Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens

Nagaraja, Archana S.; Dood, Robert; Armaiz-Peña, Guillermo N.; Kang, Yu; Wu, Sherry Y.; Allen, Julie K.; Jennings, Nicholas B.; Mangala, Lingegowda S.; Pradeep, Sunila; Lyons, Yasmin; Haemmerle, Monika; Gharpure, Kshipra M.; Sadaoui, Nouara C.; Rodríguez-Aguayo, Cristian; Ivan, Cristina; Wang, Ying; Baggerly, Keith A.; Ram, Prahlad T.; López-Berestein, Gabriel; Liu, Jinsong; Mok, Samuel C.; Cohen, Lorenzo; Lutgendorf, Susan K.; Cole, Steve W.; Sood, Anil K.

doi:10.1172/jci.insight.93076

Cited by 42 publications

(17 citation statements)

References 43 publications

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“…1a. The "Cytokine-cytokine receptor interaction" transduction pathway, including IL1B, IL1A, IL1R, IL6, IL6ST, IL7R, IL1RAP, INHBA, OSMR and TGFBR2 that are strongly associated with breast cancer progression [35][36][37][38][39][40][41], was found significantly correlated with HIF-1α. Next, we performed gene set enrichment analysis (GSEA) in order to explore the "Cytokine-cytokine receptor interaction" expression profile according to the high and low HIF-1α phenotypes of both TCGA and METABRIC cohorts of TNBC patients.…”

Section: Expression Levels Of Hif-1α and Il-1β Are Correlated In Tnbcmentioning

confidence: 99%

The IL1β-IL1R signaling is involved in the stimulatory effects triggered by hypoxia in breast cancer cells and cancer-associated fibroblasts (CAFs)

Lappano

Talia

Cirillo

et al. 2020

J Exp Clin Cancer Res

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Background: Hypoxia plays a relevant role in tumor-related inflammation toward the metastatic spread and cancer aggressiveness. The pro-inflammatory cytokine interleukin-1β (IL-β) and its cognate receptor IL1R1 contribute to the initiation and progression of breast cancer determining pro-tumorigenic inflammatory responses. The transcriptional target of the hypoxia inducible factor-1α (HIF-1α) namely the G protein estrogen receptor (GPER) mediates a feedforward loop coupling IL-1β induction by breast cancer-associated fibroblasts (CAFs) to IL1R1 expression by breast cancer cells toward the regulation of target genes and relevant biological responses. Methods: In order to ascertain the correlation of IL-β with HIF-1α and further hypoxia-related genes in triplenegative breast cancer (TNBC) patients, a bioinformatics analysis was performed using the information provided by The Invasive Breast Cancer Cohort of The Cancer Genome Atlas (TCGA) project and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets. Gene expression correlation, statistical analysis and gene set enrichment analysis (GSEA) were carried out with R studio packages. Pathway enrichment analysis was evaluated with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. TNBC cells and primary CAFs were used as model system. The molecular mechanisms implicated in the regulation of IL-1β by hypoxia toward a metastatic gene expression profile and invasive properties were assessed performing gene and protein expression studies, PCR arrays, gene silencing and immunofluorescence analysis, co-immunoprecipitation and ChiP assays, ELISA, cell spreading, invasion and spheroid formation.

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Section: Expression Levels Of Hif-1α and Il-1β Are Correlated In Tnbcmentioning

confidence: 99%

The IL1β-IL1R signaling is involved in the stimulatory effects triggered by hypoxia in breast cancer cells and cancer-associated fibroblasts (CAFs)

Lappano

Talia

Cirillo

et al. 2020

J Exp Clin Cancer Res

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“…This resulted in potentiation of migration and invasion of cancer cells and decreased access of chemotherapy/immunotherapy along with cytotoxic T-cells. These effects were abrogated by propranolol by decrease in α-smooth muscle actin (SMA) levels and thus reduced expression of CAF markers and INHBA [184].…”

