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Insights into the role of sialylation in cancer progression and metastasis.

ABSTRACT: Upregulation of sialyltransferases-the enzymes responsible for the addition of sialic acid to growing glycoconjugate chains-and the resultant hypersialylation of up to 40-60% of tumour cell surfaces are established hallmarks of several cancers, including lung, breast, ovarian, pancreatic and prostate cancer. Hypersialylation promotes tumour metastasis by several routes, including enhancing immune evasion and tumour cell survival, and stimulating tumour invasion and migration. The critical role of enzymes that regulate sialic acid in tumour cell growth and metastasis points towards targeting sialylation as a potential new anti-metastatic cancer treatment strategy. Herein, we explore insights into the mechanisms by which hypersialylation plays a role in promoting metastasis, and explore the current state of sialyltransferase inhibitor development.

SUBMITTER: Dobie C

PROVIDER: S-EPMC7782833 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Insights into the role of sialylation in cancer progression and metastasis.

Dobie Christopher C Skropeta Danielle D

British journal of cancer 20201104 1

Upregulation of sialyltransferases-the enzymes responsible for the addition of sialic acid to growing glycoconjugate chains-and the resultant hypersialylation of up to 40-60% of tumour cell surfaces are established hallmarks of several cancers, including lung, breast, ovarian, pancreatic and prostate cancer. Hypersialylation promotes tumour metastasis by several routes, including enhancing immune evasion and tumour cell survival, and stimulating tumour invasion and migration. The critical role o ...[more]

PMID: 33144696

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Project description:An increasing number of studies indicate that adrenergic signalling plays a fundamental role in chronic stress-induced tumour progression and metastasis. However, its function in gastric cancer (GC) and its potential mechanisms remain unknown. The expression levels of β-adrenergic receptor (ADRB) in GC cell lines were examined by using real-time polymerase chain reaction (RT-PCR) and western blotting. The effects of β2 adrenergic receptor (ADRB2) activation and blockade were investigated in vitro in GC cells by using proliferation, migration, invasion, cell cycle and apoptosis assays. Chronic restraint stress (CRS) increased the plasma levels of catecholamines and cortisol and also induced progression and metastasis of GC in vivo. Furthermore, immunohistochemical staining and a TUNEL assay were employed to observe the regulation of cell viability in vivo. The expression levels of ADRB2 in 100 human GC samples were measured by RT-PCR and immunohistochemistry. The stress hormones epinephrine and norepinephrine significantly accelerated GC cell proliferation, invasion and viability in culture, as well as tumour growth in vivo. These effects were reversed by the ADRB antagonists propranolol and ICI118,551 (an ADRB2-specific antagonist). Moreover, the selective ADRB1 antagonist atenolol had almost no effect on tumour cell proliferation and invasion in vitro and in vivo. ADRB2 antagonists suppressed proliferation, invasion and metastasis by inhibiting the ERK1/2-JNK-MAPK pathway and transcription factors, such as NF-κB, AP-1, CREB and STAT3. Analysis of xenograft models using GC cells revealed that ADRB2 antagonists significantly inhibited tumour growth and metastasis, and chronic stress antagonized these inhibitory effects. In addition, chronic stress increased the expression of VEGF, MMP-2, MMP-7 and MMP-9 in transplanted tumour tissue, and catecholamine hormones enhanced the expression of metastasis-related proteins. The expression of ADRB2 was upregulated in tumour tissues and positively correlated with tumour size, histological grade, lymph node metastasis and clinical stage in human GC samples. Stress hormone-induced activation of the ADRB2 signalling pathway plays a crucial role in GC progression and metastasis. These findings indicate that ADRB2 signalling regulates GC progression and suggest β2 blockade as a novel strategy to complement existing therapies for GC.

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Insights into the role of sialylation in cancer progression and metastasis.

Publications

Insights into the role of sialylation in cancer progression and metastasis.

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