bims-stacyt 2018-12-30 papers

Cancers (Basel). 2018 Dec 27. pii: E24. [Epub ahead of print]11(1):

Obesity-Induced TNFα and IL-6 Signaling: The Missing Link between Obesity and Inflammation-Driven Liver and Colorectal Cancers.

Lara Kern, Melanie J Mittenbühler, Anna Juliane Vesting, Anna Lena Ostermann, Claudia Maria Wunderlich, F Thomas Wunderlich.

Obesity promotes the development of numerous cancers, such as liver and colorectal cancers, which is at least partly due to obesity-induced, chronic, low-grade inflammation. In particular, the recruitment and activation of immune cell subsets in the white adipose tissue systemically increase proinflammatory cytokines, such as tumor necrosis factor α (TNFα) and interleukin-6 (IL-6). These proinflammatory cytokines not only impair insulin action in metabolic tissues, but also favor cancer development. Here, we review the current state of knowledge on how obesity affects inflammatory TNFα and IL-6 signaling in hepatocellular carcinoma and colorectal cancers.

Keywords: IL-6 and TNF; Obesity; liver and colon cancer; low-grade inflammation; signaling

DOI: https://doi.org/10.3390/cancers11010024

Semin Liver Dis. 2018 Dec 26.

TGF-β as Multifaceted Orchestrator in HCC Progression: Signaling, EMT, Immune Microenvironment, and Novel Therapeutic Perspectives.

Francesco Dituri, Serena Mancarella, Antonio Cigliano, Annarita Chieti, Gianluigi Giannelli.

Therapeutic attempts to treat hepatocellular carcinoma (HCC) frequently result in a poor response or treatment failure. The efficacy of approved drugs and survival expectancies is affected by an ample degree of variability that can be explained at least in part by the enormous between-patient cellular and molecular heterogeneity of this neoplasm. Transforming growth factor-β (TGF-β) is hyperactivated in a large fraction of HCCs, where it influences complex interactive networks covering multiple cell types and a plethora of other local soluble ligands, ultimately establishing several malignancy traits. This cytokine boosts the invasiveness of cancerous epithelial cells through promoting the epithelial-to-mesenchymal transition program, but also skews the phenotype of immune cells toward a tumor-supporting status. Here, we discuss recent strategies pursued to offset TGF-β-dependent processes that promote metastatic progression and immune surveillance escape in solid cancers, including HCC. Moreover, we report findings indicating that TGF-β reduces the expression of the proinflammatory factors CCL4 and interleukin-1β (IL-1β in human ex vivo treated HCC tissues. While this is consistent with the anti-inflammatory properties of TGF-β, whether it is an outright tumor promoter or suppressor is still a matter of some debate. Indeed, IL-1β has also been shown to support angiogenesis and cell invasiveness in some cancers. In addition, we describe an inhibitory effect of TGF-β on the secretion of CCL2 and CXCL1 by HCC-derived fibroblasts, which suggests the existence of an indirect stroma-mediated functional link between TGF-β and downstream immunity.

DOI: https://doi.org/10.1055/s-0038-1676121

Int J Biol Sci. 2018 ;14(14): 2083-2093

Effect of Stromal Cells in Tumor Microenvironment on Metastasis Initiation.

Sen Guo, Chu-Xia Deng.

The cellular environment where tumor cells reside is called the tumor microenvironment (TME), which consists of borders, blood vessels, lymph vessels, extracellular matrix (ECM), stromal cells, immune/inflammatory cells, secreted proteins, RNAs and small organelles. By dynamically interacting with tumor cells, stromal cells participate in all stages of tumor initiation, progression, metastasis, recurrence and drug response, and consequently, affect the fate of patients. During the processes of tumor evolution and metastasis initiation, stromal cells in TME also experience some changes and play roles in both the suppression and promotion of metastasis, while the overall function of stromal cells is beneficial for cancer cell survival and movement. In this review, we examine the effects of stromal cells in TME on metastasis initiation, including angiogenesis, epithelial-mesenchymal transition (EMT) and invasion. We also highlight functions of proteins, RNAs and small organelles secreted by stromal cells in their influences on multiple stages of tumor metastasis.

