Life science
Medical & healthcare, Drug development, Cancer treatment

The novel strategy targeting tumor vessels
in any types of cancer
Surgical Center, Osaka University Hospital
Associate Professor Takehiro Noda

https://researchmap.jp/t-noda

Life science

Department of Gastroenterological Surgery, Graduate School of Medicine
Associate Professor Shogo Kobayashi

https://researchmap.jp/30452436

Professor Hidetoshi Eguchi

https://researchmap.jp/abcdabcdabcd

Abstract
Tumor vessels, which has irregular dilatation and fragility, areseemed to become a novel target on cancer therapy via ‘normalization’. We revealed that cancer-secreted exosome effected
endothelial cells, and the specific microRNAs in that exosome
increased transparency via decrement of cell adhesion molecules,VE-cadherin and ZO-1. These tumor endothelial cells (TEC) had
a high glycolysis ability and effected tumor growth. Regulation of
the glycolysis in TEC induced ‘normalization’ of vessels and decrements of tumor growth. This could be a reliable target of cancer
therapy especially in highly diverse tumors.

change and might be more easily controlled than cancer itself. In
this study, we targeted tumor endothelial cells and revealed thatthe origin of tumor endothelial cells (TEC) were normal endothelial
cells, and cancer-associated exosome changed normal cells toTEC, and regulation of metabolism could contribute ‘normalization’of TEC. This procedure would expand to other cancer stromal cells,
like as cancer-associated fibroblast and tumor infiltrating lymphocytes.

▍ Background & Results
Recently, a main cancer treatment was shifting from cytotoxic
agents to molecular target therapy via understanding cancer itself mechanism, ‘Precision Medicine.’ Cancer genome analysis
permitted this ‘Precision Medicine’ but its also revealed the highdiverse in cancer; inter-individuals, heterogeneity, cancer evolution
by treatment or metastasis. Tumor vessels are consisted by tumor
endothelial cells, which would be raised from normal endothelial
cells and may contribute as a novel target on cancer therapy, via
simple mechanism, because there would be no genetic modification. In this study, we showed that cancer with high metastatic
ability could give transparent morphology with less cell adhesionmolecules, VE-cadherin and ZO-1, to normal endothelial cells, via
exosome from the cancer cells (Fig. 1). A part of microRNAs fromthe exosome, miR-638, miR-663a, miR-3648, and miR-4258 directly changed cell features like transparency (Fig. 1). In addition tothis insight, we revealed that these tumor endothelial cells (TEC)
had a high phosphofructokinase-2/fructose-2, 6-bisphosphatase
3 (PFKFB3)(Fig.2A), which was a key molecule of glycolysis, withhigh production of ATP and lactate, and had s different functionalfeatures from normal endothelial cells (sFig.1A). TEC induced highprogression of tumor growth and regulation of PFKFB3 by the specific inhibitor PFK15 or siRNA of PFKFB3 contributed to decrease
the production of ATP and lactate (Fig.2B), growth of tumor vessels(sFig.1B), and tumor growth (Fig.2C). After clinical analysis regarding these molecules, these basic data were compatible. Taken
together, cancer changed the features of endothelial cells via exosome, and control of the metabolism at TEC may become a noveland simple target of cancer therapy, even in high diverse cancers.

Figure 1

Figure 2▍ Significance of the research and Future perspective
Even though the cancer genome analysis provided the chanceof ‘Precision Medicine,’ actionable targets were less, and un-developed target for the mutation seemed to be extravagant. On
the contrary, cancer stroma cells would not have a huge genetic

Supplementary Figure 1

P a t e n t
Tr e a t i s e

Matsumoto, Kenichi; Noda, Takehiro; Kobayashi, Shogo et al. Inhibition of glycolytic activator PFKFB3 suppresses tumor growth and induces tumor vessel
normalization in hepatocellular carcinoma Cancer Lett. 2021, 500, p. 29-40. doi: 10.1016/j.canlet.2020.12.011
Yokota, Yuki; Noda, Takehiro; Okumura, Yuichiro; Kobayashi, Shogo et al. Serum exosomal miR-638 is a prognostic marker of HCC via downregulation ofVE-cadherin and ZO-1 of endothelial cells Cancer Sci. 2021, 112(3), p. 1275-1288. doi: 10.1111/cas.14807

URL
K e y w o r d liver cancer, tumor endothelial cell, exosome, microRNA.