Section: Preclinical Studies Using Pharmacologic Blockadementioning

confidence: 99%

Stress reduction strategies in breast cancer: review of pharmacologic and non-pharmacologic based strategies

et al. 2020

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Breast cancer is the most common cancer diagnosed in women. It is associated with multiple symptoms in both patients and caregivers, such as stress, anxiety, depression, sleep disturbance, and fatigue. Stress appears to promote cancer progression via activation of the sympathetic nervous system releasing epinephrine and norepinephrine as well as activation of hypothalamic-pituitary-adrenal axis releasing cortisol. These stress hormones have been shown to promote the proliferation of cancer cells. This review focuses on stress-reducing strategies which may decrease cancer progression by abrogating these pathways, with a main focus on the β-adrenergic signaling pathway. Patients utilize both non-pharmacologic and pharmacologic strategies to reduce stress. Non-pharmacologic stress-reduction strategies include complementary and alternative medicine techniques, such as meditation, yoga, acupuncture, exercise, use of natural products, support groups and psychology counseling, herbal compounds, and multivitamins. Pharmacologic strategies include abrogating the β2-adrenergic receptor signaling pathway to antagonize epinephrine and norepinephrine action on tumor and immune cells. β-Blocker drugs may play a role in weakening the pro-migratory and pro-metastatic effects induced by stress hormones in cancer and strengthening the anti-tumor immune response. Preclinical models have shown that non-selective β1/2-blocker use is associated with a decrease in tumor growth and metastases and clinical studies have suggested their positive impact on decreasing breast cancer recurrence and mortality. Thus, non-pharmacological approaches, along with pharmacological therapies part of clinical trials are available to cancer patients to reduce stress, and have promise to break the cycle of cancer and stress.

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“…More recently, analysis of exosomes isolated from ovarian patients with high levels of adrenergic pathway activation (associated with low social support) shows upregulation of mesenchymal-characteristic gene transcripts and downregulation of epithelial-characteristic gene transcripts, and this is mediated by the ADRB/cAMP/PKA pathway ( 111 ). Adrenergic signaling plays a vital role in promoting of metastasis ( 112 – 122 ) and could directly induce invasive genes such as MMPs by tumor cells ( 123 ) and indirectly by causing cancer-associated fibroblasts to produce high levels of collagen and extracellular matrix components, which facilitate tumor invasion and dissemination ( 124 ).…”

Section: Neural Regulation Of Tumor Growthmentioning

confidence: 99%

Adrenergic Signaling: A Targetable Checkpoint Limiting Development of the Antitumor Immune Response

et al. 2018

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An immune response must be tightly controlled so that it will be commensurate with the level of response needed to protect the organism without damaging normal tissue. The roles of cytokines and chemokines in orchestrating these processes are well known, but although stress has long been thought to also affect immune responses, the underlying mechanisms were not as well understood. Recently, the role of nerves and, specifically, the sympathetic nervous system, in regulating immune responses is being revealed. Generally, an acute stress response is beneficial but chronic stress is detrimental because it suppresses the activities of effector immune cells while increasing the activities of immunosuppressive cells. In this review, we first discuss the underlying biology of adrenergic signaling in cells of both the innate and adaptive immune system. We then focus on the effects of chronic adrenergic stress in promoting tumor growth, giving examples of effects on tumor cells and immune cells, explaining the methods commonly used to induce stress in preclinical mouse models. We highlight how this relates to our observations that mandated housing conditions impose baseline chronic stress on mouse models, which is sufficient to cause chronic immunosuppression. This problem is not commonly recognized, but it has been shown to impact conclusions of several studies of mouse physiology and mouse models of disease. Moreover, the fact that preclinical mouse models are chronically immunosuppressed has critical ramifications for analysis of any experiments with an immune component. Our group has found that reducing adrenergic stress by housing mice at thermoneutrality or treating mice housed at cooler temperatures with β-blockers reverses immunosuppression and significantly improves responses to checkpoint inhibitor immunotherapy. These observations are clinically relevant because there are numerous retrospective epidemiological studies concluding that cancer patients who were taking β-blockers have better outcomes. Clinical trials testing whether β-blockers can be repurposed to improve the efficacy of traditional and immunotherapies in patients are on the horizon.

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Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens

Cited by 42 publications

References 43 publications

The IL1β-IL1R signaling is involved in the stimulatory effects triggered by hypoxia in breast cancer cells and cancer-associated fibroblasts (CAFs)

The IL1β-IL1R signaling is involved in the stimulatory effects triggered by hypoxia in breast cancer cells and cancer-associated fibroblasts (CAFs)

Stress reduction strategies in breast cancer: review of pharmacologic and non-pharmacologic based strategies

Adrenergic Signaling: A Targetable Checkpoint Limiting Development of the Antitumor Immune Response

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