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A targeted transforming growth factor-beta (TGF-?) blocker, TTB, inhibits tumor growth and metastasis.

ABSTRACT: Transforming growth factor beta (TGF-?) promotes cancer growth in late stage cancers. To inhibit the TGF-? pathway, we investigated a tumor-targeting TGF-? receptor blocker, TTB, and its role in tumor progress. The targeted TTB comprised of the extracellular domain of the TGF-? receptor II, the endoglin domain of TGF-? receptor III, and the human immuno-globin IgG1 constant fragment (Fc). To enhance tumor microenvironment targeting, a RGD peptide was fused at the N-terminal of TTB. The targeted TTB exhibited potent TGF-? neutralization activities, and inhibited cancer cell migration and invasion as well as colony formation. In xenograft models, the TTB had potent tumor inhibition activities. The TTB also attenuated the TGF-?1-induced Smad2 phosphorylation and epithelial to mesenchymal transformation (EMT), and suppressed breast cancer metastasis. Thus, the TTB is an effective TGF-? blocker with a potential for blocking excessive TGF-? induced pathogenesis in vivo.

SUBMITTER: Zhou C

PROVIDER: S-EPMC5955403 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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A targeted transforming growth factor-beta (TGF-β) blocker, TTB, inhibits tumor growth and metastasis.

Zhou Changhua C Li Jing J Lin Limin L Shu Rui R Dong Bin B Cao Donglin D Li Qing Q Wang Zhong Z

Oncotarget 20180224 33

Transforming growth factor beta (TGF-β) promotes cancer growth in late stage cancers. To inhibit the TGF-β pathway, we investigated a tumor-targeting TGF-β receptor blocker, TTB, and its role in tumor progress. The targeted TTB comprised of the extracellular domain of the TGF-β receptor II, the endoglin domain of TGF-β receptor III, and the human immuno-globin IgG1 constant fragment (Fc). To enhance tumor microenvironment targeting, a RGD peptide was fused at the N-terminal of TTB. The targeted ...[more]

PMID: 29796175

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Project description:Appropriate growth and development of the endometrium across the menstrual cycle is key for a woman's quality of life and reproductive well-being. Recurrent pregnancy loss (RPL) and heavy menstrual bleeding (HMB) affect a significant proportion of the female population worldwide. These endometrial pathologies have a significant impact on a woman's quality of life as well as placing a high economic burden on a country's health service. An underlying cause for both conditions is unknown in approximately 50% of cases. Previous research has demonstrated that aberrant endometrial vascular maturation is associated with both RPL and HMB, where it is increased in RPL but reduced in HMB. TGFβ1 is one of the key growth factors that regulate vascular maturation, by inducing phenotypic switching of vascular smooth muscle cells (VSMCs) from a synthetic phenotype to a more contractile one. Our previous data demonstrated an increase in TGFβ1 in the endometrium of RPL, while others have shown a decrease in women with HMB. However, TGFβ1 bioavailability is tightly controlled, and we therefore sought to perform an extensive immunohistochemical analysis of different components in the pathway in the endometrium of normal controls, women with HMB or RPL. In addition, two in vitro models were used to examine the role of TGFβ1 in endometrial vascular maturation and endothelial cell (EC):VSMC association. Taken all together, the immunohistochemical data suggest a decrease in bioavailability, receptor binding capacity, and signaling in the endometrium of women with HMB compared with controls. In contrast, there is an increase in the bioavailability of active TGFβ1 in the endometrium of women with RPL compared with controls. Endometrial explants cultured in TGFβ1 had an increase in the number of vessels associated with contractile VSMC markers, although the total number of vessels did not increase. In addition, TGFβ1 increased EC:VSMC association in an in vitro model. In conclusion, TGFβ1 is a key regulator of endometrial vascular maturation and could be considered as a therapeutic target for women suffering from HMB and/or RPL.

Project description:BACKGROUND:Chronic fatigue syndrome (CFS) is a prevalent and disabling condition among adolescent. The disease mechanisms are unknown. Previous studies have suggested elevated plasma levels of several cytokines, but a recent meta-analysis of 38 articles found that of 77 different cytokines measured in plasma, transforming growth factor beta (TGF-?) was the only one that was elevated in patients compared to controls in a sufficient number of articles. In the present study we therefore compared the plasma levels of the three TGF-? isoforms in adolescent CFS patients and healthy controls. In addition, the study explored associations between TGF-? levels, neuroendocrine markers, clinical markers and differentially expressed genes within the CFS group. METHODS:CFS patients aged 12-18 years (n = 120) were recruited nation-wide to a single referral center as part of the NorCAPITAL project (ClinicalTrials ID: NCT01040429). A broad case definition of CFS was applied, requiring 3 months of unexplained, disabling chronic/relapsing fatigue of new onset, whereas no accompanying symptoms were necessary. Healthy controls (n = 68) were recruited from local schools. The three isoforms of TGF-? (TGF-?1, TGF-?2, TGF-?3) were assayed using multiplex technology. Neuroendocrine markers encompassed plasma and urine levels of catecholamines and cortisol, as well as heart rate variability indices. Clinical markers consisted of questionnaire scores for symptoms of post-exertional malaise, inflammation, fatigue, depression and trait anxiety, as well as activity recordings. Whole blood gene expression was assessed by RNA sequencing in a subgroup of patients (n = 29) and controls (n = 18). RESULTS:Plasma levels of all three isoforms of TGF-? were equal in the CFS patients and the healthy controls. Subgrouping according to the Fukuda and Canada 2003 criteria of CFS did not reveal differential results. Within the CFS group, all isoforms of TGF-? were associated with plasma cortisol, urine norepinephrine and urine epinephrine, and this association pattern was related to fatigue score. Also, TGF-?3 was related to expression of the B cell annotated genes TNFRSF13C and CXCR5. CONCLUSIONS:Plasma levels of all TGF-? isoforms were not altered in adolescent CFS. However, the TGF-? isoforms were associated with neuroendocrine markers, an association related to fatigue score. Furthermore, TGF-?3 might partly mediate an association between plasma cortisol and B cell gene expression. Trial registration Clinical Trials NCT01040429.

Dataset Information

A targeted transforming growth factor-beta (TGF-?) blocker, TTB, inhibits tumor growth and metastasis.

Publications

A targeted transforming growth factor-beta (TGF-β) blocker, TTB, inhibits tumor growth and metastasis.

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