bims-stacyt 2022-11-27 papers

Oncol Rep. 2023 Jan;pii: 14. [Epub ahead of print]49(1):

Activating transcription factor 4 regulates hypoxia inducible factor 1α in chronic hypoxia in pancreatic cancer cells.

Nancy T Chee, Candace H Carriere, Zachary Miller, Scott Welford, Shaun P Brothers.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and difficult to treat cancers with tumors typically exhibiting high levels of chronic hypoxia. Hypoxia activates hypoxia-inducible factors (HIFs) that mediate cellular responses to adapt to low oxygen environments. Hypoxia also causes endoplasmic reticulum (ER) stress, increasing activating transcription factor 4 (ATF4), a master regulator of the unfolded protein response (UPR) pathway that mediates cellular response to ER stress. ATF4 is overexpressed in PDAC and is associated with poor prognoses. While ATF4 promotes cell proliferation and tumorigenesis, most studies have been conducted under normoxia or acute hypoxia. The functions of ATF4 in chronic hypoxia remain largely unexplored. Using siRNA knockdown experiments of healthy skin fibroblast cells WS1 and PDAC cell lines PANC-1 and Mia-PaCa2 to analyze mRNA and protein expression levels, a novel ATF4 function was identified, in which it decreases HIF2α mRNA and increases HIF1α mRNA in chronic hypoxia while having no effect in acute hypoxia. A scratch assay was used to show that ATF4 decreases cell migration in chronic hypoxia as opposed to the increase in cell migration ATF4 imparts in acute hypoxia. Colony formation assay and cell viability assay showed that ATF4 promotes colony formation and cell viability in both chronic and acute hypoxia. In addition to the differential response of ATF4 in chronic hypoxia compared with acute hypoxia, this is the first time ATF4 has been implicated in regulation of response to hypoxia via interaction with HIF proteins in PDAC.

Keywords: ATF4; HIF1α; HIF2α; PDAC; UPR pathway; chronic hypoxia

DOI: https://doi.org/10.3892/or.2022.8451

Cell Commun Signal. 2022 Nov 23. 20(1): 186

The roles of metabolic profiles and intracellular signaling pathways of tumor microenvironment cells in angiogenesis of solid tumors.

Hamidreza Zalpoor, Fatemeh Aziziyan, Mahsa Liaghat, Maryam Bakhtiyari, Abdullatif Akbari, Mohsen Nabi-Afjadi, Razieh Forghaniesfidvajani, Nima Rezaei.

Innate and adaptive immune cells patrol and survey throughout the human body and sometimes reside in the tumor microenvironment (TME) with a variety of cell types and nutrients that may differ from those in which they developed. The metabolic pathways and metabolites of immune cells are rooted in cell physiology, and not only provide nutrients and energy for cell growth and survival but also influencing cell differentiation and effector functions. Nowadays, there is a growing awareness that metabolic processes occurring in cancer cells can affect immune cell function and lead to tumor immune evasion and angiogenesis. In order to safely treat cancer patients and prevent immune checkpoint blockade-induced toxicities and autoimmunity, we suggest using anti-angiogenic drugs solely or combined with Immune checkpoint blockers (ICBs) to boost the safety and effectiveness of cancer therapy. As a consequence, there is significant and escalating attention to discovering techniques that target metabolism as a new method of cancer therapy. In this review, a summary of immune-metabolic processes and their potential role in the stimulation of intracellular signaling in TME cells that lead to tumor angiogenesis, and therapeutic applications is provided. Video abstract.

Keywords: Angiogenesis; Cancer therapy; Metabolic profile; Signaling pathways; Solid tumors; Tumor microenvironment

DOI: https://doi.org/10.1186/s12964-022-00951-y

Brain Behav Immun. 2022 Nov 22. pii: S0889-1591(22)00436-6. [Epub ahead of print]

The GDF15-GFRAL axis mediates chemotherapy-induced fatigue in mice.

