bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2023–11–05
six papers selected by
Oltea Sampetrean, Keio University
  1. Metabolic interventions combined with CTLA-4 and PD-1/PD-L1 blockade for the treatment of tumors: mechanisms and strategies.
  2. Molecular Mechanism of Fasting-Mimicking Diet in Inhibiting Colorectal Cancer Progression: Implications for Immune Therapy and Metabolic Regulation.
  3. Metabolic pathway analysis using stable isotopes in patients with cancer.
  4. Tumor Metabolism-Rewriting Nanomedicines for Cancer Immunotherapy.
  5. PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy.
  6. Low-dose adropin stimulates inflammasome activation of macrophage via mitochondrial ROS involved in colorectal cancer progression.
  1. Front Med. 2023 Oct 28.
    Metabolic interventions combined with CTLA-4 and PD-1/PD-L1 blockade for the treatment of tumors: mechanisms and strategies.
    Liming Liao, Huilin Xu, Yuhan Zhao, Xiaofeng Zheng.
      Immunotherapies based on immune checkpoint blockade (ICB) have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade. To date, immune checkpoint inhibitors (ICIs) of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy. Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers, however, a large subset of refractory patients presents poor responsiveness to ICB therapy; and the underlying mechanism remains elusive. Recently, numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment (TME) with various products of metabolism, and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy. Nevertheless, a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance. Here, we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints (CTLA-4, PD-1, and PD-L1) to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.
    Keywords:  CTLA-4; PD-1; PD-L1; combined tumor therapeutic strategies; immune checkpoint blockade (ICB); metabolic reprogramming
    DOI:  https://doi.org/10.1007/s11684-023-1025-7
  2. Cancer Res. 2023 11 01. 83(21): 3493-3494
    Molecular Mechanism of Fasting-Mimicking Diet in Inhibiting Colorectal Cancer Progression: Implications for Immune Therapy and Metabolic Regulation.
    Clancy O Bush, Rachel J Perry.
      Recently, fasting-mimicking diet and caloric restriction have been shown to improve antitumor immunity. In this issue of Cancer Research, Zhong and colleagues provide insights into the molecular mechanism of fasting-mimicking diet-mediated metabolic reprogramming in colorectal cancer progression. The authors performed comprehensive mechanistic experiments in mouse models to show that fasting-mimicking diet prevents colorectal cancer progression by lowering intratumoral IgA+ B cells by accelerating fatty acid oxidation to inhibit B-cell IgA class switching. In addition, they found that fatty acid oxidation-dependent acetylation prevents IgA class switching and that IgA+ B cells interfere with the anticancer effects of fasting-mimicking diet in colorectal cancer. Overall, their study establishes that fasting-mimicking diet has the potential to activate anticancer immunity and to induce tumor regression in colorectal cancer. See related article by Zhong et al., p. 3529.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-2257
  3. Nat Rev Cancer. 2023 Oct 31.
    Metabolic pathway analysis using stable isotopes in patients with cancer.
    Caroline R Bartman, Brandon Faubert, Joshua D Rabinowitz, Ralph J DeBerardinis.
      Metabolic reprogramming is central to malignant transformation and cancer cell growth. How tumours use nutrients and the relative rates of reprogrammed pathways are areas of intense investigation. Tumour metabolism is determined by a complex and incompletely defined combination of factors intrinsic and extrinsic to cancer cells. This complexity increases the value of assessing cancer metabolism in disease-relevant microenvironments, including in patients with cancer. Stable-isotope tracing is an informative, versatile method for probing tumour metabolism in vivo. It has been used extensively in preclinical models of cancer and, with increasing frequency, in patients with cancer. In this Review, we describe approaches for using in vivo isotope tracing to define fuel preferences and pathway engagement in tumours, along with some of the principles that have emerged from this work. Stable-isotope infusions reported so far have revealed that in humans, tumours use a diverse set of nutrients to supply central metabolic pathways, including the tricarboxylic acid cycle and amino acid synthesis. Emerging data suggest that some activities detected by stable-isotope tracing correlate with poor clinical outcomes and may drive cancer progression. We also discuss current challenges in isotope tracing, including comparisons of in vivo and in vitro models, and opportunities for future discovery in tumour metabolism.
    DOI:  https://doi.org/10.1038/s41568-023-00632-z
  4. ACS Cent Sci. 2023 Oct 25. 9(10): 1864-1893
    Tumor Metabolism-Rewriting Nanomedicines for Cancer Immunotherapy.
    Xiao Dong, Shu Xia, Shubo Du, Mao-Hua Zhu, Xing Lai, Shao Q Yao, Hong-Zhuan Chen, Chao Fang.
