bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2023‒01‒15
ten papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Cancers (Basel). 2022 Dec 22. pii: 61. [Epub ahead of print]15(1):
      Despite extensive research, the 5-year survival rate of pancreatic cancer (PDAC) patients remains at only 9%. Patients often show poor treatment response, due partly to a highly complex tumor microenvironment (TME). Cancer-associated fibroblast (CAF) heterogeneity is characteristic of the pancreatic TME, where several CAF subpopulations have been identified, such as myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen presenting CAFs (apCAFs). In PDAC, cancer cells continuously adapt their metabolism (metabolic switch) to environmental changes in pH, oxygenation, and nutrient availability. Recent advances show that these environmental alterations are all heavily driven by stromal CAFs. CAFs and cancer cells exchange cytokines and metabolites, engaging in a tight bidirectional crosstalk, which promotes tumor aggressiveness and allows constant adaptation to external stress, such as chemotherapy. In this review, we summarize CAF diversity and CAF-mediated metabolic rewiring, in a PDAC-specific context. First, we recapitulate the most recently identified CAF subtypes, focusing on the cell of origin, activation mechanism, species-dependent markers, and functions. Next, we describe in detail the metabolic crosstalk between CAFs and tumor cells. Additionally, we elucidate how CAF-driven paracrine signaling, desmoplasia, and acidosis orchestrate cancer cell metabolism. Finally, we highlight how the CAF/cancer cell crosstalk could pave the way for new therapeutic strategies.
    Keywords:  CAF; PDAC; acidosis; cancer-associated fibroblast; desmoplasia; hypoxia; metabolism; pancreatic cancer; paracrine signaling
  2. Front Oncol. 2022 ;12 1019360
      Objective: Tumor hypoxia is frequently observed in primary solid malignancies, but the hypoxic status of tumor cells floating in body cavity effusions is largely unknown, especially in patients. This study was to observe the hypoxia and proliferation status of cancer cells floating in effusions in mice and patients.Methods: The distribution of hypoxia in cancer cells floating in ascites was first studied in nude mice. Hypoxia was detected by immunofluorescent visualization of pimonidazole and GLUT-1. For cancer patients, we retrospectively collected 21 ascites and 7 pleural effusion sample blocks of cancer patients, which were confirmed to contain tumor cells. Immunohistochemistry was performed to detect the expression of endogenous hypoxic markers HIF-1α and GLUT-1, proliferation index Ki-67. 18F-FDG PET/CT was performed to detect the glucose metabolism status of tumor cells in effusions.
    Results: The tumor cells collected from ascites were positive for pimonidazole and GLUT-1, which suggesting that the cancer cells floating in ascites were hypoxic. Patterns of tumor hypoxia in human patients are similar to those observed in animal. HIF-1α and GLUT-1 were expressed by tumor cells in nearly all 28 cytological cases. For Ki-67 index, ascites tumor cells had a relatively low expression level compared with their corresponding primary or its metastatic lesions. Tumor cells in effusions showed high 18F-FDG uptake indicated the enhanced activity of glucose metabolism.
    Conclusion: Tumor cells in body cavity effusions, as a unique subgroup of tumor, are in a state of hypoxia and low proliferation, which would be one of the driven causes of chemo-radiotherapy resistance. Novel therapeutic interventions are urgently needed to overcome tumor hypoxia.
    Keywords:  ascites; cancer cells; cancer patients; chemo-radiotherapy resistance; hypoxia; pleural effusion; proliferation
  3. Front Cell Dev Biol. 2022 ;10 1032360
      Tumor-infiltrating immune cells experience significant metabolic reprogramming in the tumor microenvironment (TME), and they share similar metabolic pathways and nutrient needs with malignant cells. This positions these cell types in direct nutrient competition in the TME. We currently lack a complete understanding of the similarities, differences, and functional consequences of the metabolic pathways utilized by activated immune cells from different lineages versus neoplastic cells. This study applies a novel in situ approach using implantable microdevices to expose the tumor to 27 controlled and localized metabolic perturbations in order to perform a systematic investigation into the metabolic regulation of the cellular fitness and persistence between immune and tumor cells directly within the native TME. Our findings identify the most potent metabolites, notably glutamine and arginine, that induce a favorable metabolic immune response in a mammary carcinoma model, and reveal novel insights on less characterized pathways, such as cysteine and glutathione. We then examine clinical samples from cancer patients to confirm the elevation of these pathways in tumor regions that are enriched in activated T cells. Overall, this work provides the first instance of a highly multiplexed in situ competition assay between malignant and immune cells within tumors using a range of localized microdose metabolic perturbations. The approach and findings may be used to potentiate the effects of T cell stimulating immunotherapies on a tumor-specific or personalized basis through targeted enrichment or depletion of specific metabolites.