Chelette Brandon, Chinenye L Chidomere, Dantzer Robert.

Cancer-related fatigue is defined as a distressing persistent subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and that interferes with usual functioning. This form of fatigue is highly prevalent during cancer treatment and in some patients, it can persist for years after treatment has ended. An understanding of the mechanisms that drive cancer-related fatigue is still lacking, which hampers the identification of effective treatment options. Various chemotherapeutic agents including cisplatin are known to induce mitochondrial dysfunction and this effect is known to mediate chemotherapy-induced peripheral neuropathy and cognitive dysfunction. Mitochondrial dysfunction results in the release of mitokines that act locally and at distance to promote metabolic and behavioral adjustments to this form of cellular stress. One of these mitokines, growth differentiation factor 15 (GDF15) and its receptor, growth derived neurotrophic factor family receptor α-like (GFRAL), have received special attention in oncology as activation of GFRAL mediates the anorexic response that is responsible for cancer anorexia. The present study was initiated to determine whether GDF15 and GFRAL are involved in cisplatin-induced fatigue. We first tested the ability of cisplatin to increase circulating GDF15 in mice before assessing whether GDF15 can induce behavioral fatigue measured by decreased wheel running in healthy mice and increase behavioral fatigue induced by cisplatin. Mice administered a long acting form of GDF15, mGDF15-fc, decreased their voluntary wheel running activity. When the same treatment was administered to mice receiving cisplatin, it increased the amplitude and duration of cisplatin-induced decrease in wheel running. To determine whether endogenous GDF15 mediates the behavioral fatigue induced by cisplatin, we then administered a neutralizing monoclonal antibody to GFRAL to mice injected with cisplatin. The GFRAL neutralizing antibody mostly prevented cisplatin-induced decrease in wheel running and accelerated recovery. Taken together these findings demonstrate for the first time the role of the GDF15/GFRAL axis in cisplatin-induced behaviors and indicate that this axis could be a promising therapeutic target for the treatment of cancer-related fatigue.

Keywords: Fatigue; GDF15; GFRAL; cisplatin; mice; mitokine; wheel running

DOI: https://doi.org/10.1016/j.bbi.2022.11.008

Biochim Biophys Acta Rev Cancer. 2022 Nov 19. pii: S0304-419X(22)00164-0. [Epub ahead of print] 188839

Unfolded protein response and angiogenesis in malignancies.

Amin Izadpanah, Kurtis Willingham, Bysani Chandrasekar, Eckhard U Alt, Reza Izadpanah.

Cellular stress, arising from accumulation of unfolded proteins, occurs frequently in rapidly proliferating cancer cells. This cellular stress, in turn, activates the unfolded protein response (UPR), an interconnected set of signal transduction pathways that alleviate the proteostatic stress. The UPR is implicated in cancer cell survival and proliferation through upregulation of pro-tumorigenic pathways that ultimately promote malignant metabolism and neoangiogenesis. Here, we reviewed mechanisms of signaling crosstalk between the UPR and angiogenesis pathways, as well as transmissible ER stress and the role in tumor growth and development. To characterize differences in UPR and UPR-mediated angiogenesis in malignancy, we employed a data mining approach using patient tumor data from The Cancer Genome Atlas (TCGA). The analysis of TCGA revealed differences in UPR between malignant samples versus their non-malignant counterparts.

Keywords: ATF6; IRE1α; PERK; Tumor microenvironment; Unfolded protein response; XBP1

DOI: https://doi.org/10.1016/j.bbcan.2022.188839

Am J Physiol Cell Physiol. 2022 Nov 21.

Hypoxia as a Regulator of Tumor Stroma and Metastasis.

Kyoung Eun Lee.

