL2, CXCL8 and CCL5 as readouts.…”

Section: Resultsmentioning

confidence: 99%

“…Such MSCs, originating in bone marrow (BM) or adipose tissues generally have pro-cancerous effects that promote malignancy in many tumor systems, including breast cancer [5-12]. In vitro , tumor cell products that are present in tumor-derived conditioned medium (CM) convert MSCs to CAFs which become fully and potently functional in promoting malignancy in vivo [11-14]. …”

Section: Introductionmentioning

confidence: 99%

Regulation of the inflammatory profile of stromal cells in human breast cancer: prominent roles for TNF-α and the NF-κB pathway

et al. 2015

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IntroductionBreast cancer progression is promoted by stromal cells that populate the tumors, including cancer-associated fibroblasts (CAFs) and mesenchymal stem/stromal cells (MSCs). The activities of CAFs and MSCs in breast cancer are integrated within an intimate inflammatory tumor microenvironment (TME) that includes high levels of tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). Here, we identified the impact of TNF-α and IL-1β on the inflammatory phenotype of CAFs and MSCs by determining the expression of inflammatory chemokines that are well-characterized as pro-tumorigenic in breast cancer: CCL2 (MCP-1), CXCL8 (IL-8) and CCL5 (RANTES).MethodsChemokine expression was determined in breast cancer patient-derived CAFs by ELISA and in patient biopsies by immunohistochemistry. Chemokine levels were determined by ELISA in (1) human bone marrow-derived MSCs stimulated by tumor conditioned media (Tumor CM) of breast tumor cells (MDA-MB-231 and MCF-7) at the end of MSC-to-CAF-conversion process; (2) Tumor CM-derived CAFs, patient CAFs and MSCs stimulated by TNF-α (and IL-1β). The roles of AP-1 and NF-κB in chemokine secretion were analyzed by Western blotting and by siRNAs to c-Jun and p65, respectively. Migration of monocytic cells was determined in modified Boyden chambers.ResultsTNF-α (and IL-1β) induced the release of CCL2, CXCL8 and CCL5 by MSCs and CAFs generated by prolonged stimulation of MSCs with Tumor CM of MDA-MB-231 and MCF-7 cells. Patient-derived CAFs expressed CCL2 and CXCL8, and secreted CCL5 following TNF-α (and IL-1β) stimulation. CCL2 was expressed in CAFs residing in proximity to breast tumor cells in biopsies of patients diagnosed with invasive ductal carcinoma. CCL2 release by TNF-α-stimulated MSCs was mediated by TNF-RI and TNF-RII, through the NF-κB but not via the AP-1 pathway. Exposure of MSCs to TNF-α led to potent CCL2-induced migration of monocytic cells, a process that may yield pro-cancerous myeloid infiltrates in breast tumors.ConclusionsOur novel results emphasize the important roles of inflammation-stroma interactions in breast cancer, and suggest that NF-κB may be a potential target for inhibition in tumor-adjacent stromal cells, enabling improved tumor control in inflammation-driven malignancies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0080-7) contains supplementary material, which is available to authorized users.

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“…For cancer cells producing a high level of IL1 such as in LoVo colon cancer cells and HCC1806 breast cancer cells, BM-MSCs are activated by tumor-derived IL1 to produce protumor factors such as PGE2 and IL6 to promote cancer progression (19). For cancer cells producing a low level of IL1, such as MDA-MB-231 (widely metastatic) and MCF7 (noninvasive) breast cancer cells, (i) hyaluronan produced by MSCs activates the CD44 pathway in cancers to induce LOX expression and promote the EMT and invasion of cancer cells (42); and (ii) TGFβ produced by cancer cells or tumor stromal cells promotes expression of protumor factors such as IL6 and SDF1 by BM-MSCs (4,38). Intriguingly, the expression of multiple genes related to these three pathways, including receptors for IL1 and TGFβ, IL6, SDF1, and the synthases of PGE2 and hyaluronan, as well as the production of PGE2 and hyaluronan, was dramatically lower in iPSC-MSCs with or without exposure to tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

MSCs derived from iPSCs with a modified protocol are tumor-tropic but have much less potential to promote tumors than bone marrow MSCs

Zhao¹,

Gregory²,

Lee³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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141

139

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Mesenchymal stem or stromal cells (MSCs) have many potential therapeutic applications including therapies for cancers and tissue damages caused by cancers or radical cancer treatments. However, tissue-derived MSCs such as bone marrow MSCs (BM-MSCs) may promote cancer progression and have considerable donor variations and limited expandability. These issues hinder the potential applications of MSCs, especially those in cancer patients. To circumvent these issues, we derived MSCs from transgene-free human induced pluripotent stem cells (iPSCs) efficiently with a modified protocol that eliminated the need of flow cytometric sorting. Our iPSC-derived MSCs were readily expandable, but still underwent senescence after prolonged culture and did not form teratomas. These iPSC-derived MSCs homed to cancers with efficiencies similar to BM-MSCs but were much less prone than BM-MSCs to promote the epithelial-mesenchymal transition, invasion, stemness, and growth of cancer cells. The observations were probably explained by the much lower expression of receptors for interleukin-1 and TGFβ, downstream protumor factors, and hyaluronan and its cofactor TSG6, which all contribute to the protumor effects of BM-MSCs. The data suggest that iPSC-derived MSCs prepared with the modified protocol are a safer and better alternative to BM-MSCs for therapeutic applications in cancer patients. The protocol is scalable and can be used to prepare the large number of cells required for "off-the-shelf" therapies and bioengineering applications.

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Inhibition of TGF‐β/Smad Signaling by BAMBI Blocks Differentiation of Human Mesenchymal Stem Cells to Carcinoma‐Associated Fibroblasts and Abolishes their Protumor Effects

Cited by 128 publications

References 45 publications

BAMBI overexpression together with β-sitosterol ameliorates NSCLC via inhibiting autophagy and inactivating TGF-β/Smad2/3 pathway

BAMBI overexpression together with β-sitosterol ameliorates NSCLC via inhibiting autophagy and inactivating TGF-β/Smad2/3 pathway

Regulation of the inflammatory profile of stromal cells in human breast cancer: prominent roles for TNF-α and the NF-κB pathway

MSCs derived from iPSCs with a modified protocol are tumor-tropic but have much less potential to promote tumors than bone marrow MSCs

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