    Keywords:  T-cells infiltration; cancer metabolism; immunometabolism; immunotherapy; in situ perturbation; tumor micro-environment
  4. Nat Commun. 2023 Jan 09. 14(1): 120
      IRE1α-XBP1 signaling is emerging as a central orchestrator of malignant progression and immunosuppression in various cancer types. Employing a computational XBP1s detection method applied to TCGA datasets, we demonstrate that expression of the XBP1s mRNA isoform predicts poor survival in non-small cell lung cancer (NSCLC) patients. Ablation of IRE1α in malignant cells delays tumor progression and extends survival in mouse models of NSCLC. This protective effect is accompanied by alterations in intratumoral immune cell subsets eliciting durable adaptive anti-cancer immunity. Mechanistically, cancer cell-intrinsic IRE1α activation sustains mPGES-1 expression, enabling production of the immunosuppressive lipid mediator prostaglandin E2. Accordingly, restoring mPGES-1 expression in IRE1αKO cancer cells rescues normal tumor progression. We have developed an IRE1α gene signature that predicts immune cell infiltration and overall survival in human NSCLC. Our study unveils an immunoregulatory role for cancer cell-intrinsic IRE1α activation and suggests that targeting this pathway may help enhance anti-tumor immunity in NSCLC.
  5. Nat Rev Mol Cell Biol. 2023 Jan 12.
      Traditional views of cellular metabolism imply that it is passively adapted to meet the demands of the cell. It is becoming increasingly clear, however, that metabolites do more than simply supply the substrates for biological processes; they also provide critical signals, either through effects on metabolic pathways or via modulation of other regulatory proteins. Recent investigation has also uncovered novel roles for several metabolites that expand their signalling influence to processes outside metabolism, including nutrient sensing and storage, embryonic development, cell survival and differentiation, and immune activation and cytokine secretion. Together, these studies suggest that, in contrast to the prevailing notion, the biochemistry of a cell is frequently governed by its underlying metabolism rather than vice versa. This important shift in perspective places common metabolites as key regulators of cell phenotype and behaviour. Yet the signalling metabolites, and the cognate targets and transducers through which they signal, are only beginning to be uncovered. In this Review, we discuss the emerging links between metabolism and cellular behaviour. We hope this will inspire further dissection of the mechanisms through which metabolic pathways and intermediates modulate cell function and will suggest possible drug targets for diseases linked to metabolic deregulation.
  6. J Appl Physiol (1985). 2023 Jan 12.
      No longer viewed as a metabolic waste product and cause of muscle fatigue, a contemporary view incorporates the roles of lactate in metabolism, sensing and signaling in normal as well as pathophysiological conditions. Lactate exists in millimolar concentrations in muscle, blood and other tissues and can rise more than an order of magnitude as the result of increased production and clearance limitations. Lactate exerts its powerful driver-like influence by mass action, redox change, allosteric binding, and other mechanisms described in this article. Depending on the condition, such as during rest and exercise, following injury, or pathology, lactate can serve as a myokine or exerkine with autocrine-, paracrine-, and endocrine-like functions that have important basic and translational implications. For instance, lactate signaling is: involved in reproductive biology, fueling the heart, muscle and brain, controlling cardiac output and breathing, growth and development, and a treatment for inflammatory conditions. Ironically, lactate can be disruptive of normal processes such as insulin secretion when insertion of lactate transporters into pancreatic Beta-cell membranes is not suppressed and in carcinogenesis. Lactate signaling is important in areas of intermediary metabolism, redox biology, mitochondrial biogenesis, cardiovascular and pulmonary regulation, genomics, neurobiology, gut physiology, appetite regulation, nutrition and overall health and vigor. The various roles of lactate as a myokine and exerkine are reviewed.
    Keywords:  Glucose; Glycogen Paradox; Lactate Shuttle; Metabolic Signalling; Physiological Regulation
  7. Cell Death Discov. 2023 Jan 13. 9(1): 6
      In breast cancer, the most numerous stromal cells are cancer-associated fibroblasts (CAFs), which are associated with disease progression and chemoresistance. However, few studies have explored the function of CAFs in breast cancer cell radiosensitivity. Here, CAF-derived conditioned media was observed to induce breast cancer cell growth and radioresistance. CAFs secrete interleukin 6 (IL-6) which activates signal transducer and activator of transcription 3 (STAT3) signaling pathway, thus promoting the growth and radioresistance of breast cancer cells. Treatment with an inhibitor of STAT3 or an IL-6 neutralizing antibody blocked the growth and radioresistance induced by CAFs. In in vivo mouse models, tocilizumab (an IL-6 receptor monoclonal antibody) abrogated CAF-induced growth and radioresistance. Moreover, in breast cancer, a poor response to radiotherapy was associated with IL-6 and p-STAT3 expression. These results indicated that IL-6 mediates cross-talk between breast cancer cells and CAFs in the tumor microenvironment. Our results identified the IL-6/STAT3 signaling pathway as an important therapeutic target in breast cancer radiotherapy.
