Adenosine A2a receptor promotes lymphangiogenesis and lymph node metastasis

Area of Science:

• Immunology
• Oncology
• Vascular Biology

Background:

• Lymphangiogenesis, the formation of new lymphatic vessels, is crucial for tissue repair but can be dysregulated in diseases like cancer.
• The precise molecular mechanisms regulating pathological lymphangiogenesis remain incompletely understood.
• Adenosinergic signaling is implicated in various physiological and pathological processes.

Purpose of the Study:

• To investigate the role of Adenosine A2a receptor (A2a) signaling in regulating lymphangiogenesis during inflammation and tumorigenesis.
• To determine the contribution of A2a signaling in both hematopoietic and non-hematopoietic cells to lymph node metastasis.
• To explore the therapeutic potential of targeting A2a signaling to inhibit pathological lymphangiogenesis and cancer dissemination.

Main Methods:

• Utilized Adenosine A2a receptor (Adora2a)-deficient mice to study lymphangiogenesis in models of peritoneal inflammation and tumor metastasis.
• Analyzed B cell accumulation, VEGF-C levels, and lymphatic endothelial cell (LEC) function in A2a-deficient models.
• Performed in vitro studies on primary murine LECs to assess the impact of A2a signaling blockade on capillary tube formation.
• Correlated gene expression of adenosine-related molecules with lymphangiogenesis markers in human cancer datasets.

Main Results:

• A2a signaling is essential for lymphatic vessel formation in peritoneal inflammation.
• A2a deficiency impaired tumor-associated and sentinel lymph node lymphangiogenesis, reducing lymph node metastasis.
• Both hematopoietic and non-hematopoietic A2a signaling contributed to metastasis.
• Impaired lymphangiogenesis in A2a-deficient mice was linked to reduced B cell accumulation and lower VEGF-C levels.
• A2a receptor is expressed in LECs, and its blockade inhibits their tube formation capacity in vitro.
• Adora2a, Nt5e, and Entpd1 gene expression positively correlated with lymphangiogenesis markers in human cancers.

Conclusions:

• Adenosine A2a receptor signaling is a novel and critical regulator of inflammatory and tumor-associated lymphangiogenesis.
• Targeting A2a signaling or adenosine production represents a potential therapeutic strategy to inhibit pathological lymphangiogenesis and prevent cancer metastasis.