bims-stacyt 2021-02-07 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2021–02–07
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Macrophage Responses to Environmental Stimuli During Homeostasis and Disease.
Mapping the Metabolic Networks of Tumor Cells and Cancer-Associated Fibroblasts.
The ER stress response mediator ERO1 triggers cancer metastasis by favoring the angiogenic switch in hypoxic conditions.
Stellate Cells Aid Growth-Permissive Metabolic Reprogramming and Promote Gemcitabine Chemoresistance in Pancreatic Cancer.
Tumor Metabolic Reprogramming by Adipokines as a Critical Driver of Obesity-Associated Cancer Progression.
Does C-C Motif Chemokine Ligand 2 (CCL2) Link Obesity to a Pro-Inflammatory State?
Metabolic Reprogramming Induces Immune Cell Dysfunction in the Tumor Microenvironment of Multiple Myeloma.
5-Aza-2'-deoxycytidine induces a greater inflammatory change, at the molecular levels, in normoxic than hypoxic tumor microenvironment.

Endocr Rev. 2021 Feb 01. pii: bnab004. [Epub ahead of print]

Macrophage Responses to Environmental Stimuli During Homeostasis and Disease.

Adil Rasheed, Katey J Rayner.

  Work over the last 40 years have described macrophages as a heterogeneous population that serve as the frontline surveyors of tissue immunity. As a class, macrophages are found in almost every tissue in the body and as distinct populations within discrete microenvironments in any given tissue. During homeostasis, macrophages protect these tissues by clearing invading foreign bodies and/or mounting immune responses. In addition to varying identities regulated by transcriptional programs shaped by their respective environments, macrophage metabolism serves as an additional regulator to temper responses to extracellular stimuli. The area of research known as "immunometabolism" has been established within the last decade, owing to an increase in studies focusing on the crosstalk between altered metabolism and the regulation of cellular immune processes. From this research, macrophages have emerged as a prime focus of immunometabolic studies, although macrophage metabolism and their immune responses have been studied for centuries. During disease, the metabolic profile of the tissue and/or systemic regulators such as endocrine factors, become increasingly dysregulated. Owing to these changes, macrophage responses can become skewed to promote further pathophysiologic changes. For instance, during diabetes, obesity and atherosclerosis, macrophages favor a pro-inflammatory phenotype; whereas in the tumor microenvironment, macrophages elicit an anti-inflammatory response to enhance tumor growth. Herein we have described how macrophages respond to extracellular cues including inflammatory stimuli, nutrient availability and endocrine factors that occur during and to further promote disease progression.

Keywords:  Krebs cycle; epigenetic modifications; immunometabolism; inflammation; macrophage

DOI:  https://doi.org/10.1210/endrev/bnab004
Cells. 2021 Feb 02. pii: 304. [Epub ahead of print]10(2):

Mapping the Metabolic Networks of Tumor Cells and Cancer-Associated Fibroblasts.

Jessica Karta, Ysaline Bossicard, Konstantinos Kotzamanis, Helmut Dolznig, Elisabeth Letellier.

  Metabolism is considered to be the core of all cellular activity. Thus, extensive studies of metabolic processes are ongoing in various fields of biology, including cancer research. Cancer cells are known to adapt their metabolism to sustain high proliferation rates and survive in unfavorable environments with low oxygen and nutrient concentrations. Hence, targeting cancer cell metabolism is a promising therapeutic strategy in cancer research. However, cancers consist not only of genetically altered tumor cells but are interwoven with endothelial cells, immune cells and fibroblasts, which together with the extracellular matrix (ECM) constitute the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs), which are linked to poor prognosis in different cancer types, are one important component of the TME. CAFs play a significant role in reprogramming the metabolic landscape of tumor cells, but how, and in what manner, this interaction takes place remains rather unclear. This review aims to highlight the metabolic landscape of tumor cells and CAFs, including their recently identified subtypes, in different tumor types. In addition, we discuss various in vitro and in vivo metabolic techniques as well as different in silico computational tools that can be used to identify and characterize CAF-tumor cell interactions. Finally, we provide our view on how mapping the complex metabolic networks of stromal-tumor metabolism will help in finding novel metabolic targets for cancer treatment.

Keywords:  CAF-tumor cross-talk; cancer; cancer-associated fibroblasts (CAFs); in silico modeling; metabolomics’ measurement techniques; personalized metabolic drugs; tumor metabolism

DOI:  https://doi.org/10.3390/cells10020304
Oncogene. 2021 Feb 02.

The ER stress response mediator ERO1 triggers cancer metastasis by favoring the angiogenic switch in hypoxic conditions.

Ersilia Varone, Alessandra Decio, Alexander Chernorudskiy, Lucia Minoli, Laura Brunelli, Federica Ioli, Arianna Piotti, Roberta Pastorelli, Maddalena Fratelli, Marco Gobbi, Raffaella Giavazzi, Ester Zito.

