Breast cancer extracellular vesicles-derived miR-1290 activates astrocytes in the brain metastatic microenvironment via the FOXA2→CNTF axis to promote progression of brain metastases

Sirkisoon, Sherona; Wong, Grace Lai Hung; Aguayo, Noah R.; Doheny, Daniel; Zhu, Dongqin; Regua, Angelina T.; Arrigo, Austin; Manore, Sara G.; Wagner, Calvin J.; Thomas, Alexandra; Singh, Ravi; Xing, Fei; Jin, Guangxu; Watabe, Kounosuke; Lo, Hui-Wen

doi:10.1016/j.canlet.2022.215726

Cited by 28 publications

(27 citation statements)

References 68 publications

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“…Although EVs are important for maintaining cell-to-cell communication, in a disease state, EVs could also function as pathogenic determinants. For instance, EVs released by malignant brain cells have been shown to promote the progression of brain metastases ( Sirkisoon et al., 2022 ). Likewise, the parasitic cells use EVs to transfer cargoes in modulating the host immune system ( Sabatke et al., 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Giardial lipid rafts share virulence factors with secreted vesicles and participate in parasitic infection in mice

Grajeda

Chatterjee

Villalobos

et al. 2022

Front. Cell. Infect. Microbiol.

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Giardia lamblia, a protozoan parasite, is a major cause of waterborne infection, worldwide. While the trophozoite form of this parasite induces pathological symptoms in the gut, the cyst form transmits the infection. Since Giardia is a noninvasive parasite, the actual mechanism by which it causes disease remains elusive. We have previously reported that Giardia assembles cholesterol and GM1 glycosphingolipid-enriched lipid rafts (LRs) that participate in encystation and cyst production. To further delineate the role of LRs in pathogenesis, we isolated LRs from Giardia and subjected them to proteomic analysis. Various cellular proteins including potential virulence factors—e.g., giardins, variant surface proteins, arginine deaminases, elongation factors, ornithine carbomyltransferases, and high cysteine-rich membrane proteins—were found to be present in LRs. Since Giardia secretes virulence factors encapsulated in extracellular vesicles (EVs) that induce proinflammatory responses in hosts, EVs released by the parasite were isolated and subjected to nanoparticle tracking and proteomic analysis. Two types of EV—i.e., small vesicles (SVs; <100 nm, exosome-like particles) and large vesicles (LVs; 100–400 nm, microvesicle-like particles)—were identified and found to contain a diverse group of proteins including above potential virulence factors. Although pretreatment of the parasite with two giardial lipid raft (gLR) disruptors, nystatin (27 μM) and oseltamivir (20 μM), altered the expression profiles of virulence factors in LVs and SVs, the effects were more robust in the case of SVs. To examine the potential role of rafts and vesicles in pathogenicity, Giardia-infected mice were treated with oseltamivir (1.5 and 3.0 mg/kg), and the shedding of cysts were monitored. We observed that this drug significantly reduced the parasite load in mice. Taken together, our results suggest that virulence factors partitioning in gLRs, released into the extracellular milieu via SVs and LVs, participate in spread of giardiasis and could be targeted for future drug development.

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Section: Discussionmentioning

confidence: 99%

Giardial lipid rafts share virulence factors with secreted vesicles and participate in parasitic infection in mice

Grajeda

Chatterjee

Villalobos

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Astrocytes perform a variety of functions, which include supporting nerve cells, nourishing nerve tissue, maintaining CNS homeostasis, forming a BBB, and repairing damaged CNS tissue ( 27 ). As the most important component of the CNS microenvironment, astrocytes play an important role in the formation of brain metastases ( 28 ). Following activation, astrocytes secrete a variety of cytokines that affect the proliferation, invasion, and metastatic ability of tumor cells ( 29 ).…”

Section: Characteristics Of the Microenvironment Of Brain Metastasesmentioning

confidence: 99%

Tumor microenvironment and exosomes in brain metastasis: Molecular mechanisms and clinical application

Aili

Maimaitiming²,

Hu³

et al. 2022

Front. Oncol.

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Metastasis is one of the important biological features of malignant tumors and one of the main factors responsible for poor prognosis. Although the widespread application of newer clinical technologies and their continuous development have significantly improved survival in patients with brain metastases, there is no uniform standard of care. More effective therapeutic measures are therefore needed to improve prognosis. Understanding the mechanisms of tumor cell colonization, growth, and invasion in the central nervous system is of particular importance for the prevention and treatment of brain metastases. This process can be plausibly explained by the “seed and soil” hypothesis, which essentially states that tumor cells can interact with various components of the central nervous system microenvironment to produce adaptive changes; it is this interaction that determines the development of brain metastases. As a novel form of intercellular communication, exosomes play a key role in the brain metastasis microenvironment and carry various bioactive molecules that regulate receptor cell activity. In this paper, we review the roles and prospects of brain metastatic tumor cells, the brain metastatic tumor microenvironment, and exosomes in the development and clinical management of brain metastases.

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“…In BCBM, it was demonstrated that miRNA-1290 and miRNA-1246, derived from extracellular vesicles secreted from breast cancer cells, induced a strong activation of astrocytes via the suppression of expression of the transcriptional repressor FOXA2, leading to the secretion of the Ciliary Neurotrophic Factor (CNTF). Moreover, astrocytes that overexpress miRNA-1290 increase the ability of breast cancer cells to grow and colonize the brain [ 50 ].…”

Section: Development Of Brain and Leptomeningeal Metastasesmentioning

confidence: 99%

Cytokine Landscape in Central Nervous System Metastases

et al. 2022

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The central nervous system is the location of metastases in more than 40% of patients with lung cancer, breast cancer and melanoma. These metastases are associated with one of the poorest prognoses in advanced cancer patients, mainly due to the lack of effective treatments. In this review, we explore the involvement of cytokines, including interleukins and chemokines, during the development of brain and leptomeningeal metastases from the epithelial-to-mesenchymal cell transition and blood–brain barrier extravasation to the interaction between cancer cells and cells from the brain microenvironment, including astrocytes and microglia. Furthermore, the role of the gut–brain axis on cytokine release during this process will also be addressed.

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Breast cancer extracellular vesicles-derived miR-1290 activates astrocytes in the brain metastatic microenvironment via the FOXA2→CNTF axis to promote progression of brain metastases

Cited by 28 publications

References 68 publications

Giardial lipid rafts share virulence factors with secreted vesicles and participate in parasitic infection in mice

Giardial lipid rafts share virulence factors with secreted vesicles and participate in parasitic infection in mice

Tumor microenvironment and exosomes in brain metastasis: Molecular mechanisms and clinical application

Cytokine Landscape in Central Nervous System Metastases

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