Preventing tumor progression to the bone by induced tumor-suppressing MSCs

Sun, Xun; Li, Kexin; Zha, Rongrong; Liu, Shengzhi; Fan, Yao Shan; Wu, Di; Hase, Misato; Aryal, Uma K.; Lin, Chu‐Chieh; Li, Bai‐Yan; Yokota, Hiroki

doi:10.7150/thno.58779

Cited by 33 publications

(88 citation statements)

References 50 publications

(35 reference statements)

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“…We have shown that the overexpression of Lrp5, a Wnt co-receptor, stimulated the proliferation and migration of breast cancer cells 1 . To our surprise, however, we have also shown that the conditioned medium, collected from Lrp5-overexpressing osteocytes and MSCs, can suppress tumor growth 2 . Collectively, Wnt signaling presented a conflicting pair of actions as an intracellular tumor promoter in tumor cells and a generator of tumor-suppressing proteins in osteocytes and MSCs.…”

Section: Introductionmentioning

confidence: 85%

Generation of the tumor-suppressive secretome from tumor cells

Liu¹,

Sun²,

Li³

et al. 2021

Theranostics

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Rationale : The progression of cancer cells depends on the soil and building an inhibitory soil might be a therapeutic option. We previously created tumor-suppressive secretomes by activating Wnt signaling in MSCs. Here, we examined whether the anti-tumor secretomes can be produced from tumor cells. Methods: Wnt signaling was activated in tumor cells by overexpressing β-catenin or administering BML284, a Wnt activator. Their conditioned medium (CM) was applied to cancer cells or tissues, and the effects of CM were evaluated. Tumor growth in the mammary fat pad and tibia in C57BL/6 female mice was also evaluated through μCT imaging and histology. Whole-genome proteomics analysis was conducted to determine and characterize novel tumor-suppressing proteins, which were enriched in CM. Results: The overexpression of β-catenin or the administration of BML284 generated tumor-suppressive secretomes from breast, prostate and pancreatic cancer cells. In the mouse model, β-catenin-overexpressing CM reduced tumor growth and tumor-driven bone destruction. This inhibition was also observed with BML284-treated CM. Besides p53 and Trail, proteomics analysis revealed that CM was enriched with enolase 1 (Eno1) and ubiquitin C (Ubc) that presented notable tumor-suppressing actions. Importantly, Eno1 immunoprecipitated CD44, a cell-surface adhesion receptor, and its silencing suppressed Eno1-driven tumor inhibition. A pan-cancer survival analysis revealed that the downregulation of MMP9, Runx2 and Snail by CM had a significant impact on survival outcomes ( p < 0.00001). CM presented a selective inhibition of tumor cells compared to non-tumor cells, and it downregulated PD-L1, an immune escape modulator. Conclusions: The tumor-suppressive secretome can be generated from tumor cells, in which β-catenin presented two opposing roles, as an intracellular tumor promoter in tumor cells and a generator of extracellular tumor suppressor in CM. Eno1 was enriched in CM and its interaction with CD44 was involved in Eno1's anti-tumor action. Besides presenting a potential option for treating primary cancers and metastases, the result indicates that aggressive tumors may inhibit the growth of less aggressive tumors via tumor-suppressive secretomes.

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Section: Introductionmentioning

confidence: 85%

Generation of the tumor-suppressive secretome from tumor cells

Liu¹,

Sun²,

Li³

et al. 2021

Theranostics

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“…While these agents significantly improve the quality of life in patients with bone metastasis and the risk of bone fracture, their efficacy is in many cases insufficient to prevent tumor-induced bone loss and eliminate cancer cells from the bone. To examine the possibility of developing a novel treatment option, we herein examined a recent technology of induced tumor-suppressing cells (iTSCs) that was successfully applied to osteocytes, mesenchymal stem cells (MSCs), and tumor cells [ 10 , 11 , 12 , 13 ]. In the iTSC technology, a dichotomous role of oncogenic signaling in tumor promotion as well as in tumor suppression is utilized.…”

Section: Introductionmentioning

confidence: 99%

“…While the activation of Wnt signaling is one valid strategy to generate iTSCs, we have shown that the overexpression of Akt in PI3K signaling and Snail in the induction of EMT also generated iTSCs from MSCs [ 12 ]. In this study, we employed seven pharmacological agents that were known to promote tumor progression, via activating Wnt with BML284 [ 14 ], PI3K/Akt with YS49 [ 15 ], Oct4 with OAC2 [ 16 ], PKA with CW008 [ 17 ], EGF with NSC228155 [ 18 ], JAK/STAT with RCGD423 [ 19 ], and phospholipase C with m-3M3FBS [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

