• Bulletin of the Korean Chemical Society
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• 제30권3호
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• pp.707-709
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• 2009

• Biomolecules & Therapeutics
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• 제31권4호
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• pp.456-465
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• 2023

Cervical tumors represent a prevalent form of cancer affecting women worldwide; current treatment options involve surgery, radiotherapy, and chemotherapy. Angiogenesis, the process of new blood vessel formation, is a crucial factor in cervical tumor growth. The molecular mechanisms underlying the effects of the liver kinase B1 (LKB1/STK11) tumor suppressor protein on tumor angiogenesis have not been elucidated. Therefore, we investigated the role of LKB1 in cervical tumor angiogenesis both in vitro and in vivo in this study. Our results demonstrated that LKB1 inhibited cervical tumor angiogenesis by suppressing the expression of angiogenesis-related factors such as vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1α. LKB1 directly affected both carcinoma and vascular endothelial cells, resulting in a significant reduction in tumor growth and angiogenesis. Furthermore, LKB1 was found to bind to VEGF receptor 2 (VEGFR-2) and target the VEGFR-2-mediated protein kinase B/mechanistic target of rapamycin signaling pathway in endothelial cells, thereby reducing cervical tumor growth and angiogenesis. Our study provides new insights into the molecular mechanisms underlying the anti-tumor and anti-angiogenic effects of LKB1 in cervical cancer. These findings will help develop new therapeutic strategies for cervical cancer.

• BMB Reports
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• 제41권12호
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• pp.833-839
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• 2008

Angiogenesis in tumors is driven by multiple growth factors that activate receptor tyrosine kinases. An important driving force of angiogenesis in solid tumors is signaling through vascular endothelial growth factor (VEGF) and its receptors (VEGFRs). Angiogenesis inhibitors that target this signaling pathway are now in widespread use for the treatment of cancer. However, when used alone, inhibitors of VEGF/VEGFR signaling do not destroy all blood vessels in tumors and do not slow the growth of most human cancers. VEGF/VEGFR signaling inhibitors are, therefore, used in combination with chemotherapeutic agents or radiation therapy. Additional targets for inhibiting angiogenesis would be useful for more efficacious treatment of cancer. One promising target is the signaling pathway of hepatocyte growth factor (HGF) and its receptor (HGFR, also known as c-Met), which plays important roles in angiogenesis and tumor growth. Inhibitors of this signaling pathway have been shown to inhibit angiogenesis in multiple in vitro and in vivo models. The HGF/c-Met signaling pathway is now recognized as a promising target in cancer by inhibiting angiogenesis, tumor growth, invasion, and metastasis.

• Biomolecules & Therapeutics
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• 제26권5호
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• pp.474-480
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• 2018

Most angiogenesis assays are performed using endothelial cells. However, blood vessels are composed of two cell types: endothelial cells and pericytes. Thus, co-culture of two vascular cells should be employed to evaluate angiogenic properties. Here, we developed an in vitro 3-dimensional angiogenesis assay system using spheroids formed by two human vascular precursors: endothelial colony forming cells (ECFCs) and mesenchymal stem cells (MSCs). ECFCs, MSCs, or ECFCs+MSCs were cultured to form spheroids. Sprout formation from each spheroid was observed for 24 h by real-time cell recorder. Sprout number and length were higher in ECFC+MSC spheroids than ECFC-only spheroids. No sprouts were observed in MSC-only spheroids. Sprout formation by ECFC spheroids was increased by treatment with vascular endothelial growth factor (VEGF) or combination of VEGF and fibroblast growth factor-2 (FGF-2). Interestingly, there was no further increase in sprout formation by ECFC+MSC spheroids in response to VEGF or VEGF+FGF-2, suggesting that MSCs stimulate sprout formation by ECFCs. Immuno-fluorescent labeling technique revealed that MSCs surrounded ECFC-mediated sprout structures. We tested vatalanib, VEGF inhibitor, using ECFC and ECFC+MSC spheroids. Vatalanib significantly inhibited sprout formation in both spheroids. Of note, the $IC_{50}$ of vatalanib in ECFC+MSC spheroids at 24 h was $4.0{\pm}0.40{\mu}M$, which are more correlated with the data of previous animal studies when compared with ECFC spheroids ($0.2{\pm}0.03{\mu}M$). These results suggest that ECFC+MSC spheroids generate physiologically relevant sprout structures composed of two types of vascular cells, and will be an effective pre-clinical in vitro assay model to evaluate pro- or anti-angiogenic property.

