Development of a Novel and Simple Anti-Metastatic Cancer Treatment Targeting Vasohibin-2

Development of a Novel and Simple Anti-Metastatic Cancer Treatment Targeting Vasohibin-2

Eun-Seo Lee,¹ Yasuhiro Suzuki,^1,2 Hideki Tomioka,³ Hironori Nakagami⁴ and Yasufumi Sato^1,2

¹Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, Japan
²New Industry Creation Hatchery Center, Tohoku University, Sendai, Miyagi, Japan
³Funpep Company Limited, Ibaraki, Osaka, Japan
⁴Department of Health Development and Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

Vasohibin-2 (VASH2), a homologue of vasohibin-1 (VASH1), is overexpressed in various cancer cells and promotes tumor progression. We therefore regard VASH2 as a molecular target for cancer treatment. Here we applied vaccine technology to develop a therapy against VASH2. We selected two amino acid sequences of VASH2 protein; the MTG and RRR peptides, which contain possible B cell epitopes. These sequences are identical between the human and murine VASH2 proteins and distinct from those of the VASH1 protein. We conjugated these peptides with the carrier protein keyhole limpet hemocyanin, mixed with an adjuvant, and injected subcutaneously twice at a 2-week interval in mice. Both vaccines increased antibodies against the antigen peptide; however, only the MTG peptide vaccine increased antibodies that recognized the recombinant VASH2 protein. When Lewis lung cancer (LLC) cells were subcutaneously inoculated, tumors isolated from mice immunized with the MTG peptide vaccine showed a significant decrease in the expression of epithelial-to-mesenchymal transition (EMT) markers. EMT is responsible for cancer cell invasion and metastasis. When the LLC cells were injected into the tail vein, the MTG peptide vaccine inhibited lung metastasis. Moreover, the MTG peptide vaccine inhibited the metastasis of pancreatic cancer cells to the liver in an orthotopic mouse model, and there was a significant inverse correlation between the ELISA titer and metastasis inhibition. Therefore, we propose that the MTG peptide vaccine is a novel anti-metastatic cancer treatment that targets VASH2 and can be applied even in the most malignant and highly metastatic pancreatic cancer.

Key words —— cancer metastasis; epithelial-to-mesenchymal transition; peptide vaccine; vasohibin-2

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Tohoku J. Exp. Med., 2023 November, 261(3), 239-247.

Correspondence: Yasufumi Sato, Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.

e-mail: yasufumi.sato.b3@tohoku.ac.jp