Solid tumors are often characterized by a hypoxic microenvironment which contributes, through the hypoxia-inducible factor HIF-1, to the invasion-metastasis cascade. Endoplasmic reticulum (ER) stress also leads tumor cells to thrive and spread by inducing a transcriptional and translational program, the Unfolded Protein Response (UPR), aimed at restoring ER homeostasis. We studied ERO1 alpha (henceforth ERO1), a protein disulfide oxidase with the tumor-relevant characteristic of being positively regulated by both ER stress and hypoxia. Analysis of the redox secretome indicated that pro-angiogenic HIF-1 targets, were blunted in ERO1-devoid breast cancer cells under hypoxic conditions. ERO1 deficiency reduced tumor cell migration and lung metastases by impinging on tumor angiogenesis, negatively regulating the upstream ATF4/CHOP branch of the UPR and selectively impeding oxidative folding of angiogenic factors, among which VEGF-A. Thus, ERO1 deficiency acted synergistically with the otherwise feeble curative effects of anti-angiogenic therapy in aggressive breast cancer murine models and it might be exploited to treat cancers with pathological HIF-1-dependent angiogenesis. Furthermore, ERO1 levels are higher in the more aggressive basal breast tumors and correlate inversely with the disease- and metastasis-free interval of breast cancer patients. Thus, taking advantage of our in vitro data on ERO1-regulated gene products we identified a gene set associated with ERO1 expression in basal tumors and related to UPR, hypoxia, and angiogenesis, whose levels might be investigated in patients as a hallmark of tumor aggressiveness and orient those with lower levels toward an effective anti-angiogenic therapy.

DOI: https://doi.org/10.1038/s41388-021-01659-y
Cancers (Basel). 2021 Feb 03. pii: 601. [Epub ahead of print]13(4):

Stellate Cells Aid Growth-Permissive Metabolic Reprogramming and Promote Gemcitabine Chemoresistance in Pancreatic Cancer.

Manoj Amrutkar, Ivar P Gladhaug.

  Pancreatic ductal adenocarcinoma (PDAC), also known as pancreatic cancer (PC), is characterized by an overall poor prognosis and a five-year survival that is less than 10%. Characteristic features of the tumor are the presence of a prominent desmoplastic stromal response, an altered metabolism, and profound resistance to cancer drugs including gemcitabine, the backbone of PDAC chemotherapy. The pancreatic stellate cells (PSCs) constitute the major cellular component of PDAC stroma. PSCs are essential for extracellular matrix assembly and form a supportive niche for tumor growth. Various cytokines and growth factors induce activation of PSCs through autocrine and paracrine mechanisms, which in turn promote overall tumor growth and metastasis and induce chemoresistance. To maintain growth and survival in the nutrient-poor, hypoxic environment of PDAC, tumor cells fulfill their high energy demands via several unconventional ways, a process generally referred to as metabolic reprogramming. Accumulating evidence indicates that activated PSCs not only contribute to the therapy-resistant phenotype of PDAC but also act as a nutrient supplier for the tumor cells. However, the precise molecular links between metabolic reprogramming and an acquired therapy resistance in PDAC remain elusive. This review highlights recent findings indicating the importance of PSCs in aiding growth-permissive metabolic reprogramming and gemcitabine chemoresistance in PDAC.

Keywords:  gemcitabine chemoresistance; metabolic reprogramming; pancreatic cancer; pancreatic stellate cell

DOI:  https://doi.org/10.3390/cancers13040601
Int J Mol Sci. 2021 Feb 01. pii: 1444. [Epub ahead of print]22(3):

Tumor Metabolic Reprogramming by Adipokines as a Critical Driver of Obesity-Associated Cancer Progression.

Duc-Vinh Pham, Pil-Hoon Park.

  Adiposity is associated with an increased risk of various types of carcinoma. One of the plausible mechanisms underlying the tumor-promoting role of obesity is an aberrant secretion of adipokines, a group of hormones secreted from adipose tissue, which have exhibited both oncogenic and tumor-suppressing properties in an adipokine type- and context-dependent manner. Increasing evidence has indicated that these adipose tissue-derived hormones differentially modulate cancer cell-specific metabolism. Some adipokines, such as leptin, resistin, and visfatin, which are overproduced in obesity and widely implicated in different stages of cancer, promote cellular glucose and lipid metabolism. Conversely, adiponectin, an adipokine possessing potent anti-tumor activities, is linked to a more favorable metabolic phenotype. Adipokines may also play a pivotal role under the reciprocal regulation of metabolic rewiring of cancer cells in tumor microenvironment. Given the fact that metabolic reprogramming is one of the major hallmarks of cancer, understanding the modulatory effects of adipokines on alterations in cancer cell metabolism would provide insight into the crosstalk between obesity, adipokines, and tumorigenesis. In this review, we summarize recent insights into putative roles of adipokines as mediators of cellular metabolic rewiring in obesity-associated tumors, which plays a crucial role in determining the fate of tumor cells.

