bims-stacyt 2024-12-22 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2024–12–22
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Extracellular vesicles in tumor-adipose tissue crosstalk: key drivers and therapeutic targets in cancer cachexia.
Hypoxic Human Microglia Promote Angiogenesis Through Extracellular Vesicle Release.
OPG promotes lung metastasis by reducing CXCL10 production of monocyte-derived macrophages and decreasing NK cell recruitment.
Clinical impact of cancer cachexia on the outcome of patients with non-small cell lung cancer with PD-L1 tumor proportion scores of ≥50% receiving pembrolizumab monotherapy versus immune checkpoint inhibitor with chemotherapy.
Metabolic features of tumor-derived extracellular vesicles: challenges and opportunities.
Activation of Bradykinin B2 Receptors in Astrocytes Stimulates the Release of Leukemia Inhibitory Factor for Autocrine and Paracrine Signaling.
Free Methylglyoxal as a Metabolic New Biomarker of Tumor Cell Proliferation in Cancers.
Hypoxia induces robust ATP release from erythrocytes in ApoE-LDLR double-deficient mice.

Extracell Vesicles Circ Nucl Acids. 2024 ;5(3): 371-396

Extracellular vesicles in tumor-adipose tissue crosstalk: key drivers and therapeutic targets in cancer cachexia.

Cátia C Ramos, José Pires, Esperanza Gonzalez, Clara Garcia-Vallicrosa, Celso A Reis, Juan M Falcon-Perez, Daniela Freitas.

  Cancer cachexia is a complex metabolic syndrome characterized by unintentional loss of skeletal muscle and body fat. This syndrome is frequently associated with different types of cancer and negatively affects the prognosis and outcome of these patients. It involves a dynamic interplay between tumor cells and adipose tissue, where tumor-derived extracellular vesicles (EVs) play a crucial role in mediating intercellular communication. Tumor cells release EVs containing bioactive molecules such as hormones (adrenomedullin, PTHrP), pro-inflammatory cytokines (IL-6), and miRNAs (miR-1304-3p, miR-204-5p, miR-155, miR-425-3p, miR-146b-5p, miR-92a-3p), which can trigger lipolysis and induce the browning of white adipocytes contributing to a cancer cachexia phenotype. On the other hand, adipocyte-derived EVs can reprogram the metabolism of tumor cells by transporting fatty acids and enzymes involved in fatty acid oxidation, resulting in tumor growth and progression. These vesicles also carry leptin and key miRNAs (miR-155-5p, miR-10a-3p, miR-30a-3p, miR-32a/b, miR-21), thereby supporting tumor cell proliferation, metastasis formation, and therapy resistance. Understanding the intricate network underlying EV-mediated communication between tumor cells and adipocytes can provide critical insights into the mechanisms driving cancer cachexia. This review consolidates current knowledge on the crosstalk between tumor cells and adipose tissue mediated by EVs and offers valuable insights for future research. It also addresses controversial topics in the field and possible therapeutic approaches to manage cancer cachexia and ultimately improve patient outcomes and quality of life.

Keywords:  Cancer cachexia; adipose tissue transdifferentiation; cancer; exosome; extracellular vesicles; metabolism

DOI:  https://doi.org/10.20517/evcna.2024.36
Int J Mol Sci. 2024 Nov 21. pii: 12508. [Epub ahead of print]25(23):

Hypoxic Human Microglia Promote Angiogenesis Through Extracellular Vesicle Release.

Alessandra Maria Testa, Livia Vignozzi, Diana Corallo, Sanja Aveic, Antonella Viola, Manuela Allegra, Roberta Angioni.

  Microglia, the brain-resident immune cells, orchestrate neuroinflammatory responses and are crucial in the progression of neurological diseases, including ischemic stroke (IS), which accounts for approximately 85% of all strokes worldwide. Initially deemed detrimental, microglial activation has been shown to perform protective functions in the ischemic brain. Besides their effects on neurons, microglia play a role in promoting post-ischemic angiogenesis, a pivotal step for restoring oxygen and nutrient supply. However, the molecular mechanisms underlying microglia-endothelial cell interactions remain largely unresolved, particularly in humans. Using both in vitro and in vivo models, we investigated the angiogenic signature and properties of extracellular vesicles (EVs) released by human microglia upon hypoxia-reperfusion stimulation. EVs were isolated and characterized in terms of their size, concentration, and protein content. Their angiogenic potential was evaluated using endothelial cell assays and a zebrafish xenograft model. The in vivo effects were further assessed in a mouse model of ischemic stroke. Our findings identified key proteins orchestrating the pro-angiogenic functions of human microglial EVs under hypoxic conditions. In vitro assays demonstrated that hypoxic EVs (hypEVs) promoted endothelial cell migration and tube formation. In vivo, hypEVs induced vessel sprouting in zebrafish and increased microvessel density in the perilesional area of mice following ischemic stroke.

