VEGFR3 inhibition chemosensitizes lung adenocarcinoma A549 cells in the tumor-associated macrophage microenvironment through upregulation of p53 and PTEN

Abstract

In lung adenocarcinoma, loss of p53 and PTEN in tumors are associated with decreased response to chemotherapy and decreased survival. A means to pharmacologically upregulate p53 and PTEN protein expression could improve the prognosis of patients with p53- and PTEN-deficient tumors. In the present study we revealed that vascular endothelial growth factor receptor 3 (VEGFR3) inhibition in lung adenocarcinoma cells was associated with improved expression levels of both p53 and PTEN in the tumor-associated macrophage (TAM) microenvironment. Inhibition of VEGFR3 in lung adenocarcinoma cells was associated with growth arrest and decreased migration and invasion. The upregulation of p53 and PTEN protein expression after VEGFR3 inhibition decreased chemotherapy resistance and improved chemosensitivity in co-cultured A549 cells in which p53 and PTEN expression were decreased. Finally, we demonstrated that TAMs promoted the expression of VEGF-C and its receptor VEGFR3. Western blot analysis revealed the co-cultured A549 cells with TAMs are a primary source of VEGF-C and VEGFR3 in the tumor microenvironment. Our studies revealed that VEGFR3 inhibition may be a pharmacological means to upregulate p53 and PTEN protein expression and improve the outcome of patients with p53- and PTEN-deficient tumors.

Regorafenib Regulates AD Pathology, Neuroinflammation, and Dendritic Spinogenesis in Cells and a Mouse Model of AD

“…Another study showed that Src modulates LPS-induced local inflammation in colorectal cancer [ 23 ]. Interestingly, several studies have demonstrated that regorafenib reduces pulmonary inflammation by decreasing M1 macrophages and increasing M2 macrophages [ 24 ] and significantly decreases secreted TNF-α, IL-1β, and IL-6 levels in SK-Hep1 cells [ 25 ]. However, whether regorafenib alters LPS-induced proinflammatory cytokine levels in brain glia, including microglia and astrocytes and has protective effects on neuroinflammation-associated neurodegeneration in the brain has not been studied.…”

Tumor Endothelial Cells (TECs) as Potential Immune Directors of the Tumor Microenvironment – New Findings and Future Perspectives

“…Moreover, NK cells isolated from patients with acute myeloid leukemia (AML) were found to express increased levels of VEGFR3 and lower levels of IFN-γ ( Lee et al, 2013 ). Importantly, resident macrophages in lung adenocarcinoma also expressed VEGFR3 and pharmacological inhibition of VEGFR3 signaling sensitized to chemotherapy ( Li et al, 2017 ).…”

Two Birds, One Stone: Double Hits on Tumor Growth and Lymphangiogenesis by Targeting Vascular Endothelial Growth Factor Receptor 3

“…VEGFR3 has also been shown to be expressed in neuronal progenitors, osteoblasts, and macrophages [50,51,52]. Furthermore, recent studies have indicated that VEGFR3 expression is detected in different types of cancers and it contributes to tumor progression and lymphatic metastasis (Table 1) [53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93].…”

“…Blockade of VEGFR3 signaling inhibits tumor growth and markedly suppresses the migration and invasion of tumor cells by upregulating the expression of p53 and PTEN. Furthermore, the study’s data revealed that the inhibition of VEGFR3 enhances chemosensitivity of doxorubicin in lung adenocarcinoma cells [58].…”