The dynamic roles of TGF‐β in cancer

Meulmeester, Erik; Dijke, Peter ten

doi:10.1002/path.2785

Cited by 358 publications

(357 citation statements)

References 176 publications

(195 reference statements)

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“…It is important to remember that other genes also exhibit different roles in normal and neoplastic tissues. It is worth mentioning that TGFb acts as a tumor suppressor in normal tissue, but plays an oncogenic role in tumors, 32 by promoting cell growth and development of epithelial-to-mesenchymal transition. 33,34 Interestingly, in our study, we identified two different patterns of FGFR2 immunostaining: cytoplasmic and nuclear.…”

Section: Fgfr2 Mutationsmentioning

confidence: 99%

FGFR2 alterations in endometrial carcinoma

et al. 2011

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Fibroblast growth factor receptor 2 (FGFR2) is a tyrosine kinase receptor involved in many biological processes such as embryogenesis, adult tissue homeostasis and cell proliferation. Mutations in FGFR2 have been reported in up to 10-12% of endometrial carcinomas identical to those found in congenital craniofacial disorders. Inhibition of FGFR2 could be a new therapeutic target in endometrial carcinoma. FGFR2 immunostaining was assessed in three tissue microarrays: one constructed from paraffin-embedded blocks of 60 samples of normal endometrium in different phases of menstrual cycle, and two tissue microarrays containing endometrial carcinoma samples (95 and 62 cases). FGFR2 expression was correlated with stage, histological type and grade as well as with immunostaining of PTEN, RASSF1A, estrogen and progesterone receptors, KI67, Cyclin D1, STAT-3 and SPRY2. FGFR2 mutations were assessed by PCR and direct sequencing, with DNA obtained from 31 paraffin-embedded endometrial carcinoma samples. In normal endometrium, FGFR2 expression was higher in the secretory than in the proliferative phase (P ¼ 0.001), with an inverse correlation with Ki67 (P ¼ 0.00032), suggesting a tumor-suppressor role for FGFR2 in normal endometrium. Cytoplasmic expression of FGFR2 was higher in endometrial carcinoma when compared with the atrophic endometrium from the same patients (P ¼ 0.0283), but was lower in comparison with normal endometrium from women in the menstrual cycle. Interestingly, nuclear staining was observed in some cases, and it was less frequent in endometrial carcinoma when compared with the adjacent atrophic endometrium (P ¼ 0.0465). There were no statistical differences when comparing superficial and myoinvasive endometrial carcinoma samples. Endometrioid endometrial carcinomas showed higher expression of FGFR2 than nonendometrioid endometrial carcinomas (fold change 2.56; P ¼ 0.0015). Grade III endometrioid endometrial carcinomas showed decreased FGFR2 expression when compared with grade II endometrioid endometrial carcinomas (P ¼ 0.0055). No differences were found regarding pathological stage. Two missense mutations of FGFR2 gene were detected in exons 6 and 11 (S252W and N549K, respectively; 6.45%). Results support the hypothesis that FGFR2 has a dual role in the endometrium, by inhibiting cell proliferation in normal endometrium during the menstrual cycle, but acting as an oncogene in endometrial carcinoma.

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Section: Fgfr2 Mutationsmentioning

confidence: 99%

FGFR2 alterations in endometrial carcinoma

et al. 2011

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“…During the first stages of the development of primitive tumors from epithelial origin, the TGFb/Smad cascade acts as a tumor suppressor mainly through inhibition of cell proliferation and/or promotion of cell apoptosis (11,12,17). Contrarily, during the later stages, the TGFb cascade promotes tumor progression mainly by its ability to stimulate epithelial-to-mesenchymal transition, tumor invasion, metastatic dissemination, and/or evasion of the immune system (12,13,17). With regard to bone cancers, most studies have focused on the role of TGFb in the development of bone metastasis.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Smad7 Blocks Primary Tumor Growth and Lung Metastasis Development in Osteosarcoma

Lamora

Talbot

Bougras

et al. 2014

Clinical Cancer Research

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Purpose: Osteosarcoma is the main malignant primary bone tumor in children and adolescents for whom the prognosis remains poor, especially when metastasis is present at diagnosis. Because transforming growth factor-b (TGFb) has been shown to promote metastasis in many solid tumors, we investigated the effect of the natural TGFb/Smad signaling inhibitor Smad7 and the TbRI inhibitor SD-208 on osteosarcoma behavior.Experimental Design: By using a mouse model of osteosarcoma induced by paratibial injection of cells, we assessed the impact of Smad7 overexpression or SD-208 on tumor growth, tumor microenvironment, bone remodeling, and metastasis development.Results: First, we demonstrated that TGFb levels are higher in serum samples from patients with osteosarcoma compared with healthy volunteers and that TGFb/Smad3 signaling pathway is activated in clinical samples. Second, we showed that Smad7 slows the growth of the primary tumor and increases mice survival. We furthermore demonstrated that Smad7 expression does not affect in vitro osteosarcoma cell proliferation but affects the microarchitectural parameters of bone. In addition, Smad7-osteosarcoma bone tumors expressed lower levels of osteolytic factors such as RANKL, suggesting that Smad7 overexpression affects the "vicious cycle" established between tumor cells and bone cells by its ability to decrease osteoclast activity. Finally, we showed that Smad7 overexpression in osteosarcoma cells and the treatment of mice with SD208 inhibit the development of lung metastasis.Conclusion: Taken together, these results demonstrate that the inhibition of the TGFb/Smad signaling pathway may be a promising therapeutic strategy against tumor progression of osteosarcoma, specifically against the development of lung metastasis.

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“…In normal and premalignant cells, TGF-b enforces homoeostasis and suppresses tumour progression directly through cell autonomous regulation of apoptosis and growth arrest or indirectly through blockage of paracrine factor production in the tumour stroma. However, when cancer cells lose the TGF-b tumour suppressive responses, they can utilize TGF-b as a potent promoter of cell motility, invasion, metastasis and tumour stem cell maintenance 1,10 .…”

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confidence: 99%

Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-β signalling

et al. 2014

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In advanced cancers, the TGF-b pathway acts as an oncogenic factor and is considered to be a therapeutic target. Here using a genome-wide cDNA screen, we identify nuclear receptor NR4A1 as a strong activator of TGF-b signalling. NR4A1 promotes TGF-b/SMAD signalling by facilitating AXIN2-RNF12/ARKADIA-induced SMAD7 degradation. NR4A1 interacts with SMAD7 and AXIN2, and potently and directly induces AXIN2 expression. Whereas loss of NR4A1 inhibits TGF-b-induced epithelial-to-mesenchymal transition and metastasis, slight NR4A1 ectopic expression stimulates metastasis in a TGF-b-dependent manner. Importantly, inflammatory cytokines potently induce NR4A1 expression, and potentiate TGF-b-mediated breast cancer cell migration, invasion and metastasis in vitro and in vivo. Notably, NR4A1 expression is elevated in breast cancer patients with high immune infiltration and its expression weakly correlates with phosphorylated SMAD2 levels, and is an indicator of poor prognosis. Our results uncover inflammation-induced NR4A1 as an important determinant for hyperactivation of pro-oncogenic TGF-b signalling in breast cancer.

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The dynamic roles of TGF‐β in cancer

Cited by 358 publications

References 176 publications

FGFR2 alterations in endometrial carcinoma

FGFR2 alterations in endometrial carcinoma

Overexpression of Smad7 Blocks Primary Tumor Growth and Lung Metastasis Development in Osteosarcoma

Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-β signalling

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