Endothelial cell transplantation in tumors restores normal vasculature, reduces tumor hypoxia, and suppresses tumor outgrowth

Shuji Kitahara; Aya Matsui; Asuka Yoshii; Yoshikazu Kuwahara; Miwako Nishio; Kumiko Saeki; Taichi Ezaki

doi:10.1016/j.job.2016.05.003

Endothelial cell transplantation in tumors restores normal vasculature, reduces tumor hypoxia, and suppresses tumor outgrowth

J Oral Biosci. 2016 Nov;58(4):150-157. doi: 10.1016/j.job.2016.05.003. Epub 2016 Jun 10.

Authors

Shuji Kitahara¹, Aya Matsui², Asuka Yoshii³, Yoshikazu Kuwahara⁴, Miwako Nishio⁵, Kumiko Saeki⁵, Taichi Ezaki²

Affiliations

¹ Department of Anatomy and Developmental Biology, School of Medicine, Tokyo Women׳s Medical University, Tokyo, Japan; Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: skitahara@mgh.harvard.edu.
² Department of Anatomy and Developmental Biology, School of Medicine, Tokyo Women׳s Medical University, Tokyo, Japan.
³ Department of Anatomy and Developmental Biology, School of Medicine, Tokyo Women׳s Medical University, Tokyo, Japan; Departments of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, MA, USA.
⁴ Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
⁵ Department of Disease Control, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.

PMID: 32512683
DOI: 10.1016/j.job.2016.05.003

Abstract

Objectives: Vascular normalization, or restoration of the normal structure and function of blood vessels, using molecular-targeted therapy, has emerged as a potential strategy for treating malignant cancer and other vascular disorders. We hypothesized that restoring tumor blood vessels to their normal state would alleviate hypoxic conditions and potentially enhance the delivery of anticancer drugs. Our objective was to determine if transplanting normal endothelial cells into tumor-bearing mice could trigger vascular normalization.

Methods: Tumor cells were injected into the dorsal subcutis of severe combined immunodeficiency (SCID) mice (day 0). Tumor-bearing mice were injected intraperitoneally with cisplatin at day 14 to create scaffolds for blood vessel formation in the tumors. At day 28, human microvascular endothelial cells (HMVECs) or human embryonic stem-derived endothelial cells (ESECs) were transplanted into the necrotic regions of the tumor to induce normal angiogenesis.

Results: Microscopic observation revealed that the transplanted HMVECs or ESECs formed anastomoses with the host mouse vasculature. In addition, blood vessels with blood flow could be detected after 14d. Blood vessels reconstituted by HMVECs or ESECs exhibited normal vasculature, and tumor growth was significantly inhibited upon treatment.

Conclusion: Reconstruction of tumor blood vessels to their normal state alleviated hypoxic conditions and improved the efficiency of drug delivery; the present approach provides a useful model for the development of new cancer therapies.

Keywords: Hypoxia; Normalization; Tumor vessel.