bims-stacyt 2025-01-26 papers

Front Oncol. 2024 ;14 1480074

Exercise-induced extracellular vesicles in reprogramming energy metabolism in cancer.

Marju Puurand, Alicia Llorente, Aija Linē, Tuuli Kaambre.

Cancer is caused by complex interactions between genetic, environmental, and lifestyle factors, making prevention strategies, including exercise, a promising avenue for intervention. Physical activity is associated with reduced cancer incidence and progression and systemic anti-cancer effects, including improved tumor suppression and prolonged survival in preclinical models. Exercise impacts the body's nutrient balance and stimulates the release of several exercise-induced factors into circulation. The mechanisms of how exercise modulates cancer energy metabolism and the tumor microenvironment through systemic effects mediated, in part, by extracellular vesicles (EVs) are still unknown. By transferring bioactive cargo such as miRNAs, proteins and metabolites, exercise-induced EVs may influence cancer cells by altering glycolysis and oxidative phosphorylation, potentially shifting metabolic plasticity - a hallmark of cancer. This short review explores the roles of EVs in cancer as mediators to reprogram cellular energy metabolism through exchanging information inside the tumor microenvironment, influencing immune cells, fibroblast and distant cells. Considering this knowledge, further functional studies into exercise-induced EVs and cellular energy production pathways could inform more specific exercise interventions to enhance cancer therapy and improve patient outcomes.

Keywords: cancer; cancer microenvironment; energy metabolism; extracellular vesicles; physical exercise

DOI: https://doi.org/10.3389/fonc.2024.1480074

bioRxiv. 2025 Jan 08. pii: 2025.01.07.631515. [Epub ahead of print]

Cell-death induced immune response and coagulopathy promote cachexia in Drosophila.

Ankita Singh, Yanhui Hu, Raphael Fragoso Lopes, Liz Lane, Hilina Woldemichael, Charles Xu, Namrata D Udeshi, Steven A Carr, Norbert Perrimon.

Tumors can exert a far-reaching influence on the body, triggering systemic responses that contribute to debilitating conditions like cancer cachexia. To characterize the mechanisms underlying tumor-host interactions, we utilized a BioID-based proximity labeling method to identify proteins secreted by Ykiact adult Drosophila gut tumors into the bloodstream/hemolymph. Among the major proteins identified are coagulation and immune-responsive factors that contribute to the systemic wasting phenotypes associated with Ykiact tumors. The effect of innate immunity factors is mediated by NFκB transcription factors Relish, dorsal, and Dif, which in turn upregulate the expression of the cachectic factors Pvf1, Impl2, and Upd3. In addition, Ykiact tumors secrete Eiger, a TNF-alpha homolog, which activates the JNK signaling pathway in neighboring non-tumor cells, leading to cell death. The release of damage-associated molecular patterns (DAMPs) from these dying cells presumably amplifies the inflammatory response, exacerbating systemic wasting. Targeting the inflammatory response, the JNK pathway, or the production of cachectic factors could potentially alleviate the debilitating effects of cancer cachexia.

Keywords: Cachexia; Coagulation; DAMPs; Egr/TNFalpha; Immune response; Inflammatory response; JNK; PGRP-pathway; Rel; Toll-pathway; Ykiact gut tumor

DOI: https://doi.org/10.1101/2025.01.07.631515

Bioessays. 2025 Jan 19. e202400203

Mechanisms of Lipid-Associated Macrophage Accrual in Metabolically Stressed Adipose Tissue.

Isabel Reinisch, Sarah Enzenhofer, Andreas Prokesch.

Adipose tissue (AT) inflammation, a hallmark of the metabolic syndrome, is triggered by overburdened adipocytes sending out immune cell recruitment signals during obesity development. An AT immune landscape persistent throughout weight loss and regain constitutes an immune-obesogenic memory that hinders long-term weight loss management. Lipid-associated macrophages (LAMs) are emerging as major players in diseased, inflamed metabolic tissues and may be key contributors to an obesogenic memory in AT. Our previous study found that LAM abundance increases with weight loss via intermittent fasting (IF) in obese mice, which is driven by adipocyte p53 signalling. However, the specific signals causing LAM accumulation in AT under IF remain unknown. In this piece, we hypothesise on a range of adipocyte-secreted signals that can harbor immune-attractive features upon fasting/refeeding cycles. We highlight possible mechanisms including cell death signalling, matrikines, and other damage-associated molecular patterns (DAMPs), as well as adipo(-cyto)kines, lipid mediators, metabolites, extracellular vesicles, and epigenetic rewiring. Finally, we consider how advances in mechanisms of AT LAM recruitment gleaned from preclinical models might be translatable to long-term weight management in humans. Thus, we provide vantage points to study signals driving monocyte recruitment, polarisation towards LAMs, and LAM retention, to harness the therapeutic potential of modulating AT LAM levels by impacting the immune-obesogenic memory in metabolic disease.

Keywords: adipose; lipid‐associated macrophages; metabolic syndrome; metaflammation; obesity

DOI: https://doi.org/10.1002/bies.202400203

Proc Natl Acad Sci U S A. 2025 Jan 28. 122(4): e2420005122

Complement C3 of tumor-derived extracellular vesicles promotes metastasis of RCC via recruitment of immunosuppressive myeloid cells.

Yibi Zhang, Xiaodong Wang, Yinmin Gu, Tongfeng Liu, Xujie Zhao, Shuwen Cheng, Liqiang Duan, Chang Huang, Songzhe Wu, Shan Gao.

