TGFβ1 antagonistic peptides inhibit TGFβ1-dependent angiogenesis

Serratì, Simona; Margheri, Francesca; Pucci, Marco; Cantelmo, Anna Rita; Cammarota, Rosaria; Dotor, Javier; Borrás‐Cuesta, Francisco; Fibbi, Gabriella; Albini, Adriana; Rosso, Mario Del

doi:10.1016/j.bcp.2008.10.036

Cited by 47 publications

(42 citation statements)

References 52 publications

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“…However, injection of anti-TGF-β and anti-TGF-βRI antibodies inhibits chronic synovial inflammation in rats with SCW-induced arthritis [38] and in CAIA mice [25]. In CIA, treatment with p17 TGF-β antagonist at the same doses shown previously to block activity of TGF-β in vivo [31,[39][40][41][42][43] did not prevent or modify the severity of the disease, neither during the induction phase nor during established arthritis. As Marinova-Mutafchieva et al have shown that TGF-β expression is induced in the joints at the time of arthritis onset, the time of treatment of CIA mice during clinical progression of disease is justified.…”

Section: Discussionmentioning

confidence: 99%

Transforming growth factor (TGF)-β signalling is increased in rheumatoid synovium but TGF-β blockade does not modify experimental arthritis

Gonzalo-Gil

Criado

Santiago

et al. 2013

Clinical and Experimental Immunology

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SummaryThe aim of this study was to analyse the distribution of regulatory and inhibitory mothers against decapentaplegic homologue (Smad) proteins as markers of active transforming growth factor (TGF)-β signalling in rheumatoid arthritis (RA) synovial tissue and to investigate the effect of TGF-β blockade in the development and progression of collagen-induced arthritis. The expression of Smad proteins in synovial tissues from RA, osteoarthritic and healthy controls was analysed by immunohistochemistry. Arthritis was induced in DBA/1 mice by immunization with chicken type-II collagen (CII). TGF-β was blocked in vivo with the specific peptide p17 starting at the time of immunization or on the day of arthritis onset. T cell population frequencies and specific responses to CII were analysed. The expression of cytokines and transcription factors was quantified in spleen and joint samples. Statistical differences between groups were compared using the Mann-Whitney U-test or one-way analysis of variance (anova) using the Kruskal-Wallis test. p-Smad-2/3 and inhibitory Smad-7 expression were detected in RA and control tissues. In RA, most lymphoid infiltrating cells showed nuclear p-Smad-2/3 without Smad-7 expression. Treatment with TGF-β antagonist did not affect clinical severity, joint inflammation and cartilage damage in collagen-induced arthritis. Frequency of T cell subsets, mRNA levels of cytokines and transcription factors, specific proliferation to CII, serum interleukin (IL)-6 and anti-CII antibodies were comparable in p17 and phosphate-buffered saline (PBS)-treated groups. The pattern of Smad proteins expression demonstrates active TGF-β signalling in RA synovium. However, specific TGF-β blockade does not have a significant effect in the mice model of collagen-induced arthritis.

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Section: Discussionmentioning

confidence: 99%

Transforming growth factor (TGF)-β signalling is increased in rheumatoid synovium but TGF-β blockade does not modify experimental arthritis

Gonzalo-Gil

Criado

Santiago

et al. 2013

Clinical and Experimental Immunology

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“…4 Whereas TGF-␤ often restricts tumor growth and angiogenesis in the early phase of tumor development, there is evidence for its proangiogenic and tumor-promoting activities during late-stage tumor progression. 43 TGF-␤-induced angiogenesis was linked to urokinase-type plasminogen activator receptor and its type 1 inhibitor up-regulation. 43 Furthermore, TGF-␤ was shown to up-regulate VEGF-C. 44 Our results suggest that both S1P and TGF-␤ are present in the CM AC and are needed for HIF-␣ mRNA expression regulation in macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…43 TGF-␤-induced angiogenesis was linked to urokinase-type plasminogen activator receptor and its type 1 inhibitor up-regulation. 43 Furthermore, TGF-␤ was shown to up-regulate VEGF-C. 44 Our results suggest that both S1P and TGF-␤ are present in the CM AC and are needed for HIF-␣ mRNA expression regulation in macrophages. As neither TGF-␤ nor S1P alone or in combination was sufficient in inducing HIF-1␣, we assume that combinatory and thus more complex signaling circuits are operating.…”

Section: Discussionmentioning

confidence: 99%

The supernatant of apoptotic cells causes transcriptional activation of hypoxia-inducible factor–1α in macrophages via sphingosine-1-phosphate and transforming growth factor-β

