Professor Misuzu Seo

Area and Subject Taught Molecular and Cell Biology, Cell Signaling
Research Theme(s) (1)Targeting growth factor-mediated cell signaling for cancer therapy
(2)Regulation of neuronal and vascular development
Academic Degrees Ph. D (Pharmaceutical Sciences)
Keywords for Research Field Cancer Molecular Target Therapy, Angiogenesis, Neurogenesis, VEGF, FGF, Neuropilin-1
Office Phone Number 81-75-705-1488

Research Overview

VEGF-A /NRP1 signaling induces GIPC1/Syx complexes,
resulting in RhoA activation to promote survival and
growth of human malignant skin cancer cells.

Exploration of therapeutic target molecules, the identification of mechanisms for neural diseases and the progression of Cancer cells.

Cell growth factors and axonal guidance molecules bind to cell receptors as extracellular signalling molecules, thereby activating intracellular signalling. This then leads to the control of cell proliferation, differentiation, migration, and morphogenesis.
Solid tumour growth in animals and in humans is accompanied by neovascularization called angiogenesis. New capillary growth is elicited by a diffusible factor such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). These are generated by malignant tumour cells. There is evidence that over expression of VEGF and FGF and deregulation of their receptors correlate poor prognosis. It is because of this we are investigating the molecular mechanisms whereby VEGF and FGF mediate tumour progression. Our contributions in these fields of research are expected to lead to the development of regenerative therapies for neuronal disorder patients, which, are currently the center of attention as well as novel cancer treatments.

  1. VEGF-A promotes cancer cell proliferation and invasion through Neuropilin(NRP)-dependent signaling.
      Tumour-Secreted Vascular endothelial growth factor-A (VEGF-A) is a crucial factor for tumour angiogenesis and tumour malignancy. Besides the aspect of tumour angiogenesis, there are reports to account that VEGF-A may promote proliferation and survival of tumours themselves. We are investigating the molecular mechanisms in which VEGF mediates tumour progression. Anti-VEGF antibodies (such as Avastin) have received much attention lately for their ability to block tumour angiogenesis and prolonging the life of cancer patients. Neuropilins (NRP1 and NRP2) are receptors for the VEGF family of angiogenesis stimulators. Previously, it was shown that VEGFs act via VEGF receptor, tyrosine kinases, but it now appears that VEGF activity is also modulated by NRPs. NRPs have no kinase activity. We focus on developing new anti-tumour agents, which target the VEGF/NRPs mediated cell signalling in malignant tumour cells. 
  2. Enhanced expression of Fibroblast Growth Factor Receptor 3IIIc promotes human oesophageal cancer malignant progression. 
      More than 90% of cancer in the oesophagus is squamous cell carcinoma. The oesophageal squamous cell carcinoma (ESCC) is an invasive and progressive cancer. The percentage of patients in which there is lymph node metastasis of ESCC is more than 30%. That is quite high compared with other digestive tract cancers, for example 11.9% in gastric cancer and 10 % in sigmoid colon cancer. The ESCC is well known to show poor prognosis, and 5-year overall survival remains approximately just 20% despite the use of multimodal treatments such as extensive surgery. 
    The expression of FGFR isoforms is temporally and spatially regulated in embryos and in normal adult organs. Alternative splicing of the FGFR gene has been implicated in carcinogenesis. Switch expressions of FGFR to mesenchymal isoforms, enable cells to receive signals usually restricted to the connective tissue. FGFR3 has two different transmembrane-type isoforms, FGFR3 IIIb and IIIc, which are produced by alternative splicing and have distinctive ligand-specificities. In normal tissues, IIIb isoform is mainly expressed in the epithelium, whereas IIIc isoform is mainly expressed in the mesenchyme.  Previously, we have found the expression of FGFR3 IIIc isoforms in 86 % of the ESCC specimens, tested by RT-PCR, has been enhanced. Thus, it suggests that enhanced expression of FGFR3 IIIc isoforms may promote the malignant progression of ESCC. The aim of our study is to elucidate the mechanism of promoting malignant progression by enhanced expression of FGFR3 IIIc isoform. 
  3. An axonal guidance molecule Anosmin-1 enhances angiogenesis in endothelial cells.
      Anosmin-1 is a 100 kDa-secreted glycoprotein, which is encoded by the Kallmann syndrome (KS) causative gene termed KAL-1. Anosmin-1 is an axon guidance molecule, which induces olfactory nerve from olfactory epithelium and forms the olfactory bulbs (OBs). KS is a congenital disease which is characterised by hypogonadism. This is due to gonadotropin-releasing hormone (GnRH) deficiency and a defective sense of smell related to the defective development of the olfactory bulbs and olfactory tracts. It is thought that the hypoplasia of olfactory bulbs is caused by a disorder of the olfactory nerve, axonal elongation. In addition to the bioactivity of Anosmin-1, that induces axonal elongation and axon guidance, we have recently found that Anosmin-1 stimulates proliferation, migration, and tube formation of endothelial cells (ECs) in vitro. Furthermore, Anosmin-1 induces tube formation of olfactory bulb in vitro. Therefor, we hypothesised that the cause of the hypoplasia in OBs is due to the lack of the induction of angiogenesis in OB by Anosmin-1. Our research has been undertaken to clarify that Anosmin-1 has the physiological function of endothelial cells through binding to VEGFR2 and induces angiogenesis in OBs using chick embryo.

