The Emergence of Natural Killer Cells as a Major Target in Cancer Immunotherapy

Bone physiological microenvironment and healing mechanism: Basis for future bone-tissue engineering scaffolds.

Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis.

Transforming growth factor-β (TGF-β) signaling triggers diverse biological actions in inflammatory diseases. In tissue fibrosis, it acts as a key pathogenic regulator for promoting immunoregulation via controlling the activation, proliferation, and apoptosis of immunocytes. In cancer, it plays a critical role in tumor microenvironment (TME) for accelerating invasion, metastasis, angiogenesis, and immunosuppression. Increasing evidence suggest a pleiotropic nature of TGF-β signaling as a critical pathway for generating fibrotic TME, which contains numerous cancer-associated fibroblasts (CAFs), extracellular matrix proteins, and remodeling enzymes. Its pathogenic roles and working mechanisms in tumorigenesis are still largely unclear. Importantly, recent studies successfully demonstrated the clinical implications of fibrotic TME in cancer. This review systematically summarized the latest updates and discoveries of TGF-β signaling in the fibrotic TME.

TGF-β Signaling: From Tissue Fibrosis to Tumor Microenvironment

An increasing number of studies have shown that long noncoding RNAs (lncRNAs) play important roles in diverse cellular processes, including proliferation, apoptosis, migration, invasion, chromatin remodeling, metabolism and immune escape. Clinically, the expression of MIR22HG is increased in many human tumors (colorectal cancer, gastric cancer, hepatocellular carcinoma, lung cancer, and thyroid carcinoma), while in others (esophageal adenocarcinoma and glioblastoma), it is significantly decreased. Moreover, MIR22HG has been reported to function as a competitive endogenous RNA (ceRNA), be involved in signaling pathways, interact with proteins and interplay with miRNAs as a host gene to participate in tumorigenesis and tumor progression. In this review, we describe the biological functions of MIR22HG, reveal its underlying mechanisms for cancer regulation, and highlight the potential role of MIR22HG as a novel cancer prognostic biomarker and therapeutic target that can increase the efficacy of immunotherapy and targeted therapy for cancer treatment.

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Emerging impact of the long noncoding RNA MIR22HG on proliferation and apoptosis in multiple human cancers

TGF-β receptors: In and beyond TGF-β signaling.

Enzalutamide, a second-generation small-molecule inhibitor of the androgen receptor (AR), has been approved for patients who failed with androgen deprivation therapy and have developed castration-resistant prostate cancer. More than 80% of these patients develop bone metastases. The binding of enzalutamide to the AR prevents the nuclear translocation of the receptor, thus inactivating androgen signaling. However, prostate cancer cells eventually develop resistance to enzalutamide treatment. Studies have found resistance both in patients and in laboratory models. The mechanisms of and approaches to overcoming such resistance are significant issues that need to be addressed. In this review, we focus on the major mechanisms of acquired enzalutamide resistance, including genetic mutations and splice variants of the AR, signaling pathways that bypass androgen signaling, intratumoral androgen biosynthesis by prostate tumor cells, lineage plasticity, and contributions from the tumor microenvironment. Approaches for overcoming these mechanisms to enzalutamide resistance along with the associated problems and solutions are discussed. Emerging questions, concerns, and new opportunities in studying enzalutamide resistance will be addressed as well.

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Mechanisms and Approaches for Overcoming Enzalutamide Resistance in Prostate Cancer

Loss of TGF-β signaling in osteoblasts increases basic-FGF and promotes prostate cancer bone metastasis.

The role of myeloid cell-specific TGF-β signaling in non-small-cell lung cancer (NSCLC)-induced osteolytic bone lesion development is unknown. We used a genetically engineered mouse model, Tgfbr2LysMCre knockout (KO), which has a loss of TGF-β signaling specifically in myeloid lineage cells, and we found that the area of H1993 cell-induced osteolytic bone lesions was decreased in Tgfbr2LysMCre KO mice, relative to the area in control littermates. The bone lesion areas were correlated with tumor cell proliferation, angiogenesis, and osteoclastogenesis in the microenvironment. The smaller bone lesion area was partially rescued by bFGF, which was expressed by osteoblasts. Interestingly, bFGF was able to rescue the osteoclastogenesis, but not the tumor cell proliferation or angiogenesis. We then focused on identifying osteoclast factors that regulate bFGF expression in osteoblasts. We found that the expression and secretion of CTHRC1 was downregulated in osteoclasts from Tgfbr2LysMCre KO mice; CTHRC1 was able to promote bFGF expression in osteoblasts, possibly through the Wnt/β-catenin pathway. Functionally, bFGF stimulated osteoclastogenesis and inhibited osteoblastogenesis, but had no effect on H1993 cell proliferation. On the other hand, CTHRC1 promoted osteoblastogenesis and H1993 cell proliferation. Together, our data show that myeloid-specific TGF-β signaling promoted osteolytic bone lesion development and bFGF expression in osteoblasts; that osteoclast-secreted CTHRC1 stimulated bFGF expression in osteoblasts in a paracrine manner; and that CTHRC1 and bFGF had different cell-specific functions that contributed to bone lesion development.

Loss of Myeloid-Specific TGF-β Signaling Decreases CTHRC1 to Downregulate bFGF and the Development of H1993-Induced Osteolytic Bone Lesions.

Abstract Metabolic programming of the innate immune cells known as dendritic cells (DCs) changes in response to different stimuli, influencing their function. While the mechanisms behind increased glycolytic metabolism in response to inflammatory stimuli are well-studied, less is known about the programming of mitochondrial metabolism in DCs. We used lipopolysaccharide (LPS) and interferon-β (IFN-β), which differentially stimulate the use of glycolysis and oxidative phosphorylation (OXPHOS), respectively, to identify factors important for mitochondrial metabolism. We found that the expression of peroxisome proliferator-activated receptor gamma co-activator 1β (PGC-1β), a transcriptional co-activator and known regulator of mitochondrial metabolism, decreases when DCs are activated with LPS, when OXPHOS is diminished, but not with IFN-β, when OXPHOS is maintained. We examined the role of PGC-1β in bioenergetic metabolism of DCs and found that PGC-1β deficiency indeed impairs their mitochondrial respiration. PGC-1β-deficient DCs are more glycolytic compared to controls, likely to compensate for reduced OXPHOS. PGC-1β deficiency also causes decreased capacity for ATP production at steady state and in response to IFN-β treatment. Loss of PGC-1β in DCs leads to increased expression of genes in inflammatory pathways, and reduced expression of genes encoding proteins important for mitochondrial metabolism and function. Collectively, these results demonstrate that PGC-1β is a key regulator of mitochondrial metabolism and negative regulator of inflammatory gene expression in DCs. 

/pdf/pgc-1b-maintains-mitochondrial-metabolism-and-restrains-1zyazeyj.pdf

Alexandra Vander Ark

Papers

TGF-β receptors: In and beyond TGF-β signaling.

Mechanisms and Approaches for Overcoming Enzalutamide Resistance in Prostate Cancer

Loss of TGF-β signaling in osteoblasts increases basic-FGF and promotes prostate cancer bone metastasis.

Loss of Myeloid-Specific TGF-β Signaling Decreases CTHRC1 to Downregulate bFGF and the Development of H1993-Induced Osteolytic Bone Lesions.

PGC-1β maintains mitochondrial metabolism and restrains inflammatory gene expression