Restoration of natural killer cell cytotoxicity by VEGFR-3 inhibition in myelogenous leukemia

The non-canonical role of vascular endothelial growth factor-C axis in cancer progression

“…38,39 A negative correlation of VEGF-C with tumor-infiltrating dendritic cells has been observed in gastric cancer, 40 implying a role for VEGF-C in immune modulation. Natural killer (NK) cells from AML patients express higher levels of VEGFR-3 and inhibition of VEGFR-3 restored cytotoxic activity of the AML-NK cells 41,42 further supporting the importance of VEGF-C-VEGFR-3 axis in tumor immunity. Another study in a mouse mammary carcinoma model showed that knockdown of VEGF-C switches the infiltration and phenotype of T cell and dendritic cells toward an antitumor environment.…”

Blockade of FLT4 suppresses metastasis of melanoma cells by impaired lymphatic vessels

“…After injection of tumors (melanomas) and injection of MAZ51 or the same volume of PBS as previously described [17], lung tissue was harvested and subjected to immunohistochemistry with a FLT4 antibody for lymphatic vessel staining. Lymphatic capillary density (number of FLT4þ lymphatic vessels) was calculated from at least 10 randomly selected fields from 4 mouse heads.…”

The progress of angiogenic factors in the development of leukemias

“…Lenalidomide is an IMID immunomodulatory agent clinically active in patients with CLL, the anti-CLL effect of lenalidomide is mediated through the alteration of microenvironmental elements, implying the modulation of several angiogenesis-related factors and disruption of CLL crosstalk with endothelial cells (38). Indeed, the leukemic environment is highly enriched with lymphangiogenic stimuli, and that inhibition of VEGFR-3 restored function of NK cells, providing therapeutic value of modulation of NK cells by blocking VEGFR-3 and provided a possibility of advanced therapeutic approaches using immune cells against myelogenous leukemia (39). Understanding the functional characterization of lymphangiogenic factors in the BM niche in AML will also be helpful in interrupting the engraftment of leukemic stem cells and enhancing immune cell function by modulating the tumor microenvironment (25).…”