Notable Publications and Works in the Last Three Years

  1. Shimizu A, Zankov D P, Kurokawa-Seo M, Ogita H. Vascular endothelial growth factor exerts diverse cellular effects via small G proteins, Rho and Rap. Int J Mol Sci, in press (2018)
  2. Ueno N, Ueda S, Asano, Kamiyoshi S, Shobuike K, Seo M. Significance of FGFR3IIIc isoform expression in prognosis of esophageal squamous cell carcinoma patients. ConBio2017 (The 90th Annual Meeting of the Japanese Biochemical Society, The 40th Annual Meeting of the Molecular Biology Society of Japan)、Kobe、2017.12.8. (Poster presentation)
  3. Ohtaka K, Fujisawa Y, Takada F, Hasegawa Y, Miyoshi T, Hasegawa T, Miyoshi H, Kameda H, Kurokawa-Seo M, Fukami M, Ogata T. FGFR1 analyses in four patients with hypogonadotropic hypogonadism with Split-Hand/foot malformation: Implications for the promoter region. Hum Mutat. 38(5):503-506. (2017)
  4. Yoshida A, Shimizu A, Asano H, Kadonosono T, Kondoh SK, Seo M. The cell penetrating peptide blocking VEGF-A/NRP1 signaling inhibits tumor growth and metastasis. The 21st annual meeting of the Japanese association for Molecular Target Therapy of Cancer. Hakata, 2017.6.14-16(Poster presentation)
  5. *Ueno N, Shimizu A, Kanai M, Iwaya Y, Ueda S, Nakayama J, Seo K M*. Enhanced expression of Fibroblast Growth Factor Receptor 3 IIIc promotes human esophageal carcinoma cell proliferation. J. Histochem. Cytochem. 64(1):7-17 (2016)
  6. Ueno N, Shimizu A, Kanai M, Iwaya Y, Ueda S, Nakayama J, Kurokawa-Seo M. Enhanced expression of fibroblast growth factor receptor 3 IIIc promotes human esophageal carcinoma cell proliferation. World Biomedical Frontiers. (2016; Apr-May):*The article 5 was republished to draw public attention to promising findings in preclinical basic research, expediting their entry into the pipeline that may lead to development of new therapies.)
  7. Ayumi Yoshida, Akio Shimizu, Hirotsugu Asano, Michael Klagsbrun, Misuzu Seo. The cytoplasmic domain of NRP1 interacts with GIPC1 and Syx to induce tumor proliferation. Sakura Science Plan, Kyoto Sangyo University, Faculty of Life Sciences, 2016.2.20 Poster presentation.
  8. Yoshida A, Shimizu A, Asano H, Kadonosono T, Kondoh SK, Geretti E, Mammoto A, Klagsbrun M, Seo M., VEGF-A/NRP1 stimulates GIPC1 and Syx complex formation to promote RhoA activation and proliferation in skin cancer cells. Biol Open(9):1063-76 (2015)
  9. **Yoshida A, Shimizu A, Ueno N, Asano H, Kadonosono T, Kondoh SK, Klagsbrun M, Seo M.,VEGF-A/Neuropilin signal activates RhoA and promotes cancer growth and metastasis. BMB2015 (Biochemistry and Molecular Biology), Kobe, 2015.12.1-4. **Best Young Scientist Awards at the Annual Meeting of the BMB2015, Japan.
  10. Matsushima S., Shimizu A., Kondoh M., Asano H., Seo M. Anosmin-1 activated the PLC-PKC signaling pathway to induce tube formation in endothelial cells. Ibid.
  11. Kida A., Yasuki, M., Tokumura, S., Shimizu A., Asano H., Ishi Y., Seo M. Axonal guidance molecules Anosmin-1 and Netrin1 partially co-localize in developing embryonic chick olfactory nervous system. Ibid.
  12. Asano H., Takeuch Y., Shimizu A., Sato N., Seo M. Anosmin-1 directly regulates Netrin-1-induced growth cone collapus. Ibid.
  13. Ueno N, Shimizu A, Kanai M, Iwaya Y, Ueda S, Nakayama J, Seo K M*. Enhanced expression of Fibroblast Growth Factor Receptor 3 IIIc promotes human esophageal cancer malignant progression. Ibid.
  14. Ayumi Yoshida*, Akio Shimizu, Tetsuya Kadonosono, Shinae Kondo、Misuzu Seo:The VEGF-A/NRP1 signaling promotes cancer cell proliferation and metastasis. The 19th annual meeting of the Japanese association for Molecular Target Therapy of Cancer. Matsuyama, 2015.6.10-12(Workshop, Oral presentation)
  15. Asano H., Takeuchi Y., Shimizu A., Sato N., Seo M.:Kallmann syndrome responsible gene Anosmin-1 directly binds to Netrin-1. The 62st annual meeting of the Japanese Biochemical Society, Kinki Branch, Kusatsu, 2015.5.16(Oral &Poster presentation)
  16. Matsushima S., Kondo M., Shimizu A., Asano H., Seo, M.:Analysis of Anosmin-1 signaling during blood vessel formation. Ibid. 2015.5.16(Oral &Poster presentation)
  17. Kondo M., Shimizu A., Asano H., Seo M. :Neuronal guidance molecule Anosmin-1 has the effect of endothelial cell proliferation, migration, and tube formation. Ibid. 2015.5.16(Oral &Poster presentation)
  18. Yoshida A., Shimizu A., Kadonosono T., Kondo S., Klagsbrun M., Seo M. Inhibition of VEGF-A/NRP1signaling prevents cancer proliferation and metasatasis. bid. 2015.5.16(Oral &Poster presentation).
  19. Ayumi Yoshida, Akio Shimizu, Nobuhiro Ueno, Hirotsugu Asano, Misuzu Seo. The VEGF-A/NRP-1 signaling promotes cancer cell proliferation, metastasis, and tumor angiogenesis. Sakura Science Plan, Kyoto Sangyo University, Faculty of Life Sciences, 2015.2.21 Poster presentation