Heterogeneous roles of complement C3 have been implicated in tumor metastasis and are highly context dependent. However, the underlying mechanisms linking C3 to tumor metastasis remain elusive in renal cell carcinoma (RCC). Here, we demonstrate that C3 of RCC cell-derived extracellular vesicles (EVs) contributes to metastasis via polarizing tumor-associated macrophages (TAMs) into the immunosuppressive phenotype and recruiting polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, EV C3 induces the secretion of CCL2 and CXCL1 by lung macrophages and subsequently enhances TAM polarization and PMN-MDSC recruitment. Notably, targeting the CCL2/CCR2 or CXCL1/CXCR2 axis with the inhibitors RS504393 or Navarixin, respectively, effectively suppresses lung metastasis induced by RCC-derived C3 in a mouse model. Clinically, RCC patients with high expression of C3 demonstrate poor prognosis. Collectively, our findings reveal that tumor-derived EV C3 induces an immunosuppressive tumor microenvironment via TAMs, and thus promoting RCC metastasis.

Keywords: PMN-MDSCs; RCC; TAMs; metastasis; tumor-derived EV C3

DOI: https://doi.org/10.1073/pnas.2420005122

Cell Biol Int. 2025 Jan 20.

Hypoxic Cancer Cells-Derived Exosomes Strengthen the Development of Cancer Stem Cell-Like Properties Through Delivering LINC00665 in Thyroid Cancer Cells.

Ming Zhou, Chengcheng Peng, Qiong Zhang, Yanchu Tong.

Hypoxia is a common phenomenon for solid tumors due to a lack of effective vascular system, and has been deemed as an important factor that drives the progression of thyroid cancer (TC) via altering the characteristics of tumor cells. The present study suggested that hypoxic TC cells enhanced cancer stem cell properties and progression of TC by delivering long intergenic non-protein coding RNA 665 (LINC00665)-containing exosomes. Specifically, TPC1 cells were exposed to normoxic or hypoxic environment, and it was found that hypoxic TPC1 cells-secreted exosomes (H-exo) were enriched with LINC00665, compared to normoxic TPC1 cells-derived exosomes (N-exo). In addition, by establishing the in vitro exosomes-TC cells coculture system, we found that in contrast to N-exo, H-exo apparently promoted cell proliferation, epithelial mesenchymal transition (EMT) and cancer stem cell properties via delivering LINC00665. This was supported by the in vivo results that H-exo transferred LINC00665 to promote tumorigenesis and the expression of EMT and stemness-associated markers in xenograft tumor-bearing mice models. Further mechanical experiments validated that LINC00665 combined with EPHB4 mRNA to sustain its stability to enhance cancer aggressiveness of TC. Altogether, our findings verified that hypoxic TC cells-secreted exosomes regulated the LINC00665/EPHB4 axis to enhance cancer stem cell properties of TC, providing novel signatures for TC diagnosis and therapy.

Keywords: EPHB4; LINC00665; epithelial mesenchymal transition; stemness; thyroid cancer

DOI: https://doi.org/10.1002/cbin.12274

Curr Mol Med. 2025 Jan 20.

The Hormetic Potential of GDF15 in Skeletal Muscle Health and Regeneration: A Comprehensive Systematic Review.

Livio Tarchi, Gaia Maiolini, Gianluca Villa, Paolo Rovero, Francesco De Logu, Romina Nassini, Rachele Garella, Chiara Sassoli, Valdo Ricca, Giovanni Castellini, Roberta Squecco.

BACKGROUND: Growth Differentiation Factor 15 (GDF15) has been described as influencing skeletal physiology. Nevertheless, no systematic appraisal of the effect of GDF15 on skeletal muscle tissues has been developed to the present day.
OBJECTIVE: The aim of the present work was to review the evidence on the topic.
METHODS: In this preregistered systematic review (https://osf.io/wa8xr), articles were retrieved from MEDLINE/PubMed, EMBASE, and WebOfScience. Inclusion criteria comprised studies on humans or animal models, assessment of peripheral or local tissue GDF15 concentrations, as well as the direct expression of GDF15 in skeletal muscle, and direct or indirect correlates of GDF15 with physical activity/ sarcopenia/trophism/ function.
RESULTS: A total of 646 studies were retrieved, and 144 finally included. Molecular inducers or inhibitors of GDF15 in skeletal muscle tissues were described. GDF15 was reported to promote skeletal muscle health, metabolic homeostasis, and overall physical conditioning. In pathology, GDF15 seems to be correlated to the degree of muscle impairment and mitochondrial stress. GDF15 has also been described as having the potential to stratify patients based on clinical prognosis and functional outcome.
CONCLUSION: A hormetic hypothesis for GDF15 on skeletal muscle was proposed. In fact, GDF15 exhibited beneficial effects when expressed at high levels facing acute stressors (i.e., "myoprotection"). Conversely, GDF15 exhibited maladaptive effects, such as chronic low-grade inflammation, when chronically expressed in pathological processes (e.g., obesity, aging). GDF15 may be a potential molecular target for disease-modifying interventions. The current review underscores the need for further research on GDF15 to elucidate its therapeutic potential across different pathological states. The study protocol, registered before data collection and analysis, can be retrieved at https://osf.io/wa8xr. It should be noted that the study deviated from the protocol after peer review, including other electronic databases beyond MEDLINE/PubMed alone.

Keywords: Cytokines; Growth Factors; Mitokines; Muscle Fatigue; Muscle Strength; Myokines; Psychomotor Performance; TGF-β Superfamily.

DOI: https://doi.org/10.2174/0115665240327723241018073535