• 생명과학회지
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• 제23권9호
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• pp.1177-1182
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• 2013

선모충(Trichinella spiralis)은 감염 후 nurse cell 형성과정에서 영양분 공급 및 배설을 위해 혈관신생인자인 vascular endothelial cell growth factor (VEGF)를 유도하여 혈관신생을 촉진한다. 하지만 이러한 과정 중 선모충이 어떻게 VEGF의 발현을 유도하는지에 대해서는 아직 밝혀지지 않았다. Nurse cell 형성 과정에서 저산소현상이 발생되고 이러한 저산소 현상이 VEGF의 발현을 유도할 것이라는 제안이 있지만 실제 nurse cell 형성 과정에 저산호 현상이 일어나는지도 조사되지 않았으며 저산소 현상이 실제 VEGF를 통한 혈관신생을 유도하는지도 규명되지 않았다. 최근 연구결과에 의하면 VEGF의 발현을 유도하는 티모신베타4 단백질이 초기의 선모충 감염 nurse cell에서 강력하게 유도되는 것이 관찰되었다. 게다가 저산소 현상이 nurse cell 형성 과정에서 관찰되지 않았고 면역세포들이 응집되어 있는 파괴되는 nurse cell에서만 관찰되는 것이 밝혀졌다. 이러한 결과는 티모신베타4가 저산소 현상과 무관하게 선모충 감염 nurse cell에서의 VEGF 유도 및 혈관신생을 유도할 가능성을 제시해 준다.

• BMB Reports
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• 제42권10호
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• pp.685-690
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• 2009

Angiogenesis is essential for tumor growth and vascular endothelial cell growth factor (VEGF) plays a key role in this process. Conversely, sphingosine 1-phosphate (S1P) is a biologically active sphingolipid known to play a key role in cancer progression by regulating endothelial cell proliferation and migration. In this study, the authors found that S1P increases the level of VEGF mRNA in human umbilical vein endothelial cells (HUVECs) and immortalized HUVECs (iHUVECs). Additionally, S1P was found to increase VEGF promoter activity in MS-1 mouse pancreatic islet endothelial cells. Furthermore, a pharmacological inhibitory study revealed that $G_{\alpha i/o}$-mediated phospholipase C, Akt, Erk, and p38 MAPK signaling are involved in this S1P-induced expression of VEGF. A component of AP1 transcription factor is important for S1P-induced VEGF expression. Taken together, these findings suggest that S1P enhances endothelial cell proliferation and migrat ion by upregulating the expression of VEGF mRNA.

• 생명과학회지
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• 제34권2호
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• pp.128-137
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• 2024

이 리뷰 논문에서는 혈관 투과성, 내피세포 모집, 종양관련 혈관 및 림프관의 유지 등에서 핵심적인 과정인 angiogenesis와 lymphangiogenesis에 있어서 vascular endothelial growth factors (VEGF)가 이행하는 중요한 역할에 대해 재조명하고자 한다. VEGF는 tyrosine-kinase receptor인 VEGFR-1, VEGFR-2, VEGFR-3를 통해 그 역할을 이행하며, 이러한 VEGF-VEGFR 시스템은 암에서뿐만 아니라 비정상적인 혈관 및 림프관 형성으로 인해 야기되는 다른 질병들에 있어서도 핵심적인 요소로 각광받고 있다. 암의 측면에서 보았을 때, VEGF와 그 수용체는 종양관련 혈관 및 림프관을 형성하는 과정에서 필수적이라는 점에서 치료적인 타겟으로 이목을 끌고 있다. 때문에 암세포의 성장을 방해하기 위한 항VEGF 항체, 수용체 길항체, 수용체 기능 억제제 등과 같은 여러 가지 시도들이 있었지만, 아직까지 그 임상효과가 불확실하며 더 많은 연구들이 필요한 실정이다. 이 논문에서는 VEGF의 생리적 역할을 VEGF-A, VEGF-B, VEGF-C, VEGF-D, PLGF에 따라 나누어 설명하면서 VEGF/VEGFR 시스템의 중요성을 강조한다. VEGFR-1과 VEGFR-3은 각각 angiogenesis와 lymphangiogenesis에 핵심적인 인자이며, VEGFR-2의 경우 두 가지 모두를 일으킨다. 전반적으로 이 리뷰는 현재까지 밝혀진 암을 포함한 다양한 질병에서의 VEGF와 VEGFR의 역할에 대해 상세히 설명하고자 하였다. 이를 통해 치료 표적으로서 VEGF와 VEGFR의 활용이 더욱 촉진될 것으로 기대된다.

