bims-stacyt 2020-08-02 papers

Cancer Lett. 2020 Jul 23. pii: S0304-3835(20)30359-1. [Epub ahead of print]

Hypoxia-driven intratumor heterogeneity and immune evasion.

Stéphane Terry, Agnete S T Engelsen, Stéphanie Buart, Walid Shaaban Elsayed, Goutham Hassan Venkatesh, Salem Chouaib.

While it is widely accepted that high intratumoral heterogeneity confers serious challenges in the emerging resistance and the subsequent effective therapeutic targeting of cancer, the underlying biology of intratumoral heterogeneity remains elusive. In particular, it remains to be fully elucidated how microenvironmental factors shape genetic and non-genetic heterogeneity, which in turn determine the course of tumor evolution and clinical progression. In this context, hypoxia, a hallmark of most growing cancers, characterized by decreased O2 partial pressure is a key player of the tumor microenvironment. Despite extensive data indicating that hypoxia promotes cellular metabolic adaptation, immune suppression and various steps of tumor progression via hypoxia regulated gene transcription, much less is known about the role of hypoxia in mediating therapy resistance as a driver of tumor evolution through genetic and non-genetic mechanisms. In this review, we will discuss recent evidence supporting a prominent role of hypoxia as a driver of tumor heterogeneity and highlight the multifaceted manner by which this in turn could impact cancer evolution, reprogramming and immune escape. Finally, we will discuss how detailed knowledge of the hypoxic footprint may open up new therapeutic avenues for the management of cancer.

Keywords: Antitumor immunity; DNA repair; Epigenetics; Hypoxia; Immune escape; Intratumoral heterogeneity; Tumor plasticity; Tumor resistance

DOI: https://doi.org/10.1016/j.canlet.2020.07.004

Biochem Biophys Res Commun. 2020 Aug 27. pii: S0006-291X(20)31287-0. [Epub ahead of print]529(3): 714-719

Glucosamine regulation of fibroblast growth factor 21 expression in liver and adipose tissues.

Ting-Yu Chen, David Sun, Wei-Shen Lin, Yi-Ling Lin, Yu-Ming Chao, Shan-Yu Chen, Yun-Ru Chen, Yuh-Lin Wu.

Obesity is associated with metabolic disorders. Fibroblast growth factor 21 (FGF21) has been recognized as important in metabolism. Glucosamine (GLN) has been demonstrated to perform diverse beneficial functions. This study aimed to reveal whether and how GLN would modulate FGF21 production in relation to metabolism. With in vivo model of normal diet (ND) and high-fat diet (HFD) mice receiving GLN injection and in vitro model of mouse AML12 liver cells and differentiated 3T3L1 adipocytes challenged with GLN, GLN appeared to improve the glucose metabolism in HFD and ND mice and to elevate FGF21 protein expression in HFD liver and to increase both FGF21 protein and mRNA levels in WAT from HFD and ND mice and it also upregulated FGF21 expression in both AML12 and differentiated 3T3L1 cells. By using inhibitors against various signaling pathways, p38, Akt, NF-κB, and PKA appeared potentially involved in GLN-mediated FGF21 production in AML12 cells; GLN was able to mediate activation of NF-κB, p38 or PKA/CREB signaling. Our accumulated findings suggest that GLN may potentially improve the metabolic performance by inducing FGF21 production in liver and adipose tissues and such induction in liver cells may act in part due to GLN induction of the NF-κB, p38 and PKA pathways.

Keywords: Fibroblast growth factor 21; Glucosamine; Metabolism; Signal transduction

DOI: https://doi.org/10.1016/j.bbrc.2020.06.070

Front Immunol. 2020 ;11 1346

Metabolic Flexibility and Innate Immunity in Renal Ischemia Reperfusion Injury: The Fine Balance Between Adaptive Repair and Tissue Degeneration.

Alessandra Tammaro, Jesper Kers, Angelique M L Scantlebery, Sandrine Florquin.

Renal ischemia reperfusion injury (IRI), a common event after renal transplantation, causes acute kidney injury (AKI), increases the risk of delayed graft function (DGF), primes the donor kidney for rejection, and contributes to the long-term risk of graft loss. In the last decade, epidemiological studies have linked even mild episodes of AKI to chronic kidney disease (CKD) progression, and innate immunity seems to play a crucial role. The ischemic insult triggers an acute inflammatory reaction that is elicited by Pattern Recognition Receptors (PRRs), expressed on both infiltrating immune cells as well as tubular epithelial cells (TECs). Among the PRRs, Toll-like receptors (TLRs), their synergistic receptors, Nod-like receptors (NLRs), and the inflammasomes, play a pivotal role in shaping inflammation and TEC repair, in response to renal IRI. These receptors represent promising targets to modulate the extent of inflammation, but also function as gatekeepers of tissue repair, protecting against AKI-to-CKD progression. Despite the important considerations on timely use of therapeutics, in the context of IRI, treatment options are limited by a lack of understanding of the intra- and intercellular mechanisms associated with the activation of innate immune receptors and their impact on adaptive tubular repair. Accumulating evidence suggests that TEC-associated innate immunity shapes the tubular response to stress through the regulation of immunometabolism. Engagement of innate immune receptors provides TECs with the metabolic flexibility necessary for their plasticity during injury and repair. This could significantly affect pathogenic processes within TECs, such as cell death, mitochondrial damage, senescence, and pro-fibrotic cytokine secretion, well-known to exacerbate inflammation and fibrosis. This article provides an overview of the past 5 years of research on the role of innate immunity in experimental and human IRI, with a focus on the cascade of events activated by hypoxic damage in TECs: from programmed cell death (PCD) and mitochondrial dysfunction-mediated metabolic rewiring of TECs to maladaptive repair and progression to fibrosis. Finally, we will discuss the important crosstalk between metabolism and innate immunity observed in TECs and their therapeutic potential in both experimental and clinical research.

Keywords: cell death; innate immunity; kidney transplantation; mitochondria; senescence; tubular repair

DOI: https://doi.org/10.3389/fimmu.2020.01346