Keywords: Breast Cancer; Metastasis Initiation; Stromal cells; TME

DOI: https://doi.org/10.7150/ijbs.25720

Cell Metab. 2018 Dec 13. pii: S1550-4131(18)30737-X. [Epub ahead of print]

Starvation and Pseudo-Starvation as Drivers of Cancer Metastasis through Translation Reprogramming.

Custodia García-Jiménez, Colin R Goding.

Considerable progress has been made in identifying microenvironmental signals that effect the reversible phenotypic transitions underpinning the early steps in the metastatic cascade. However, although the general principles underlying metastatic dissemination have been broadly outlined, a common theme that unifies many of the triggers of invasive behavior in tumors has yet to emerge. Here we discuss how many diverse signals that induce invasion converge on the reprogramming of protein translation via phosphorylation of eIF2α, a hallmark of the starvation response. These include starvation as a consequence of nutrient or oxygen limitation, or pseudo-starvation imposed by cell-extrinsic microenvironmental signals or by cell-intrinsic events, including oncogene activation. Since in response to resource limitation single-cell organisms undergo phenotypic transitions remarkably similar to those observed within tumors, we propose that a starvation/pseudo-starvation model to explain cancer progression provides an integrated and evolutionarily conserved conceptual framework to understand the progression of this complex disease.

Keywords: cancer heterogeneity; eIF2α; invasion; nutrient supply and demand; phenotypic plasticity; pseudo-starvation; translation reprogramming

DOI: https://doi.org/10.1016/j.cmet.2018.11.018

J Oral Sci. 2018 ;60(4): 544-551

Effect of hypoxia on the expression of CCAAT/enhancer-binding protein β and receptor activator of nuclear factor kappa-B ligand in periodontal ligament cells.

Hisanori Ito, Takashi Kifune, Misa Ishiyama, Satoko Iwasa, Hiroki Takei, Tomokazu Hasegawa, Masatake Asano, Tetsuo Shirakawa.

Hypoxia after traumatic injuries to a tooth is one of the causes of subsequent root resorption. Inflammatory cytokines produced under hypoxic conditions are associated with root resorption, but the mechanism has not been fully understood. In this study, the role of hypoxia-inducible factor-1 (HIF-1) signaling in the regulation of CCAAT (cytosine-cytosine-adenosine-adenosine-thymidine)/enhancer-binding protein-β (C/EBPβ) and the receptor activator of nuclear factor kappa-B ligand (RANKL) expressions in immortalized human periodontal ligament (PDL) cells was investigated. PDL cells cultured under a hypoxic condition showed an increase in the expression of C/EBPβ and RANKL messenger RNAs (mRNAs), whereas the expression of osteoprotegerin and HIF-1α mRNAs was unaffected. Hypoxia had no effects on the secretion of interleukin (IL)-1β, IL-6, IL-8, IL-17A, tumor necrosis factor-alpha, macrophage migration inhibitory factor, monocyte chemoattractant protein-1, and macrophage colony-stimulating factor in the culture media. Treatment of the cells with dimethyloxaloylglycine, a competitive HIF prolyl hydroxylase inhibitor, significantly increased the expression of C/EBPβ and RANKL mRNAs. This suggested that the hypoxia-induced elevation of C/EBPβ and RANKL mRNAs was dependent on the HIF-1 activity. PDL cells transfected with a specific small interfering RNA designed to target the C/EBPβ gene showed a significant suppression of the RANKL mRNA. These findings indicated that C/EBPβ may play an important role in tooth root resorption via RANKL activation in hypoxia-exposed PDL cells.

Keywords: C/EBPβ; HIF-1; RANKL; hypoxia; periodontal ligament cells

DOI: https://doi.org/10.2334/josnusd.17-0436