“…As a potential anti-tumor mechanism of BML284-treated osteoclast-derived CM (BM CM), we examined the role of three atypical tumor-suppressing proteins: Hsp90ab1, enolase 1 (Eno1), and polyubiquitin C (Ubc). These proteins were initially identified as tumor suppressors via a mass-spectrometry-based, whole-genome proteomics analysis in our previous iTSC studies [ 12 , 13 ]. Notably, they are moonlighting proteins known as tumor-promoting proteins in varying tumor cells [ 24 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

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Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells

Sun

et al. 2021

Cancers

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Osteoclasts are a driver of a vicious bone-destructive cycle with breast cancer cells. Here, we examined whether this vicious cycle can be altered into a beneficial one by activating Wnt signaling with its activating agent, BML284. The conditioned medium, derived from Wnt-activated RAW264.7 pre-osteoclast cells (BM CM), reduced the proliferation, migration, and invasion of EO771 mammary tumor cells. The same inhibitory effect was obtained with BML284-treated primary human macrophages. In a mouse model, BM CM reduced the progression of mammary tumors and tumor-induced osteolysis and suppressed the tumor invasion to the lung. It also inhibited the differentiation of RANKL-stimulated osteoclasts and enhanced osteoblast differentiation. BM CM was enriched with atypical tumor-suppressing proteins such as Hsp90ab1 and enolase 1 (Eno1). Immunoprecipitation revealed that extracellular Hsp90ab1 interacted with latent TGFβ (LAP-TGFβ) as an inhibitor of TGFβ activation, while Hsp90ab1 and Eno1 interacted and suppressed tumor progression via CD44, a cell-adhesion receptor and a cancer stem cell marker. This study demonstrated that osteoclast-derived CM can be converted into a bone-protective, tumor-suppressing agent by activating Wnt signaling. The results shed a novel insight on the unexplored function of osteoclasts as a potential bone protector that may develop an unconventional strategy to combat bone metastasis.

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“…Although breast cancer is peculiarly prone to bone metastasis, our understanding of the molecular mechanism of bone metastasis in breast cancer is still limited. Induced tumor-suppressing mesenchymal stem cells protect bones from metastasis in breast tumors [ 6 ] and the bone microenvironment and soluble factors participate in breast cancer bone metastasis. In this complex signaling network, interleukin is a key regulator, affecting the differentiation and function of osteocytes, as both cancer cells and osteocytes secrete interleukin and express the corresponding receptors [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Bioinformatics analysis for the identification of key genes and long non-coding RNAs related to bone metastasis in breast cancer

Teng

Yang

Huang

et al. 2021

Aging

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The molecular mechanism of bone metastasis in breast cancer is largely unknown. Herein, we aimed to identify the key genes and long non-coding RNAs (lncRNAs) related to the bone metastasis of breast cancer using a bioinformatics approach. We screened differentially expressed genes and lncRNAs between normal breast and breast cancer bone metastasis samples using the GSE66206 dataset from the Gene Expression Omnibus. We also constructed a differentially expressed lncRNA-mRNA interaction network and analyzed the node degrees to identify the driving genes. After finding potential pathogenic modules of breast cancer bone metastasis, we identified breast cancer bone metastasis-related modules and functional enrichment analysis of the genes and lncRNAs in the modules. Based on the above analysis, we constructed a differentially expressed lncRNA-mRNA network related to bone metastasis in breast cancer and identified core driver genes, including BNIP3 and the lncRNA RP11-317-J19.1. The role of core driver genes and lncRNAs in the network implies their biological functions in regulating bone development and remodeling. Thus, targeting the core driver genes and lncRNAs in the network may be a promising therapeutic strategy to manage bone metastasis.

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Preventing tumor progression to the bone by induced tumor-suppressing MSCs

Cited by 33 publications

References 50 publications

Generation of the tumor-suppressive secretome from tumor cells

Generation of the tumor-suppressive secretome from tumor cells

Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells

Bioinformatics analysis for the identification of key genes and long non-coding RNAs related to bone metastasis in breast cancer

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