Korpal M, Kang YTargeting the transforming growth factor-beta signalling pathway in metastatic cancer. Eur J Cancer 46: 1232-1240
Transforming growth factor (TGF)-beta signalling plays a dichotomous role in tumour progression, acting as a tumour suppressor early and as a pro-metastatic pathway in late-stages. There is accumulating evidence that advanced-stage tumours produce excessive levels of TGF-beta, which acts to promote tumour growth, invasion and colonisation of secondary organs. In light of the pro-metastasis function, many strategies are currently being explored to antagonise the TGF-beta pathway as a treatment for metastatic cancers. Strategies such as using large molecule ligand traps, reducing the translational efficiency of TGF-beta ligands using antisense technology, and antagonising TGF-beta receptor I/II kinase function using small molecule inhibitors are the most prominent methods being explored today. Administration of anti-TGF-beta therapies alone, or in combination with immunosuppressive or cytotoxic therapies, has yielded promising results in the preclinical and clinical settings. Despite these successes, the temporal- and context-dependent roles of TGF-beta signalling in cancer has made it challenging to define patient subgroups that are most likely to respond, and the therapeutic regimens that will be most effective in the clinic. Novel mouse models and diagnostic tools are being developed today to circumvent these issues, which may potentially expedite anti-TGF-beta drug development and clinical application.
Available from: Joanna Magdalena Zarzynska
- "In preclinical trials another mAB, 2G7, showed efficacy in inhibiting breast cancer metastasis by increasing NK cells activity and preventing radiation induced acceleration of metastases [20, 104, 106–108]. Genzyme had developed three fully humanized mABs: GC-1008 (Fresolimumab), CAT-152 (Lerdelimimab), and CAT-192 (Metelimumab), which were tested in clinical trials [3, 104]. "
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ABSTRACT: Breast cancer (BC) is potentially life-threatening malignancy that still causes high mortality among women. Scientific research in this field is focused on deeper understanding of pathogenesis and progressing of BC, in order to develop relevant diagnosis and improve therapeutic treatment. Multifunctional cytokine TGF- β 1 is one of many factors that have a direct influence on BC pathophysiology. Expression of TGF- β 1, induction of canonical and noncanonical signaling pathways, and mutations in genes encoding TGF- β 1 and its receptors are correlated with oncogenic activity of this cytokine. In early stages of BC this cytokine inhibits epithelial cell cycle progression and promotes apoptosis, showing tumor suppressive effects. However, in late stages, TGF- β 1 is linked with increased tumor progression, higher cell motility, cancer invasiveness, and metastasis. It is also involved in cancer microenvironment modification and promotion of epithelial to mesenchymal transition (EMT). This review summarizes the current knowledge on the phenomenon called "TGF- β 1 paradox", showing that better understanding of TGF- β 1 functions can be a step towards development of new therapeutic approaches. According to current knowledge several drugs against TGF- β 1 have been developed and are either in nonclinical or in early stages of clinical investigation.
Mediators of Inflammation 05/2014; 2014(1):141747. DOI:10.1155/2014/141747 · 3.24 Impact Factor
Available from: Goto Akiteru
- "Transforming growth factor (TGF)-β reportedly promotes cancer metastasis by affecting the tumor microenvironment in a manner that facilitates tumor cell invasion [3,4]. Several tumors, including those arising in the lung [5-7], express high levels of TGF-β, which correlate with tumor progression and clinical prognosis. "
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Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) with fibrous stromal invasion are newly introduced subtypes of small lung adenocarcinoma. AIS is a small localized adenocarcinoma in which growth is restricted to neoplastic cells along preexisting alveolar structures without fibrous stromal invasion. In MIA, by contrast, tumor cells have infiltrated the myofibroblastic stroma. Transforming growth factor (TGF)-β is known to be produced by progressor tumors, and excessive TGF-β contributes to a pathological excess of tissue fibrosis. TGF-β1 is the most abundant isoform, and its expression is a key event fostering tumor invasion and metastasis. We therefore analyzed the relationship between TGF-β1 expression and clinicopathological microinvasion in patients with small lung adenocarcinoma.
The study participants were 45 patients who underwent curative surgery for AIS and MIA 3 cm or less in size. Those tumors were assessed based on immunohistochemical staining using anti-TGF-β1 antibody. The TGF-β1 status was assessed immunohistochemically using the Allred 8-unit system.
The rates of TGF-β1 positivity in the AIS and MIA groups were 27.3% and 65.2%, respectively (P <0.05). The median of Allred score was 0.5 (range 0–5) in the AIS group and 3.0 (range 0–6) in the MIA group (P = 0.0017).
We suggest that TGF-β1 expression is likely to be significantly stronger in patients with MIA than in those with AIS, and the increased expression may be associated with minimal invasion and infiltration of the myofibroblastic stroma.
World Journal of Surgical Oncology 05/2013; 11(1):113. DOI:10.1186/1477-7819-11-113 · 1.41 Impact Factor
Available from: Melanie Bruchard
- "Notably, we have shown that Th17 cells differentiated without TGF-b failed to express ectonucleotidases, suggesting that ectonucleotidase expression actually determines the effector immunoregulatory fate of Th17 cells. TGF-b is a major immunoregulatory cytokine that has been shown to favor cancer progression in humans (Bierie and Moses, 2010; Korpal and Kang, 2010). The high amounts of TGF-b in the tumor microenvironment promote the survival of cancer cells through the induction of Foxp3 + regulatory T cells and the "
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ABSTRACT: Although Th17 cells are known to promote tissue inflammation and autoimmunity, their role during cancer progression remains elusive. Here, we showed that in vitro Th17 cells generated with the cytokines IL-6 and TGF-β expressed CD39 and CD73 ectonucleotidases, leading to adenosine release and the subsequent suppression of CD4(+) and CD8(+) T cell effector functions. The IL-6-mediated activation of the transcription factor Stat3 and the TGF-β-driven downregulation of Gfi-1 transcription factor were both essential for the expression of ectonucleotidases during Th17 cell differentiation. Stat3 supported whereas Gfi-1 repressed CD39 and CD73 expression by binding to their promoters. Accordingly, Th17 cells differentiated with IL-1β, IL-6, and IL-23 but without TGF-β did not express ectonucleotidases and were not immunosuppressive. Finally, adoptive transfer of Th17 cells induced by TGF-β and IL-6 promoted tumor growth in a CD39-dependent manner. Thus, ectonucleotidase expression supports the immunosuppressive fate of Th17 cells in cancer.
Immunity 03/2012; 36(3):362-73. DOI:10.1016/j.immuni.2011.12.019 · 21.56 Impact Factor
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