Transforming growth factor β (TGF-β) and inflammation in cancer

Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA.
Cytokine & growth factor reviews (Impact Factor: 5.36). 12/2009; 21(1):49-59. DOI: 10.1016/j.cytogfr.2009.11.008
Source: PubMed


The transforming growth factor beta (TGF-beta) has been studied with regard to the regulation of cell behavior for over three decades. A large body of research has been devoted to the regulation of epithelial cell and derivative carcinoma cell populations in vitro and in vivo. TGF-beta has been shown to inhibit epithelial cell cycle progression and promote apoptosis that together significantly contribute to the tumor suppressive role for TGF-beta during carcinoma initiation and progression. TGF-beta is also able to promote an epithelial to mesenchymal transition that has been associated with increased tumor cell motility, invasion and metastasis. However, it has now been shown that loss of carcinoma cell responsiveness to TGF-beta stimulation can also promote metastasis. Interestingly, enhanced metastasis in the absence of a carcinoma cell response to TGF-beta stimulation has been shown to involve increased chemokine production resulting in recruitment of pro-metastatic myeloid derived suppressor cell (MDSC) populations to the tumor microenvironment at the leading invasive edge. When present, MDSCs enhance angiogenesis, promote immune tolerance and provide matrix degrading enzymes that promote tumor progression and metastasis. Further, the recruitment of MDSC populations in this context likely enhances the classic role for TGF-beta in immune suppression since the MDSCs are an abundant source of TGF-beta production. Importantly, it is now clear that carcinoma-immune cell cross-talk initiated by TGF-beta signaling within the carcinoma cell is a significant determinant worth consideration when designing therapeutic strategies to manage tumor progression and metastasis.

Download full-text


Available from: Brian Bierie, Jan 16, 2015
68 Reads
  • Source
    • "The ectonucleotidases-degraded ATP led to adenosine release and, subsequently, suppression of helper CD4 + and cytotoxic CD8 + T cell effector functions. TGFí µí»½ which is commonly found in tumour microenvironments has, therefore , been suggested to augment the immune suppressive and tumour-promoting functions of Th17 cells [75] [76]. Th17 cells have also been reported to promote cancer by virtue of their ability to induce angiogenesis [65]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Th17 cells provide protective immunity to infections by fungi and extracellular bacteria as well as cancer but are also involved in chronic inflammation. The cells were first identified by their ability to produce interleukin 17A (IL-17A) and, subsequently, associated with chronic inflammation and autoimmunity. Th17 cells have some gene profile similarity with stem cells and can remain dormant in mucosal tissues for long periods. Indeed, recent studies suggest that functionally distinct subsets of pro- and anti-inflammatory Th17 cells can interchange phenotype and functions. For development, Th17 cells require activation of the transcription factors STAT3 and RORγt while RUNX1, c-Maf, and Aiolos are involved in changes of phenotype/functions. Attempts to harness Th17 cells against pathogens and cancer using vaccination strategies are being explored. The cells gain protective abilities when induced to produce interferon γ (IFNγ). In addition, treatment with antibodies to IL-17 is effective in treating patients with psoriasis, psoriatic arthritis, and refectory rheumatoid arthritis. Moreover, since RORγt is a nuclear receptor, it is likely to be a potential future drug target for modulating Th17 functions. This review explores pathways through which Th17 subsets are induced, the molecular basis of their plasticity, and potential therapeutic strategies for their modulation in diseases.
    Mediators of Inflammation 06/2015; 2015:1-11. DOI:10.1155/2015/205156 · 3.24 Impact Factor
  • Source
    • "In addition, tumor cells create an immunosuppressive microenvironment via the elaboration of various cytokines and chemokines, such as TGF-β, IL- 10, prostaglandins (PGs), chemokine (C-C motif) ligand 2 (CCL-2), and VEGF. TGF-β inhibits T-and natural killer (NK)-cell proliferation and function [14] and promotes the expansion of regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs) [15] [16] . IL-10 inhibits antitumor immunity [17] . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Considerable progress has been made in the field of cancer immunotherapy in recent years. This has been made possible in large part by the identification of new immune-based cellular targets and the development of novel approaches aimed at stimulating the immune system. The role played by the immunosuppressive microenvironment in the development of tumors has been established. The success of checkpoint-inhibiting antibodies and cancer vaccines has marked the beginning of a new era in cancer treatment. This review highlights the clinically relevant principles of cancer immunology and various immunotherapeutic approaches that have either already entered mainstream oncologic practice or are currently in the process of being evaluated in clinical trials. Furthermore, the current barriers to the development of effective immunotherapies and the potential strategies of overcoming them are also discussed.
    Ai zheng = Aizheng = Chinese journal of cancer 09/2014; 33(9):445-57. DOI:10.5732/cjc.014.10123 · 2.16 Impact Factor
  • Source
    • "The low numbers of CD4+CD103+-lymphocytes in RE might indicate low levels of tissue TGF-β, which led to a diminished ability of CD4+-cells to upregulate CD103 or to an impaired influx of CD4+CD103+-cells from peripheral blood. Lower levels of TGF-β can point at a pro-inflammatory environment [42]. This is supported by the finding that CD103+-lymphocytes have an immunosuppressive phenotype placing them in an anti-inflammatory tissue environment [27], [43], [44]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background and Objective Reflux esophagitis (RE) is characterized by inflammation of the squamous epithelium (SQ) of the esophagus and may progress to Barrett’s esophagus (BE) characterized by intestinal metaplasia. The role of inflammation in this transition has been postulated but lacks experimental evidence. Here, the inflammatory responses in the esophagus of these patients were investigated. Patients and Methods Fifty-one esophageal biopsies from with patients BE (n = 19), RE (n = 8) and controls (n = 23) were analyzed. T-cells were analyzed before and after ex vivo expansion (14 days) by multicolor flow cytometric analysis. The following markers were studied: CD3, CD4, CD8 (T-cell markers), Granzyme B (marker of cytotoxicity), CD103 (αE/epithelial integrin) and NKg2a (inhibitory receptor on T-cells and NK-cells). Results Analysis of ex vivo cultures from normal looking SQ from controls, RE patients, and BE patients revealed no significant differences in the number and phenotypes of T-cells. In contrast, tissue from RE was different to normal SQ in four aspects: 1) higher percentages of CD3+CD4+-cells (72±7% vs 48±6%, p = 0.01) and 2) CD8+GranzymeB+ -cells (53±11% vs 26±4%, p<0.05), while 3) lower percentages of CD4+CD103+-cells (45±19% vs 80±3%, p = 0.02) and 4) CD8+NKg2a+- cells (31±12% vs 44±5%). Conclusion Despite the fact that both tissues are exposed to the same reflux associated inflammatory triggers, the immune response observed in RE is clearly distinct from that in SQ of BE. The differences in immune responses in BE tissue might contribute to its susceptibility for transformation into intestinal metaplasia.
    PLoS ONE 08/2014; 9(8):e106261. DOI:10.1371/journal.pone.0106261 · 3.23 Impact Factor
Show more