bims-stacyt 2024-05-19 papers

Sci Signal. 2024 May 14. 17(836): eadq3321

Activation of GPR81 in white adipose tissue by lactate results in cancer-associated cachexia.

DOI: https://doi.org/10.1126/scisignal.adq3321

Purinergic Signal. 2024 May 16.

Metastasis and angiogenesis in cervical cancer: key aspects of purinergic signaling in platelets and possible therapeutic targets.

Paula C L Faria, Rackel S Resende, Andréia M Cardoso.

Cervical cancer ranks as the fourth most common and fatal cancer among women worldwide. Studies have demonstrated a strong association between purinergic platelet signaling and tumor progression in this type of cancer. The literature shows that neoplastic cells, when in the bloodstream, secrete adenosine triphosphate (ATP) and adenosine nucleotide diphosphate (ADP) that act on their corresponding platelet P2Y and P2X receptors. The interaction of these nucleotides with their receptors results in platelet activation and degranulation, ensuing several consequences, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor, matrix metalloproteinases, ADP, and ATP. These molecules play essential roles in angiogenesis and tumor metastasis in cervical cancer. Several purinergic receptors are found in endothelial cells. Their activation, especially P2Y2, by the nucleotides released by platelets can induce relaxation of the endothelial barrier and consequent extravasation of tumor cells, promoting the development of metastases. Cancer cells that enter the bloodstream during the metastatic process are also subject to high shear stress and immune surveillance. In this context, activated platelets bind to circulating tumor cells and protect them against shear stress and the host's immune system, especially against natural killer cells, facilitating their spread throughout the body. Furthermore, activation of the P2Y12 receptor present on the platelet surface promotes the release of VEGF, the main inducer of angiogenesis in cervical cancer, in addition to increasing the concentration of several other pro-angiogenic molecules. Therefore, this review will address the role of platelet purinergic signaling in tumor progression of cervical cancer and propose possible therapeutic targets.

Keywords: Angiogenesis; Cervical cancer; Metastasis; Platelets; Purinergic system; Therapeutic targets

DOI: https://doi.org/10.1007/s11302-024-10020-3

Cancer Res. 2024 May 15. 84(10): 1543-1545

Overcoming Nutrient Stress: Integrin αvβ3-Driven Metabolic Adaptation Supports Tumor Initiation.

Elena Rainero.

Nutrient stress accompanies several stages of tumor progression, including metastasis formation. Metabolic reprogramming is a hallmark of cancer, and it has been associated with stress tolerance and anchorage-independent cell survival. Adaptive responses are required to support cancer cell survival under these conditions. In this issue of Cancer Research, Nam and colleagues showed that the extracellular matrix (ECM) receptor integrin β3 was upregulated in lung cancer cells in response to nutrient starvation, resulting in increased cell survival that was independent from ECM binding. Delving into the molecular mechanisms responsible for this, the authors found that integrin β3 promoted glutamine metabolism and oxidative phosphorylation (OXPHOS) by activating a Src/AMPK/PGC1α signaling pathway. Importantly, in vivo experiments confirmed that OXPHOS inhibition suppressed tumor initiation in an orthotopic model of lung cancer, while β3 knockout completely abrogated tumor initiation. These observations indicate that targeting signaling pathways downstream of αvβ3 could represent a promising therapeutic avenue to prevent lung cancer progression and metastasis. See related article by Nam et al., p. 1630.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0453

Cancers (Basel). 2024 Apr 27. pii: 1709. [Epub ahead of print]16(9):

Immune System Disorder and Cancer-Associated Cachexia.

Lingbing Zhang, Philip D Bonomi.

Cancer-associated cachexia (CAC) is a debilitating condition marked by muscle and fat loss, that is unresponsive to nutritional support and contributes significantly to morbidity and mortality in patients with cancer. Immune dysfunction, driven by cytokine imbalance, contributes to CAC progression. This review explores the potential relationship between CAC and anti-cancer immune response in pre-clinical and clinical studies. Pre-clinical studies showcase the involvement of cytokines like IL-1β, IL-6, IL-8, IFN-γ, TNF-α, and TGF-β, in CAC. IL-6 and TNF-α, interacting with muscle and adipose tissues, induce wasting through JAK/STAT and NF-κB pathways. Myeloid-derived suppressor cells (MDSCs) exacerbate CAC by promoting inflammation. Clinical studies confirm elevated pro-inflammatory cytokines (IL-6, IL-8, TNFα) and immune markers like the neutrophil-to-lymphocyte ratio (NLR) in patients with CAC. Thus, immunomodulatory mechanisms involved in CAC may impact the anti-neoplastic immune response. Inhibiting CAC mechanisms could enhance anti-cancer therapies, notably immunotherapy. R-ketorolac, a new immunomodulator, reversed the weight loss and increased survival in mice. Combining these agents with immunotherapy may benefit patients with cancer experiencing CAC. Further research is vital to understand the complex interplay between tumor-induced immune dysregulation and CAC during immunotherapy.

Keywords: CAC; IL-6; TNF-α; cytokines; immune disorder; inflammation; muscle wasting

DOI: https://doi.org/10.3390/cancers16091709

Aging Cell. 2024 May 16. e14165

The integrated stress response promotes neural stem cell survival under conditions of mitochondrial dysfunction in neurodegeneration.

Mohamed Ariff Iqbal, Maria Bilen, Yubing Liu, Vanessa Jabre, Bensun C Fong, Imane Chakroun, Smitha Paul, Jingwei Chen, Steven Wade, Michel Kanaan, Mary-Ellen Harper, Mireille Khacho, Ruth S Slack.

Impaired mitochondrial function is a hallmark of aging and a major contributor to neurodegenerative diseases. We have shown that disrupted mitochondrial dynamics typically found in aging alters the fate of neural stem cells (NSCs) leading to impairments in learning and memory. At present, little is known regarding the mechanisms by which neural stem and progenitor cells survive and adapt to mitochondrial dysfunction. Using Opa1-inducible knockout as a model of aging and neurodegeneration, we identify a decline in neurogenesis due to impaired stem cell activation and progenitor proliferation, which can be rescued by the mitigation of oxidative stress through hypoxia. Through sc-RNA-seq, we identify the ATF4 pathway as a critical mechanism underlying cellular adaptation to metabolic stress. ATF4 knockdown in Opa1-deficient NSCs accelerates cell death, while the increased expression of ATF4 enhances proliferation and survival. Using a Slc7a11 mutant, an ATF4 target, we show that ATF4-mediated glutathione production plays a critical role in maintaining NSC survival and function under stress conditions. Together, we show that the activation of the integrated stress response (ISR) pathway enables NSCs to adapt to metabolic stress due to mitochondrial dysfunction and metabolic stress and may serve as a therapeutic target to enhance NSC survival and function in aging and neurodegeneration.

Keywords: Hypoxia; Opa1; adult neurogenesis; intergrated stress response; metabolic adaptation; mitochondrial dynamics; neurodegeneration

DOI: https://doi.org/10.1111/acel.14165