Keywords:  angiogenesis; extracellular vesicles; hypoxia; microglia; neuroinflammation; stroke

DOI:  https://doi.org/10.3390/ijms252312508
EBioMedicine. 2024 Dec 13. pii: S2352-3964(24)00539-5. [Epub ahead of print]111 105503

OPG promotes lung metastasis by reducing CXCL10 production of monocyte-derived macrophages and decreasing NK cell recruitment.

Haitian Hu, Xuan Li, Zhanao Xu, Yuwei Tao, Luyang Zhao, Huiwen You, Guoyuan Xu, Tengjiang Zhang, Yuan Zhang, Huijuan Fan, Xuxiang Wang, Wenjing Chen, Christopher G Lin, Hanqiu Zheng.

   BACKGROUND: Lung metastasis is a critical and often fatal progression in cancer patients, with monocyte-derived macrophages (Mo-macs) playing multifaceted roles in this process. Despite the recognized importance of Mac-macs, most studies focus on these cells themselves, while the precise mechanisms through which tumor cells manipulate Mo-macs to promote metastasis remain poorly understood.
METHODS: We developed an in vivo CRISPR screening system to identify genes involved in macrophage-dependent metastasis by depleting Mo-macs. Osteoprotegerin (OPG) was identified as the factor significantly enhances lung metastasis. We validated its function in lung metastasis by modulating the expression of OPG in an array of cell lines and performed spontaneous and experimental lung metastasis assays. Genetically engineered mice were utilized to confirm the role of RANKL-RANK signaling in OPG-mediated metastasis. Additionally, we employed different neutralizing antibodies to elucidate the roles of Mo-macs and NK cells and inhibitor to clarify the role of CXCL10 signaling.
FINDINGS: Employing in vivo screening techniques, we elucidate the role of OPG, a protein secreted by cancer cells, in driving lung metastasis, contingent upon regulating Mo-mac activity. OPG blocks the signaling cascade between receptor activator of nuclear factor kappa-B ligand (RANKL) and its receptor RANK on Mo-macs, thereby hindering Mo-macs from secreting CXCL10, a chemokine crucial for recruiting natural killer (NK) cells that help control lung metastasis. Moreover, we observe an enrichment of OPG amplifications in metastatic cancer patients, and elevated levels of OPG expression in lung metastatic sites compared to paired primary breast cancer samples.
INTERPRETATION: Our work revealed that OPG works as a lung metastasis promoting factor by blocking the RANKL-RANK-CXCL10 axis to drive the paucity of NK cells, which could be a therapeutic target for lung metastatic cancer patients.
FUNDING: The full list of funding supporting this study can be found in the Acknowledgements section.

Keywords:  CXCL10; Lung metastasis; Macrophages; NK cells; OPG; RANKL

DOI:  https://doi.org/10.1016/j.ebiom.2024.105503
Oncoimmunology. 2025 Dec;14(1): 2442116

Clinical impact of cancer cachexia on the outcome of patients with non-small cell lung cancer with PD-L1 tumor proportion scores of ≥50% receiving pembrolizumab monotherapy versus immune checkpoint inhibitor with chemotherapy.

Hayato Kawachi, Tadaaki Yamada, Motohiro Tamiya, Yoshiki Negi, Takashi Kijima, Yasuhiro Goto, Akira Nakao, Shinsuke Shiotsu, Keiko Tanimura, Takayuki Takeda, Asuka Okada, Taishi Harada, Koji Date, Yusuke Chihara, Isao Hasegawa, Nobuyo Tamiya, Yuki Katayama, Naoya Nishioka, Kenji Morimoto, Masahiro Iwasaku, Shinsaku Tokuda, Takayuki Shimose, Koichi Takayama.