• Journal of Gastric Cancer
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• 제2권4호
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• pp.195-199
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• 2002

Purpose: Angiogenesis is essential for tumor growth and metastasis and depends on the production of angiogenic factors that are secreted by tumor cells. Vascular endothelial growth factor (VEGF) is the most significant angiogenic factor and a selective mitogen for endothelial cells. VEGF, also known as the vascular permeability factor, acts on endothelial cells to increase microvascular permeability and directly stimulate the growth of new blood vessels. Several studies have reported that the expression of VEGF is correlated with hematogenous recurrence via angiogenesis in gastric carcinomas. This research evaluated the relationship between the expression of VEGF and hepatic and peritoneal recurrence in gastric carcinomas. Materials and Methods: Thirty specimens resected from patients with primary gastric carcinomas who had undergone curative resections were divided into three group: Group I, early gastric carcinomas without recurrence; Group II, advanced gastric carcinomas with hepatic recurrence; and Group III, advanced gastric carcinomas with peritoneal recurrence. The expression of VEGF and the density of the microvessel count were examined using immunohistochemistry. Results: 1) The expression of VEGF in Group II and Group III ($63.2\pm\24.3\%$) was stronger than that in Group I ($7\pm\4.2\%$). The expression of VEGF in Group II ($76.5\pm\13.2\%$) was stronger than that of the Group III ($50\pm\14.2\%$) (P<0.05). 2) The microvessel count in Group II ($49.9\pm14.5$) was more than that in Group I ($8.6\pm2.6$) and Group III ($29.1\pm18.1$) (P<0.05). 3) The microvessel count was increased significantly with increasing the expression of VEGF. Conclusions: The expression of VEGF is associated with advanced stomach cancer and hepatic recurrence has a higher expression of VEGF than peritoneal recurrence with neovascularization. Thus the expression of VEGF can be considered to be a useful indicator of recurrence in gastric carcinoma and especially in hepatic recurrence.

• 생명과학회지
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• 제19권3호
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• pp.327-333
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• 2009

건선(psoriasis)은 각화(keratinization)의 장애에 의한 질병으로 잘 알려져 있다. 이 질병에있어서, 몇몇 보고에 따르면 피부 미세혈관이 증가되고, 혈관 신생 유도 인자들인 내피 성장 인자(VEGF) 및 섬유아세포 성장 인자(bFGF)가 과발현된다고 보고 되어져 있다. 신생혈관(angiogenesis)은 건선의 진행성에 있어 중요한 역할을 할지도 모른다. Acitretin은 keratinocyte 성장과 분화에 그것의 잠재적인 활동 때문에 anti-psoriatic 약으로 널리 이용된다. 그러나 신생혈관에 대한 효과는 여전히 불명확하다. 본 면역혈청학적 연구 목표는 건선염 피부에 있는 VEGF의 발현에 acitretin의 효과를 조사하기 위한 것이었다. 우리는 10명의 건선염 피부환자와 대조군으로 3명의 정상인 피부에 acitretin의 치료 전과 후의 VEGF의 발현량을 비교하였다. 치료 전 대조군인 정상인 피부에서보다 건선염 피부환자에서 VEGF의 발현은 명백히 높은 수준이었다. 건선염 피부환자에서 VEGF의 발현량은 acitretin 치료 후 치료 전과 비교시 감소되었다. Acitretin은 건선 피부에서 VEGF와 같은 혈관 신생 유도 인자의 발현을 감소 시켜 신생혈관형성에 있어 억제의 효과가 있음을 나타낸다. 우리는 신생혈관 관점에서 acitretin이 건선에 대한 치료 수단이 될 수 있다는 것을 제안한다.

• BMB Reports
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• 제49권3호
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• pp.191-196
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• 2016

Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis and critical for normal embryonic development and repair of pathophysiological conditions in adults. Although phospholipase D (PLD) activity has been implicated in angiogenic processes, its role in VEGF signaling during angiogenesis in mammals is unclear. Here, we found that silencing of PLD2 by siRNA blocked VEGF-mediated signaling in immortalized human umbilical vein endothelial cells (iHUVECs). Also, VEGF-induced endothelial cell survival, proliferation, migration, and tube formation were inhibited by PLD2 silencing. Furthermore, while Pld2-knockout mice exhibited normal development, loss of PLD2 inhibited VEGF-mediated ex vivo angiogenesis. These findings suggest that PLD2 functions as a key mediator in the VEGF-mediated angiogenic functions of endothelial cells.