  8. J Gastrointest Oncol. 2022 Dec;13(6): 2989-3008
      Background: Stemness acquirement is one of the hallmarks of cancer and the major reason for the chemoresistance and poor prognosis of colorectal cancer (CRC). Previous research has revealed the stimulatory role of paired related homeobox 1 (PRRX1) on CRC metastasis. However, the role of PRRX1 in stemness acquirement and chemoresistance of CRC is still not clear.Methods: A retrospective cohort study was performed to investigate the relationship between PRRX1 expression and multiple clinicopathological characteristics of CRC patients. The functional effects of PRRX1 on stemness and chemoresistance of CRC cells were validated by in vitro and in vivo assays. Gene set enrichment analysis (GSEA) and JASPAR software were performed to predict the underlying mechanisms. Enzyme-linked immunosorbent assay (ELISA), Western blot, immunofluorescence, and dual-luciferase reporter assays were used to confirm the PRRX1-mediated signaling and its downstream factors.
    Results: The expression of PRRX1 was up-regulated in CRC tissues and cell lines compared to normal epithelial tissues and cell lines. High expression of PRRX1 was tightly associated with the metastasis, chemoresistance, and poor prognosis of CRC patients. Additionally, PRRX1 significantly promoted the proliferation, viability, stemness, and chemoresistance of CRC cells, as well as the activation of the interleukin-6 (IL-6)/JAK2/STAT3 axis. Inhibiting the expression of IL-6 dramatically eliminated the effects of PRRX1 on CRC cell stemness and chemoresistance.
    Conclusions: PRRX1 plays a vital role in the stemness and chemoresistance of CRC cells via JAK2/STAT3 signaling by targeting IL-6. Further, PRRX1 may be a valid biomarker for predicting the effect of chemotherapy and prognosis of CRC patients.
    Keywords:  Colorectal cancer (CRC); chemoresistance; interleukin-6 (IL-6); paired related homeobox 1 (PRRX1); stemness
  9. Theranostics. 2023 ;13(2): 704-723
      The Kelch-like ECH-associated protein 1/nuclear factor erythroid-derived 2-like 2 (KEAP1/NRF2) pathway is well recognized as a key regulator of redox homeostasis, protecting cells from oxidative stress and xenobiotics under physiological circumstances. Cancer cells often hijack this pathway during initiation and progression, with aberrant KEAP1-NRF2 activity predominantly observed in non-small cell lung cancer (NSCLC), suggesting that cell/tissue-of-origin is likely to influence the genetic selection during malignant transformation. Hyperactivation of NRF2 confers a multi-faceted role, and recently, increasing evidence shows that a close interplay between metabolic reprogramming and tumor immunity remodelling contributes to its aggressiveness, treatment resistance (radio-/chemo-/immune-therapy) and susceptibility to metastases. Here, we discuss in detail the special metabolic and immune fitness enabled by KEAP1-NRF2 aberration in NSCLC. Furthermore, we summarize the similarities and differences in the dysregulated KEAP1-NRF2 pathway between two major histo-subtypes of NSCLC, provide mechanistic insights on the poor response to immunotherapy despite their high immunogenicity, and outline evolving strategies to treat this recalcitrant cancer subset. Finally, we integrate bioinformatic analysis of publicly available datasets to illustrate the new partners/effectors in NRF2-addicted cancer cells, which may provide new insights into context-directed treatment.
    Keywords:  KEAP1-NRF2 signaling; bioinformatics; metabolic reprogramming; non-small cell lung cancer; therapeutic vulnerabilities; tumor immune microenvironment
  10. Int J Mol Sci. 2023 Jan 01. pii: 737. [Epub ahead of print]24(1):
      Oral squamous cell carcinoma (OSCC) has a five-year survival rate of less than 50% due to its susceptibility to invasion and metastasis. Crosstalk between tumor cells and macrophages has been proven to play a critical role in tumor cell migration and invasion. However, the specific mechanisms by which tumor cells interact with macrophages have not been fully elucidated. This study sought to investigate the regulatory mechanism of tumor cell-derived alpha-enolase (ENO1) in the interaction between tumor cells and macrophages during OSCC progression. Small interfering RNA (siRNA) transfection and recombinant human ENO1 (rhENO1) stimulation were used to interfere with the interaction between tumor cells and macrophages. Our results showed that ENO1 was expressed higher in CAL27 cells than in HaCaT cells and regulated lactic acid release in CAL27 cells. Conditioned medium of macrophages (Macro-CM) significantly up-regulated the ENO1 mRNA expression and protein secretion in CAL27 cells. ENO1 promoted the migration and invasion of tumor cells by facilitating the epithelial-mesenchymal transition (EMT) through macrophages. ENO1 orchestrated the IL-6 secretion of macrophages via tumor cell-derived lactic acid and the paracrine ENO1/Toll-like receptor (TLR4) signaling pathway. In turn, IL-6 promoted the migration and invasion of tumor cells. Collectively, ENO1 promotes tumor cell migration and invasion by orchestrating IL-6 secretion of macrophages via a dual mechanism, thus forming a positive feedback loop to promote OSCC progression. ENO1 might be a promising therapeutic target which is expected to control OSCC progression.
    Keywords:  alpha-enolase; interleukin-6; lactic acid; macrophage; oral squamous cell carcinoma