Metastasis is the leading cause of mortality in most cancer patients. Despite its clinical importance, mechanistic underpinnings of metastatic progression remain poorly understood. Hypoxia, a condition of insufficient oxygen availability, frequently occurs in solid tumors because of their high oxygen/nutrient demand and abnormal tumor vasculature. In this review, we describe the roles of hypoxia and hypoxia-inducible factor (HIF) signaling in the metastatic cascade, with an emphasis on recent biological insights from in vivo studies.

Keywords: hypoxia; hypoxia-induced factor; metastasis; stroma; tumor microenvironment

DOI: https://doi.org/10.1152/ajpcell.00158.2022

Cells. 2022 Nov 10. pii: 3556. [Epub ahead of print]11(22):

CD36-Fatty Acid-Mediated Metastasis via the Bidirectional Interactions of Cancer Cells and Macrophages.

Noorzaileen Eileena Zaidi, Nur Aima Hafiza Shazali, Thean-Chor Leow, Mohd Azuraidi Osman, Kamariah Ibrahim, Wan-Hee Cheng, Kok-Song Lai, Nik Mohd Afizan Nik Abd Rahman.

Tumour heterogeneity refers to the complexity of cell subpopulations coexisting within the tumour microenvironment (TME), such as proliferating tumour cells, tumour stromal cells and infiltrating immune cells. The bidirectional interactions between cancer and the surrounding microenvironment mark the tumour survival and promotion functions, which allow the cancer cells to become invasive and initiate the metastatic cascade. Importantly, these interactions have been closely associated with metabolic reprogramming, which can modulate the differentiation and functions of immune cells and thus initiate the antitumour response. The purpose of this report is to review the CD36 receptor, a prominent cell receptor in metabolic activity specifically in fatty acid (FA) uptake, for the metabolic symbiosis of cancer-macrophage. In this review, we provide an update on metabolic communication between tumour cells and macrophages, as well as how the immunometabolism indirectly orchestrates the tumour metastasis.

Keywords: CD36; macrophage; metabolism; metastasis; tumour microenvironment

DOI: https://doi.org/10.3390/cells11223556

Eur J Med Res. 2022 Nov 21. 27(1): 256

Tumor microenvironment-associated lactate metabolism regulates the prognosis and precise checkpoint immunotherapy outcomes of patients with lung adenocarcinoma.

Song Qiu, Ying Wang, Hui Rao, Qiuyang Que, Yanyang Wu, Rui Zhu, Xiaofei Feng, Jun Chi, Weiling Lai, Yihang Sun, Qi Xiao, Huaqiu Shi, Yi Xiang.

BACKGROUND: Despite the wide clinical application of checkpoint inhibitor immunotherapy in lung adenocarcinoma, its limited benefit to patients remains puzzling to researchers. One of the mechanisms of immunotherapy resistance may be the dysregulation of lactate metabolism in the immunosuppressive tumor microenvironment (TME), which can inhibit dendritic cell maturation and prevent T-cell invasion into tumors. However, the key genes related to lactate metabolism and their influence on the immunotherapeutic effects in lung adenocarcinoma have not yet been investigated in depth.METHODS: In this study, we first surveyed the dysregulated expression of genes related to lactate metabolism in lung adenocarcinoma and then characterized their biological functions. Using machine learning methods, we constructed a lactate-associated gene signature in The Cancer Genome Atlas cohort and validated its effectiveness in predicting the prognosis and immunotherapy outcomes of patients in the Gene Expression Omnibus cohorts.
RESULTS: A 7-gene signature based on the metabolomics related to lactate metabolism was found to be associated with multiple important clinical features of cancer and was an independent prognostic factor.
CONCLUSIONS: These results suggest that rather than being simply a metabolic byproduct of glycolysis, lactate in the TME can affect immunotherapy outcomes. Therefore, the mechanism underlying this effect of lactate is worthy of further study.

Keywords: Gene signature; Immunotherapy benefit; Lactate metabolism; Lung adenocarcinoma; Prognosis; Risk score

DOI: https://doi.org/10.1186/s40001-022-00895-6