  This retrospective, multicenter cohort study aimed to determine whether cancer cachexia serves as a biomarker for determining the most effective treatment for patients having non-small-cell lung cancer (NSCLC) with high programmed death ligand 1 (PD-L1) expression treated with immune checkpoint inhibitors (ICIs) alone or combined with chemotherapy (ICI/chemotherapy). We included 411 patients with advanced NSCLC with a PD-L1 tumor proportion score of ≥50%. The patients were treated with pembrolizumab monotherapy or ICI/chemotherapy. Cancer cachexia was defined as a weight loss of >5% of the total body weight or a body mass index of <20 kg/m2 coupled with an additional weight loss of >2% within 6 months before starting treatment. Eighty-five (21%) patients met the cancer cachexia criteria. Overall survival (OS) was significantly shorter in patients with cachexia than in those without cachexia in both the pembrolizumab monotherapy group (17.2 vs. 35.8 months, p < 0.001) and the ICI/chemotherapy group (27.0 months vs. not reached, p = 0.044). However, after stratifying by cancer cachexia status, no significant difference in OS was observed between the pembrolizumab monotherapy and chemoimmunotherapy groups, regardless of cachexia. In conclusion, ICI/chemotherapy offers limited benefits for NSCLC patients with high PD-L1 expression and concurrent cancer cachexia. Considering the frailty associated with cachexia, ICI monotherapy may be preferred to ICI/chemotherapy for these patients. New interventions that can better address the negative prognostic impact of cachexia in patients treated using ICIs with or without chemotherapy remain warranted.

Keywords:  Cancer cachexia; combination therapy; immune checkpoint inhibitor; non-small cell lung cancer; treatment outcome

DOI:  https://doi.org/10.1080/2162402X.2024.2442116
Extracell Vesicles Circ Nucl Acids. 2024 ;5(3): 455-470

Metabolic features of tumor-derived extracellular vesicles: challenges and opportunities.

Pilar Espiau-Romera, Andrés Gordo-Ortiz, Inés Ortiz-de-Solórzano, Patricia Sancho.

  Tumor-derived extracellular vesicles (TDEVs) play crucial roles in intercellular communication both in the local tumor microenvironment and systemically, facilitating tumor progression and metastatic spread. They carry a variety of molecules with bioactive properties, such as nucleic acids, proteins and metabolites, that trigger different signaling processes in receptor cells and induce, among other downstream effects, metabolic reprogramming. Interestingly, the cargo of TDEVs also reflects the metabolic status of the producing cells in a time- and context-dependent manner, providing information on the functionality and state of those cells. For these reasons, together with their ability to be detected in diverse biofluids, there is increasing interest in the study of TDEVs, particularly their metabolic cargo, as diagnostic and prognostic tools in cancer management. This review presents a compilation of metabolism-related molecules (enzymes and metabolites) described in cancer extracellular vesicles (EVs) with potential use as cancer biomarkers, and discusses the challenges arising in this rapidly evolving field.

Keywords:  Extracellular vesicles; biomarkers; cancer; metabolism; metabolites

DOI:  https://doi.org/10.20517/evcna.2024.12
Int J Mol Sci. 2024 Dec 05. pii: 13079. [Epub ahead of print]25(23):

Activation of Bradykinin B2 Receptors in Astrocytes Stimulates the Release of Leukemia Inhibitory Factor for Autocrine and Paracrine Signaling.

Ying Lu, Yishan Gu, Anthony S L Chan, Ying Yung, Yung H Wong.

  Communications between different cell types within a tissue are often critical for the proper functioning of an organ. In the central nervous system, interactions among neurons and glial cells are known to modulate neurotransmission, energy metabolism, extracellular ion homeostasis, and neuroprotection. Here we showed that bradykinin, a proinflammatory neuropeptide, can be detected by astrocytes, resulting in the secretion of cytokines that act on neurons. In astrocytic cell lines and primary astrocytes, bradykinin and several other ligands acting on Gq-coupled receptors stimulated Ca2+ mobilization, which subsequently led to the release of leukemia inhibitory factor (LIF) and interleukin-6 (IL-6). The bradykinin B2 receptor antagonist, HOE-140, effectively blocked the ability of bradykinin to mobilize Ca2+ and stimulate mitogen-activated protein kinases (MAPKs) in astrocytes. Interestingly, incubation of neuronal cell lines and primary cortical neurons with conditioned media from bradykinin-treated astrocytes resulted in the activation of STAT3, a key component downstream of LIF and IL-6 receptors. LIF was apparently the major active factor in the conditioned media as the STAT3 response was almost completely neutralized by an anti-LIF antiserum. The presence of kininogen and kallikrein transcripts in neuronal cells but not in astrocytic cells indicates that neurons can produce bradykinin. Correspondingly, conditioned media from neuronal cells stimulated MAPKs in astrocytes in a HOE-140-sensitive manner. These studies demonstrate that paracrine signaling between neurons and astrocytes may involve ligands of Gq-coupled receptors and cytokines such as LIF.

