cyclic-guanosine-monophosphate-adenosine-monophosphate and Brain-Neoplasms

The second messenger 2'3'-cyclic-GMP-AMP (cGAMP) is thought to be transmitted from brain carcinomas to astrocytes via gap junctions, which functions to promote metastasis in the brain parenchyma. In the current study, we established a method to introduce cGAMP into astrocytes, which simulates the state of astrocytes that have been invaded by cGAMP around tumors. Astrocytes incorporating cGAMP were analyzed by metabolomics, which demonstrated that cGAMP increased glutamate production and astrocyte secretion. The same trend was observed for γ-aminobutyric acid (GABA). Conversely, glutamine production and secretion were decreased by cGAMP treatment. Due to the fundamental role of astrocytes in regulation of the glutamine-glutamate cycle, such metabolic changes may represent a potential mechanism and therapeutic target for alteration of the central nervous system (CNS) environment and the malignant transformation of brain carcinomas.

Topics: Animals; Astrocytes; Brain Neoplasms; gamma-Aminobutyric Acid; Glucose; Neoplasm Metastasis; Nucleotides, Cyclic; Primary Cell Culture; Rats, Wistar

Brain metastasis represents a substantial source of morbidity and mortality in various cancers, and is characterized by high resistance to chemotherapy. Here we define the role of the most abundant cell type in the brain, the astrocyte, in promoting brain metastasis. We show that human and mouse breast and lung cancer cells express protocadherin 7 (PCDH7), which promotes the assembly of carcinoma-astrocyte gap junctions composed of connexin 43 (Cx43). Once engaged with the astrocyte gap-junctional network, brain metastatic cancer cells use these channels to transfer the second messenger cGAMP to astrocytes, activating the STING pathway and production of inflammatory cytokines such as interferon-α (IFNα) and tumour necrosis factor (TNF). As paracrine signals, these factors activate the STAT1 and NF-κB pathways in brain metastatic cells, thereby supporting tumour growth and chemoresistance. The orally bioavailable modulators of gap junctions meclofenamate and tonabersat break this paracrine loop, and we provide proof-of-principle that these drugs could be used to treat established brain metastasis.

Topics: Animals; Astrocytes; Benzamides; Benzopyrans; Brain Neoplasms; Breast Neoplasms; Cadherins; Cell Line, Tumor; Coculture Techniques; Connexin 43; Drug Resistance, Neoplasm; Female; Gap Junctions; Humans; Immunity, Innate; Interferon-alpha; Lung Neoplasms; Meclofenamic Acid; Membrane Proteins; Mice; NF-kappa B; Nucleotides, Cyclic; Paracrine Communication; Protocadherins; STAT1 Transcription Factor; Tumor Necrosis Factors; Xenograft Model Antitumor Assays

Astrocytes are emerging as essential regulators of brain metastasis progression. In a current issue of Nature, Chen et al. identify a novel mechanism of astrocyte-carcinoma interaction and exploit vulnerabilities therein to slow brain metastatic growth in pre-clinical models.

Topics: Astrocytes; Brain; Brain Neoplasms; Gap Junctions; Humans; Nucleotides, Cyclic