CRIP1 Reshapes the Gastric Cancer Microenvironment to Facilitate Development of Lymphatic Metastasis

Abstract

Lymphangiogenesis in tumors provides an auxiliary route for cancer cell invasion to drainage lymph nodes, facilitating the development of lymphatic metastasis (LM). However, the mechanisms governing tumor lymphangiogenesis and lymphatic permeability in gastric cancer (GC) remain largely unknown. Here, the unprecedented role and mechanism of cysteine‐rich intestinal protein‐1 (CRIP1) in mediating the development of GC LM is uncovered. A series of assays are performed to identify downstream targets of CRIP1, and rescue experiments are performed to confirm the effects of this regulatory axis on LM. CRIP1 overexpression facilitates LM in GC by promoting lymphangiogenesis and lymphatic vessel permeability. CRIP1 promotes phosphorylation of cAMP responsive element binding protein 1(CREB1), which then mediates vascular endothelial growth factor C (VEGFC) expression necessary for CRIP1‐induced lymphangiogenesis and transcriptionally promotes C‐C motif chemokine ligand 5 (CCL5) expression. CCL5 recruits macrophages to promote tumor necrosis factor alpha (TNF‐α) secretion, eventually enhancing lymphatic permeability. The study highlights CRIP1 regulates the tumor microenvironment to promote lymphangiogenesis and LM in GC. Considering the current limited understanding of LM development in GC, these pathways provide potential targets for future therapeutics.

CRIP1 involves the pathogenesis of multiple myeloma via dual-regulation of proteasome and autophagy

“…CRIP1 reshapes the TME by increasing the secretion of vascular endothelial growth factor C (VEGFC) and C–C motif chemokine ligand 5 (CCL5) from the GC cells. 49 CRIP1 fosters MDSC trafffcking via facilitating NF-κB/p65 nuclear translocation in pancreatic ductal adenocarcinoma. 50 …”

Tumour‐associated macrophages in gastric cancer: From function and mechanism to application

“…Similarly, MSR1 facilitated the polarisation of M2 TAMs by enhancing arginine and proline metabolism in macrophages 46 . Meanwhile, increased levels of chemokines in the TME, CXCL5, CXCL12 and CCL5, can induce a higher proportion of M2 TAMs 41,83,85 . The results of flow cytometry and immunohistochemistry of a transplanted tumour model indicated that EZH2 induced the polarisation of M2 TAMs 86 .…”

“…Furthermore, EVs containing ApoE derived from M2 TAMs activated the PI3K–Akt pathway to enhance the cell migration of GC cells 38 . Several studies have reported and validated the promoting effects of M2 TAMs on cell migration and invasion in GC 14,60,61,85,88,109,113–116 …”

Lymphatic vessel: Origin, heterogeneity, biological functions and therapeutic targets

“… 182 , 183 Our recent study reported that CRIP1 reshaped the gastric TME to increase the lymphangiogenesis and lymphatic vessel permeability by increasing the amount of secreted VEGFC and CCL5. 184 Additionally, tumor-associated lymphangiogenesis and lymph node metastasis is influenced by metabolic factors. Yang et al demonstrated that the elevation of oxLDL levels in plasma induced the activation of the nuclear factor (NF)-κB pathway through binding with LOX-1, leading to the upregulation of VEGFC expression and subsequently facilitating lymphangiogenesis.…”