Keywords:  astrocytes; bradykinin; leukemia inhibitory factor; receptor; signaling

DOI:  https://doi.org/10.3390/ijms252313079
Cancers (Basel). 2024 Nov 22. pii: 3922. [Epub ahead of print]16(23):

Free Methylglyoxal as a Metabolic New Biomarker of Tumor Cell Proliferation in Cancers.

Dominique Belpomme, Stéphanie Lacomme, Clément Poletti, Laurent Bonesso, Charlotte Hinault-Boyer, Sylvie Barbier, Philippe Irigaray.

   BACKGROUND: A fundamental property of cancer cells is their metabolic reprogramming, allowing them to increase glucose uptake and glycolysis. Using a rat colon adenocarcinoma model, we previously showed that blood levels of free methylglyoxal (MG), a side-product of glycolysis, remained normal in animals grafted with a non-growing tumor cell clone, while MG levels were significantly increased and positively correlated with tumor growth in animals grafted with a tumorigenic cell clone issued from the same tumor.
METHODS: We measured free MG in the blood of cancerous non-diabetic patients and compared the results to healthy subjects and non-cancerous diabetic patients. We also measured free MG in tumors and in the corresponding non-cancer tissues, and the peripheral blood.
RESULTS: We show that free MG levels in the peripheral blood of cancer patients are significantly increased in comparison with free MG levels in the peripheral blood of healthy controls (p < 0.0001), and similar to those in the peripheral blood of hyperglycemic diabetic patients (p = 0.965). In addition, we show that repeated free MG level measurement could be used for the therapeutic monitoring of cancer patients. Moreover, we confirmed that free MG is produced by tumor cells at significantly higher levels than cells from their corresponding tissues (p < 0.0001), and is subsequently released in the peripheral blood.
CONCLUSIONS: Free MG measured in the blood could be a new metabolic biomarker useful for the diagnostic, prognostic and follow-up of non-diabetic patients with cancers, such as bronchus carcinoma, pancreatic carcinoma and glioblastoma, for which there are presently no available useful biomarkers.

Keywords:  biomarker; blood; cancer; diagnostic; methylglyoxal; staging; tumor proliferation

DOI:  https://doi.org/10.3390/cancers16233922
Front Physiol. 2024 ;15 1497346

Hypoxia induces robust ATP release from erythrocytes in ApoE-LDLR double-deficient mice.

Fatih Celal Alcicek, Jakub Dybas, Katarzyna Bulat, Tasnim Mohaissen, Ewa Szczesny-Malysiak, Magdalena Franczyk-Zarow, Katarzyna M Marzec.

  Red blood cells (RBCs) play a role in the regulation of vascular tone via release of adenosine triphosphate (ATP) into the vasculature in response to various stimuli. Interestingly, ApoE/LDLR double-deficient (ApoE/LDLR-/-) mice, a murine model of atherosclerosis, display a higher exercise capacity compared to the age-matched controls. However, it is not known whether increased exercise capacity in ApoE/LDLR-/- mice is linked to the altered ATP release from RBCs. In this work, we characterized the ATP release feature of RBCs from ApoE/LDLR-/- mice by exposing them to various stimuli in vitro. The results are linked to the previously reported mechanical and biochemical alterations in RBCs. 3V-induced ATP release from RBCs was at comparable levels for all groups, which indicated that the activity of adenylyl cyclase and the components of upstream signal-transduction pathway were intact. Moreover, hypoxia- and low pH-induced ATP release from RBCs was higher in ApoE/LDLR-/- mice compared to their age-matched controls, a potential contributing factor and a finding in line with the higher exercise capacity. Taken together, augmented hypoxia-induced ATP release from RBCs in ApoE/LDLR-/- mice indicates a possible deterioration in the ATP release pathway. This supports our previous reports on the role of the protein structure alterations of RBC cytosol in hypoxia-induced ATP release from RBCs in ApoE/LDLR-/- mice. Thus, we emphasize that the presented herein results are the first step to future pharmacological modification of pathologically impaired microcirculation.

Keywords:  ATP release; atherosclerosis; hemoglobin; hypoxia; red blood cells

DOI:  https://doi.org/10.3389/fphys.2024.1497346