bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2023–01–01
six papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Effects of metabolic cancer therapy on tumor microenvironment.
  2. Oral Squamous Cell Carcinoma-Derived ANGPTL3 Induces Cancer Associated Fibroblastic Phenotypes in Surrounding Fibroblasts.
  3. Obesity triggers tumoral senescence and renders poorly immunogenic malignancies amenable to senolysis.
  4. Leukemia inhibitory factor, a double-edged sword with therapeutic implications in human diseases.
  5. 4EBP1 senses extracellular glucose deprivation and initiates cell death signaling in lung cancer.
  6. Inhibition of the PI3K/AKT/mTOR signaling promotes an M1 macrophage switch by repressing the ATF3-CXCL8 axis in Ewing sarcoma.
  1. Front Oncol. 2022 ;12 1046630
    Effects of metabolic cancer therapy on tumor microenvironment.
    Petra Hyroššová, Mirko Milošević, Josef Škoda, Jiří Vachtenheim, Jakub Rohlena, Kateřina Rohlenová.
      Targeting tumor metabolism for cancer therapy is an old strategy. In fact, historically the first effective cancer therapeutics were directed at nucleotide metabolism. The spectrum of metabolic drugs considered in cancer increases rapidly - clinical trials are in progress for agents directed at glycolysis, oxidative phosphorylation, glutaminolysis and several others. These pathways are essential for cancer cell proliferation and redox homeostasis, but are also required, to various degrees, in other cell types present in the tumor microenvironment, including immune cells, endothelial cells and fibroblasts. How metabolism-targeted treatments impact these tumor-associated cell types is not fully understood, even though their response may co-determine the overall effectivity of therapy. Indeed, the metabolic dependencies of stromal cells have been overlooked for a long time. Therefore, it is important that metabolic therapy is considered in the context of tumor microenvironment, as understanding the metabolic vulnerabilities of both cancer and stromal cells can guide new treatment concepts and help better understand treatment resistance. In this review we discuss recent findings covering the impact of metabolic interventions on cellular components of the tumor microenvironment and their implications for metabolic cancer therapy.
    Keywords:  cancer; endothelial cells; fatty acid metabolism; glycolysis; metabolism; nucleotide metabolism; oxidative phoshorylation; tumor micro environment (TME)
    DOI:  https://doi.org/10.3389/fonc.2022.1046630
  2. Asian Pac J Cancer Prev. 2022 Dec 01. pii: 90424. [Epub ahead of print]23(12): 4315-4322
    Oral Squamous Cell Carcinoma-Derived ANGPTL3 Induces Cancer Associated Fibroblastic Phenotypes in Surrounding Fibroblasts.
    Jue Young Kim, Sook Moon, Dokyeong Kim.
       OBJECTIVE: Angiopoietin-like proteins (ANGPTLs) have emerged as both important regulator of lipid and glucose metabolism as well as insulin sensitivity. In particular, ANGPTL3 activity is one of the most important factors in cancer growth and invasion. Although ANGPTL3 have been studied in OSCC, but the role of ANGPTL3 between OSCC and CAFs has yet to be clearly defined. Thus, this study aimed to investigate the roles of ANGPTL3 in the differentiation of CAFs.
    METHODS: For our study, we used hTERT-hNOFs to replace CAFs by coculturing them with oral squamous cell carcinoma (OSCC) cells. We did a microarray dataset analysis to investigate what factors secreted from OSCC cells can induce cancer associated fibroblastic phenotype in surrounding fibroblasts. The secreted factors were confirmed by RT-PCR, real-time PCR, and Western blot.
    RESULT: ANGPTL3 has the most secreted factor derived from various oral cancer cells. To investigate the role of ANGPTL3 in CAFs, we treated rhANGPTL3 in hTERT-hNOFs. The fibroblasts showed an increase of tumor-promoting cytokines (IL-6 and IL-8) and myofibroblastic markers, such as α-SMA and FAP.
    CONCLUSION: In conclusion, our study reports the first evidence that ANGPTL3 plays a crucial role in tumor microenvironments by inducing CAF. Therefore, targeting ANGPTL3 may be promising treatment strategy for CAF-targeted therapy in CAF-rich tumors.
    Keywords:  Angiopoietin-like 3 protein (ANGPTL3); Cancer associated fibroblast (CAF); Tumor Microenvironment; oral squamous cell carcinoma (OSCC)
    DOI:  https://doi.org/10.31557/APJCP.2022.23.12.4315
  3. Proc Natl Acad Sci U S A. 2023 Jan 03. 120(1): e2209973120
    Obesity triggers tumoral senescence and renders poorly immunogenic malignancies amenable to senolysis.
    Frédérik Fournier, Roberto Diaz-Marin, Frédérique Pilon, Mathieu Neault, Rachel Juneau, Gabrielle Girouard, Ariel M Wilson, Bruno Larrivée, Frédérick A Mallette, Sergio Crespo-Garcia, Przemyslaw Sapieha.
      Obesity is a major risk factor for cancer. Conventional thought suggests that elevated adiposity predisposes to heightened inflammatory stress and potentiates tumor growth, yet underlying mechanisms remain ill-defined. Here, we show that tumors from patients with a body mass index >35 carry a high burden of senescent cells. In mouse syngeneic tumor models, we correlated a pronounced accretion of senescent cancer cells with poorly immunogenic tumors when mice were subjected to diet-induced obesity (DIO). Highly immunogenic tumors showed lesser senescence burden suggesting immune-mediated elimination of senescent cancer cells, likely targeted as a consequence of their senescence-associated secretory phenotype. Treatment with the senolytic BH3 mimetic small molecule inhibitor ABT-263 selectively stalled tumor growth in mice with DIO to rates comparable to regular diet-fed mice. Thus, consideration of body adiposity in the selection of cancer therapy may be a critical determinant for disease outcome in poorly immunogenic malignancies.