      Cancer immunotherapy has become an established therapeutic paradigm in oncologic therapy, but its therapeutic efficacy remains unsatisfactory in the majority of cancer patients. Accumulating evidence demonstrates that the metabolically hostile tumor microenvironment (TME), characterized by acidity, deprivation of oxygen and nutrients, and accumulation of immunosuppressive metabolites, promotes the dysfunction of tumor-infiltrating immune cells (TIICs) and thereby compromises the effectiveness of immunotherapy. This indicates the potential role of tumor metabolic intervention in the reinvigoration of antitumor immunity. With the merits of multiple drug codelivery, cell and organelle-specific targeting, controlled drug release, and multimodal therapy, tumor metabolism-rewriting nanomedicines have recently emerged as an attractive strategy to strengthen antitumor immune responses. This review summarizes the current progress in the development of multifunctional tumor metabolism-rewriting nanomedicines for evoking antitumor immunity. A special focus is placed on how these nanomedicines reinvigorate innate or adaptive antitumor immunity by regulating glucose metabolism, amino acid metabolism, lipid metabolism, and nucleotide metabolism at the tumor site. Finally, the prospects and challenges in this emerging field are discussed.
    DOI:  https://doi.org/10.1021/acscentsci.3c00702
  5. Nat Metab. 2023 Oct 30.
    PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy.
    Xuefeng Dou, Qiang Fu, Qilai Long, Shuning Liu, Yejun Zou, Da Fu, Qixia Xu, Zhirui Jiang, Xiaohui Ren, Guilong Zhang, Xiaoling Wei, Qingfeng Li, Judith Campisi, Yuzheng Zhao, Yu Sun.
      Senescent cells remain metabolically active, but their metabolic landscape and resulting implications remain underexplored. Here, we report upregulation of pyruvate dehydrogenase kinase 4 (PDK4) upon senescence, particularly in some stromal cell lines. Senescent cells display a PDK4-dependent increase in aerobic glycolysis and enhanced lactate production but maintain mitochondrial respiration and redox activity, thus adopting a special form of metabolic reprogramming. Medium from PDK4+ stromal cells promotes the malignancy of recipient cancer cells in vitro, whereas inhibition of PDK4 causes tumor regression in vivo. We find that lactate promotes reactive oxygen species production via NOX1 to drive the senescence-associated secretory phenotype, whereas PDK4 suppression reduces DNA damage severity and restrains the senescence-associated secretory phenotype. In preclinical trials, PDK4 inhibition alleviates physical dysfunction and prevents age-associated frailty. Together, our study confirms the hypercatabolic nature of senescent cells and reveals a metabolic link between cellular senescence, lactate production, and possibly, age-related pathologies, including but not limited to cancer.
    DOI:  https://doi.org/10.1038/s42255-023-00912-w
  6. BMC Cancer. 2023 Oct 30. 23(1): 1042
    Low-dose adropin stimulates inflammasome activation of macrophage via mitochondrial ROS involved in colorectal cancer progression.
    Linghui Jia, Liting Liao, Yongshuai Jiang, Xiangyu Hu, Guotao Lu, Weiming Xiao, Weijuan Gong, Xiaoqin Jia, Jia Xiaoqin.
      Adropin is encoded by the energy homeostasis-associated (ENHO) gene and widely present in liver, pancreas, heart, kidney, brain, and vascular tissues. Abnormal adropin is associated with metabolic, inflammatory, immune, and central nervous disorders. Whether adropin is involved in the development of colorectal cancer (CRC) is still unclear. Here, decreased adropin expression of tumor-nest cells in advanced-stage CRC was demonstrated. Adropin expressed by carcinoma cells was negatively correlated with macrophage infiltration in the matrix of CRC tissues. However, tumor macrophages enhanced adropin expression and were positively correlated with tumor invasion and metastasis. ENHO gene transfection into colon cancer (MC38) cells inhibited tumor growth in vivo, accompanying the increase of M1 macrophages. Treatment with low-dose adropin (< 100 ng/mL) on macrophages ex vivo directly increased mitochondrial reactive oxygen species for inflammasome activation. Furthermore, ENHO-/- mice had less M1 macrophages in vivo, and ENHO-/- macrophages were inert to be induced into the M1 subset ex vivo. Finally, low-dose adropin promoted glucose utilization, and high-dose adropin enhanced the expression of CPT1α in macrophages. Therefore, variations of adropin level in carcinoma cells or macrophages in tumor tissues are differently involved in CRC progression. Low-dose adropin stimulates the antitumor activity of macrophages, but high-dose adropin facilitates the pro-tumor activity of macrophages. Increasing or decreasing the adropin level can inhibit tumor progression at different CRC stages.
    Keywords:  Adropin; Colorectal cancer; Inflammasome; Macrophage; mROS
    DOI:  https://doi.org/10.1186/s12885-023-11519-5
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