Herr

Zhou

Werno

et al. 2009

Blood

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IntroductionTumor-associated macrophages (TAMs) infiltrate tumors, which often predicts a poor survival prognosis. TAMs apparently support tumor development by improving vascularization and cell survival rather than behaving tumoricidally (for review, see Lewis and Pollard 1 ).Features characterizing TAMs are often elicited by alternative activation, which polarizes cells toward regulatory macrophages, a subgroup of the so-called M2 phenotype. They share anti-inflammatory characteristic, for example, reduced interleukin (IL)-12 production 2,3 compared with classical stimulation and M1 polarization. 2 Unfortunately, it is only poorly understood which factors influence the TAM phenotype profile. The phenotype alteration occurs in the tumor microenvironment, with the likely contribution of tumor-derived molecules such as IL-4, IL-10, transforming growth factor (TGF)-␤, prostaglandin E 2 (PGE 2 ), chemokines, or tumor hypoxia. 1,2 Interestingly, apoptotic cells (AC) also release anti-inflammatory cytokines such as TGF-␤ and IL-10 4,5 and reduce tumor-directed macrophage cytotoxicity. 6 It became apparent that phagocytosis of AC by macrophages is an immunoregulatory process that shapes the regulatory macrophage phenotype. [7][8][9][10] Macrophages cocultured in vitro with AC or exposed to the supernatant of AC express a pattern of markers that overlaps with those established for TAMs. [11][12][13] Furthermore, sphingosine-1-phosphate (S1P) provoked M2 macrophage polarization, 13,14 and S1P is released from AC. 13,15 S1P activates distinct G proteincoupled receptors, 16 elicits a variety of immune cell responses, 17 and promotes tumor angiogenesis. 18,19 Hypoxia-inducible factor (HIF)-1 is known for its importance in tumorigenesis, and controls angiogenesis, proliferation, metabolism, metastasis, and differentiation. 20 HIF-1, composed of a HIF-1␣ and HIF-1␤ subunit, senses and coordinates adaptation to low oxygen availability. Under normoxia (21% O 2 ), HIF-1␤ is constitutively expressed, whereas HIF-1␣ is hydroxylated by prolyl hydroxylases, polyubiquitinated by an E3-ubiquitin ligase complex containing the von Hippel Lindau protein, and concomitantly degraded (for review, see Semenza 21 ). Because hypoxia mainly affects HIF-1␣ protein stability, HIF-1␣ mRNA expression regulation only recently attracted some interest. In macrophages, lipopolysaccharide (LPS) induced nuclear factor (NF)-B binding to the HIF-1␣ promoter and increased its mRNA expression. 22 Nuclear factor of activated T cells (NFAT)c1 increased the HIF-␣ mRNA content in mast cells after stimulation with ionomycin, 23 and signal transducer and activator of transcription (STAT)3 up-regulated HIF-1␣ mRNA in human tumor cells, 24 substantiating the importance of transcriptional control mechanisms governing HIF-1 appearance/activity.We provide evidence that HIF-1␣ under normoxia is transcriptionally activated via NFAT in response to apoptotic cell-derived S1P and TGF-␤. As verified in cells from HIF-1␣ conditional knockout mice, activation of HIF-1 in pola...

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“…P144 blocked TGF-β signaling and displayed potent inhibition of angiogenesis in several in vitro assays [131]. Phase I clinical trials have been completed and P144 is currently in phase II clinical trials sponsored by ISDIN in collaboration with DigNa Biotech, to assess efficacy and safety of topical application of P144 in the treatment of skin fibrosis in patients with systemic sclerosis [132].…”

Section: Tgf-β As Therapeutic Targetmentioning

confidence: 99%

TGF-β in the Bone Microenvironment: Role in Breast Cancer Metastases

Buijs

Stayrook

Guise

2011

Cancer Microenvironment

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Breast cancer is the most prevalent cancer among females worldwide. It has long been known that cancers preferentially metastasize to particular organs, and bone metastases occur in ∼70% of patients with advanced breast cancer. Breast cancer bone metastases are predominantly osteolytic and accompanied by bone destruction, bone fractures, pain, and hypercalcemia, causing severe morbidity and hospitalization. In the bone matrix, transforming growth factor-β (TGF-β) is one of the most abundant growth factors, which is released in active form upon tumor-induced osteoclastic bone resorption. TGF-β, in turn, stimulates bone metastatic cells to secrete factors that further drive osteolytic destruction of the bone adjacent to the tumor, categorizing TGF-β as a crucial factor responsible for driving the feed-forward vicious cycle of cancer growth in bone. Moreover, TGF-β activates epithelial-to-mesenchymal transition, increases tumor cell invasiveness and angiogenesis and induces immunosuppression. Blocking the TGF-β signaling pathway to interrupt this vicious cycle between breast cancer and bone offers a promising target for therapeutic intervention to decrease skeletal metastasis. This review will describe the role of TGF-β in breast cancer and bone metastasis, and pre-clinical and clinical data will be evaluated for the potential use of TGF-β inhibitors in clinical practice to treat breast cancer bone metastases.

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TGFβ1 antagonistic peptides inhibit TGFβ1-dependent angiogenesis

Cited by 47 publications

References 52 publications

Transforming growth factor (TGF)-β signalling is increased in rheumatoid synovium but TGF-β blockade does not modify experimental arthritis

Transforming growth factor (TGF)-β signalling is increased in rheumatoid synovium but TGF-β blockade does not modify experimental arthritis

The supernatant of apoptotic cells causes transcriptional activation of hypoxia-inducible factor–1α in macrophages via sphingosine-1-phosphate and transforming growth factor-β

TGF-β in the Bone Microenvironment: Role in Breast Cancer Metastases

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