Cancer Vaccine Therapy Using Tumor Endothelial Cells as Antigens Suppresses Solid Tumor Growth and Metastasis

Abstract

Tumor angiogenesis plays an important role in tumor growth and metastasis, with tumor cells requiring nutrients and oxygen via blood flow for their proliferation. In comparison, angiogenesis also occurs under normal physiological conditions, such as wound healing and in the formation of the corpus luteum. Herein, we report on the development of a novel dendritic cell (DC) vaccine therapy using tumor endothelial cells (TECs) derived from tumor vessels as tumor antigens. After density gradient centrifugation and the detection of angiotensin-converting enzyme activities, a TEC-rich fraction was separated from solid tumor tissues. Prophylactic or therapeutic immunization using DCs pulsed with TECs as vaccine antigens significantly suppressed solid tumor growth in a Colon-26 colorectal adenocarcinoma tumor-bearing mouse model, compared with the use of tumor cells as DC vaccine antigens. Tumor tissues showed reduced angiogenesis. However, vaccination using DCs pulsed with TECs did not inhibit physiological angiogenesis as evidenced by a wound healing assay. Additionally, in a B16/BL6 mouse melanoma lung metastasis model, DC vaccination using TECs derived not only from the same tumor tissue but from a different type of tumor also suppressed metastasis. These results thus show that cancer vaccine therapy targeting TECs is an effective therapy against angiogenesis in several types of cancer, but does not affect normal blood vessel growth.Key words tumor endothelial cell; angiogenesis; dendritic cell; vaccine; metastasis Endothelial cells that enable tumor angiogenesis are recruited from neighboring, pre-existing capillaries 1,2) by tumor angiogenesis mediators, such as vascular endothelial growth factor (VEGF),3) fibroblast growth factors, 4) and transforming growth factor, 5) in the process of tumor progression or metastasis.6,7) Newly produced blood vessels, which are constructed by tumor endothelial cells (TECs), provide oxygen and nutrients, and remove metabolic waste from tumor cells; tumor cell proliferation also depends on new blood vessel formation. 6,8) In addition, TECs in different types of cancers express common, tumor-associated antigens (TAAs), since the tumor's new blood vessels are constructed from endothelial cells of the host. In this regard, it is expected that the inhibition of angiogenesis in tumor tissue will effectively induce tumor regression for several types of cancer, compared with the direct inhibition of tumor cells themselves. In fact, several antiangiogenic agents, such as the VEGF receptor and tyrosine kinase inhibitor, sunitinib, 9) and the anti-VEGF antibody, bevacizumab, 10) are commonly applied in clinical practice today since they tend to show a survival advantage for patients. However, angiogenesis also occurs during the processes of wound healing and corpus luteum formation, 11) with the implication that the clinical application of antiangiogenic agents in cancer patients may result in damage to normal blood vessels, 12) in addition to those of the tumor. Therefore, the selective in...

DC-Based Immunotherapy Using Vascular Endothelial Cells Cultured in Conditioned Medium as a Vaccine Antigen Exerts an Anti-Tumor Effect by Inhibiting Angiogenesis

“…Our previous studies elucidated that DC immunization, using the TEC-rich-containing fraction separated from tumor tissues as antigenic proteins, showed anti-tumor effects by inhibiting angiogenesis in tumor tissues. 18,19) In addition, we demonstrated that DC immunization with the TEC-richcontaining fraction did not affect physiological angiogenesis during wound healing. 18) These results indicate that a specific tumor-associated antigen exists in the in vitro TEC model.…”

“…18,19) In addition, we demonstrated that DC immunization with the TEC-richcontaining fraction did not affect physiological angiogenesis during wound healing. 18) These results indicate that a specific tumor-associated antigen exists in the in vitro TEC model. In the future, identification of specific antigen expressed in TECs derived from human is promising for the development of tumor blood vessel selective therapeutics such as TEC-specific antibodies and vaccine therapy for clinical trial.…”

Development of Dendritic Cell-Based Immunotherapy Targeting Tumor Blood Vessels in a Mouse Model of Lung Metastasis

“…1) In the process of tumor angiogenesis, tumor cells, fibroblasts and epithelial cells secrete vascular endothelial growth factor (VEGF), basic fibroblast growth factor, hepatocyte growth factor, or epidermal growth factor (EGF), and endothelial cells (ECs) are recruited from neighboring, pre-existing vasculatures in the tumor microenvironment. [2][3][4][5] In our previous study, we showed that cancer immunotherapy with TECs isolated from solid tumors suppressed tumor growth via the prevention of new blood vessel formation. 6) Tumor blood vessels also have a role as conduits for cancer metastasis.…”

5-Acetamido-1-(methoxybenzyl) isatin inhibits tumor cell proliferation, migration, and angiogenesis

“…In that case, inhibiting angiogenesis is essential for the spread and deterioration of tumors. 22 Using these assays, we examined the potential of 5-acetamido-1-(methoxybenzyl) isatin to be used as an effective anti-tumor agent in multiple aspects.…”