    Keywords:  cancer; immunogenicity; obesity; senescence
    DOI:  https://doi.org/10.1073/pnas.2209973120
  4. Mol Ther. 2022 Dec 26. pii: S1525-0016(22)00720-1. [Epub ahead of print]
    Leukemia inhibitory factor, a double-edged sword with therapeutic implications in human diseases.
    Jianming Wang, Chun-Yuan Chang, Xue Yang, Fan Zhou, Juan Liu, Zhaohui Feng, Wenwei Hu.
      Leukemia inhibitory factor (LIF) is a pleiotropic cytokine of the IL-6 superfamily. LIF was initially discovered as a factor to induce the differentiation of myeloid leukemia cells and thus inhibit their proliferation. Subsequent studies have highlighted the multi-functions of LIF under a wide variety of physiological and pathological conditions in a highly cell-, tissue-, and context-dependent manner. Emerging evidence has demonstrated that LIF plays essential roles in the stem cell niche, where it maintains the homeostasis and regeneration of multiple somatic tissues, including intestine, neuron, and muscle. Further, LIF exerts a crucial regulatory role in immunity, and functions as a protective factor against many immunopathological diseases, such as infection, inflammatory bowel disease (IBD), and graft-verse-host disease (GVHD). It is worth noting that while LIF displays a tumor-suppressive function in leukemia, recent studies have highlighted the oncogenic role of LIF in many types of solid tumors, further demonstrating the complexities and context-dependent effects of LIF. In this review, we summarize the recent insights into the roles and mechanisms of LIF in stem cell homeostasis and regeneration, immunity, and cancer, and discuss the potential therapeutic options for human diseases by modulating LIF levels and functions.
    DOI:  https://doi.org/10.1016/j.ymthe.2022.12.016
  5. Cell Death Dis. 2022 Dec 27. 13(12): 1075
    4EBP1 senses extracellular glucose deprivation and initiates cell death signaling in lung cancer.
    Yanan Wang, Jiapeng Lei, Song Zhang, Xiaomei Wang, Jiangbo Jin, Yufeng Liu, Mingxi Gan, Yi Yuan, Longhua Sun, Xiaolei Li, Tianyu Han, Jian-Bin Wang.
      Nutrient-limiting conditions are common during cancer development. The coordination of cellular glucose levels and cell survival is a fundamental question in cell biology and has not been completely understood. 4EBP1 is known as a translational repressor to regulate cell proliferation and survival by controlling translation initiation, however, whether 4EBP1 could participate in tumor survival by other mechanism except for translational repression function, especially under glucose starvation conditions remains unknown. Here, we found that protein levels of 4EBP1 was up-regulated in the central region of the tumor which always suffered nutrient deprivation compared with the peripheral region. We further discovered that 4EBP1 was dephosphorylated by PTPMT1 under glucose starvation conditions, which prevented 4EBP1 from being targeted for ubiquitin-mediated proteasomal degradation by HERC5. After that, 4EBP1 translocated to cytoplasm and interacted with STAT3 by competing with JAK and ERK, leading to the inactivation of STAT3 in the cytoplasm, resulting in apoptosis under glucose withdrawal conditions. Moreover, 4EBP1 knockdown increased the tumor volume and weight in xenograft models by inhibiting apoptosis in the central region of tumor. These findings highlight a novel mechanism for 4EBP1 as a new cellular glucose sensor in regulating cancer cell death under glucose deprivation conditions, which was different from its classical function as a translational repressor.
    DOI:  https://doi.org/10.1038/s41419-022-05466-5
  6. Cancer Lett. 2022 Dec 21. pii: S0304-3835(22)00529-8. [Epub ahead of print]555 216042
    Inhibition of the PI3K/AKT/mTOR signaling promotes an M1 macrophage switch by repressing the ATF3-CXCL8 axis in Ewing sarcoma.
    Ramona Palombo, Ilaria Passacantilli, Francesca Terracciano, Alessia Capone, Alessandro Matteocci, Simon Tournier, Antonio Alberdi, Valerio Chiurchiù, Elisabetta Volpe, Maria Paola Paronetto.
      Ewing sarcomas are aggressive pediatric tumors of bone and soft tissues driven by in frame chromosomal translocations that yield fusion proteins guiding the oncogenic program. Promising alternative strategies to ameliorate current treatments involve inhibition of the PI3K/AKT/mTOR pathway. In this study, we identified the activating transcription factor 3 (ATF3) as an important mediator of the PI3K/AKT/mTOR pathway in Ewing sarcoma cells. ATF3 exerted its pro-tumoral activity through modulation of several chemokine-encoding genes, including CXCL8. The product of CXCL8, IL-8, acts as a pro-inflammatory chemokine critical for cancer progression and metastasis. We found that ATF3/IL-8 axis impacts macrophages populating the surrounding tumor microenvironment by promoting the M2 phenotype. Our study reveals valuable information on the PI3K/AKT/mTOR derived chemokine signaling in Ewing sarcoma cells: by promoting ATF3 and CXCL8 downregulation, inhibition of the PI3K/AKT/mTOR signaling promotes a proinflammatory response leading to upregulation of the protective anti-tumoral M1 macrophages.
    Keywords:  ATF3; Ewing sarcoma; PI3K/AKT/mTOR signaling; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2022.216042
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