Keywords:  adipokine; cancer metabolism; metabolic reprogramming; obesity

DOI:  https://doi.org/10.3390/ijms22031444
Int J Mol Sci. 2021 Feb 02. pii: 1500. [Epub ahead of print]22(3):

Does C-C Motif Chemokine Ligand 2 (CCL2) Link Obesity to a Pro-Inflammatory State?

Sebastian Dommel, Matthias Blüher.

  The mechanisms of how obesity contributes to the development of cardio-metabolic diseases are not entirely understood. Obesity is frequently associated with adipose tissue dysfunction, characterized by, e.g., adipocyte hypertrophy, ectopic fat accumulation, immune cell infiltration, and the altered secretion of adipokines. Factors secreted from adipose tissue may induce and/or maintain a local and systemic low-grade activation of the innate immune system. Attraction of macrophages into adipose tissue and altered crosstalk between macrophages, adipocytes, and other cells of adipose tissue are symptoms of metabolic inflammation. Among several secreted factors attracting immune cells to adipose tissue, chemotactic C-C motif chemokine ligand 2 (CCL2) (also described as monocyte chemoattractant protein-1 (MCP-1)) has been shown to play a crucial role in adipose tissue macrophage infiltration. In this review, we aimed to summarize and discuss the current knowledge on CCL2 with a focus on its role in linking obesity to cardio-metabolic diseases.

Keywords:  adipokine; adipose tissue; chemokine; inflammation; obesity

DOI:  https://doi.org/10.3390/ijms22031500
Front Oncol. 2020 ;10 591342

Metabolic Reprogramming Induces Immune Cell Dysfunction in the Tumor Microenvironment of Multiple Myeloma.

Shaojie Wu, Huixian Kuang, Jin Ke, Manfei Pi, Dong-Hua Yang.

  Tumor cells rewire metabolism to meet their increased nutritional demands, allowing the maintenance of tumor survival, proliferation, and expansion. Enhancement of glycolysis and glutaminolysis is identified in most, if not all cancers, including multiple myeloma (MM), which interacts with a hypoxic, acidic, and nutritionally deficient tumor microenvironment (TME). In this review, we discuss the metabolic changes including generation, depletion or accumulation of metabolites and signaling pathways, as well as their relationship with the TME in MM cells. Moreover, we describe the crosstalk among metabolism, TME, and changing function of immune cells during cancer progression. The overlapping metabolic phenotype between MM and immune cells is discussed. In this sense, targeting metabolism of MM cells is a promising therapeutic approach. We propose that it is important to define the metabolic signatures that may regulate the function of immune cells in TME in order to improve the response to immunotherapy.

Keywords:  immune cell dysfunction; metabolic reprogramming; multiple myeloma; signaling pathways; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2020.591342
Mol Biol Rep. 2021 Feb 05.

5-Aza-2'-deoxycytidine induces a greater inflammatory change, at the molecular levels, in normoxic than hypoxic tumor microenvironment.

Ísis Salviano Soares de Amorim, Juliana Alves Rodrigues, Pedro Nicolau, Sandra König, Carolina Panis, Adenilson de Souza da Fonseca, Andre Luiz Mencalha.

  Hypoxia is associated with tumor aggressiveness and poor prognosis, including breast cancer. Low oxygen levels induces global genomic hypomethylation and hypermethylation of specific loci in tumor cells. DNA methylation is a reversible epigenetic modification, usually associated with gene silencing, contributing to carcinogenesis and tumor progression. Since the effects of DNA methyltransferase inhibitor are context-dependent and as there is little data comparing their molecular effects in normoxic and hypoxic microenvironments in breast cancer, this study aimed to understand the gene expression profiles and molecular effects in response to treatment with DNA methyltransferase inhibitor in normoxia and hypoxia, using the breast cancer model. For this, a cDNA microarray was used to analyze the changes in the transcriptome upon treatment with DNA methyltransferase inhibitor (5-Aza-2'-deoxycytidine: 5-Aza-2'-dC), in normoxia and hypoxia. Furthermore, immunocytochemistry was performed to investigate the effect of 5-Aza-2'-dC on NF-κB/p65 inflammation regulator subcellular localization and expression, in normoxia and hypoxia conditions. We observed that proinflammatory pathways were upregulated by treatment with 5-Aza-2'-dC, in both conditions. However, treatment with 5-Aza-2'-dC in normoxia showed a greater amount of overexpressed proinflammatory pathways than 5-Aza-2'-dC in hypoxia. In this sense, we observed that the NF-κB expression increased only upon 5-Aza-2'-dC in normoxia. Moreover, nuclear staining for NF-κB and NF-κB target genes upregulation, IL1A and IL1B, were also observed after 5-Aza-2'-dC in normoxia. Our results suggest that 5-Aza-2'-dC induces a greater inflammatory change, at the molecular levels, in normoxic than hypoxic tumor microenvironment. These data may support further studies and expand the understanding of the DNA methyltransferase inhibitor effects in different tumor contexts.

Keywords:  5-Aza-2’-deoxycytidine; Hypoxia; Inflammation; Normoxia; Transcritome

DOI:  https://doi.org/10.1007/s11033-020-05931-4