유방암의 원격전이에서 COX-2, VEGF, Cyclin D1의 예후인자로서의 가치

최정훈 한국유방암학회 2007 Journal of breast cancer Vol.10 No.1

Purpose: The most important independent prognostic factors of breast cancer have been reported to the tumor size and lymph node metastasis, as well as DNA ploidy, proliferation index, and various receptors, including estrogen receptor (ER) and progesteron receptor (PR) and oncogenes, such as c-erbB-2, and the tumor suppressor gene, p53. However, all these prognostic factors are still unable to exactly estimate distant metastasis for breast cancer. Based on this, our aim was to study for the prognostic factors that associated distant metastasis of breast cancer with cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF), which are related to angiogenesis, and Cyclin D1, which participates in cell proliferation in breast cancer. Methods: A retrospective study was carried out on 95 patients, who has undergone an operation for breast cancer, with or without metastasis between January 1993 and July 2001, at the Department of Surgery, Chungnam National University Hospital. The study was based on the immunohistochemical staining of primary tumors for COX-2, VEGF, Cyclin D1, ER, PR and c-erbB-2, which were obtained from tissue samples of 45 and 50 patients with and with no distant metastatic breast cancer. SPSS for Windows, Version 10.0 was used for the statistical analyses. Results: The expressions of COX-2, VEGF and Cyclin D1 were statistically significant in distant metastatic breast cancer. The clinicopathological parameters associated with distant metastasis were the tumor size and histological grade, and lymph node metastasis, lymphovascular invasion, ER and PR. There were positive correlations between 1) COX-2 and VEGF, 2) COX-2 and Cyclin D1, 3) c-erbB-2 and Cyclin D1 and 4) VEGF and Cyclin D1, COX-2 also had positive relationships with the tumor size and c-erbB-2, VEGF had positive relationships with lymph node metastasis, histological grade and lymphovascular invasion, as well as with ER and PR. The overexpressions of COX-2, VEGF and Cyclin D1 shortened the disease-free survival and survival period. Conclusion: The overexpressions of COX-2, VEGF and Cyclin D1 were considered poor prognostic factors for the induction of distant metastasis. Therefore, COX-2, VEGF and Cyclin D1 could be used in the prevention of distant metastasis, and prescribed for the treatment of metastatic breast cancer.

난소의 상피성 종양에서 신생혈관형성과 Cathepsin D 발현의 상관관계

박일수,배용철 대한부인종양 콜포스코피학회 2003 Journal of Gynecologic Oncology Vol.14 No.3

목적 : 악성종양의 진행과 전이과정에 관여하는 인자로 신생혈관형성 및 단백분해효소에 대한 관심이 높아지고 있으나, 이러한 인자들의 예후에 대한 중요성은 아직 확립되어 있지 않다. 본 연구에서는 양성, 경계성, 악성종양에서 신생혈관형성 유발인자인 VEGF의 발현도와 신생혈관수 및 Cathepsin D의 발현도와의 관계를 알아보고자 한다. 연구 방법 : 1997년부터 1999년까지 경북대학교병원에서 수술로 절제된 난소조직중 장액성 종양 41예와 점액성 종양 50예를 대상으로 면역조직화학적 염색을 이용하여 VEGF와 Cathepsin D의 발현 정도를 분석하였고, CD31에 대한 monoclonal antibody를 이용하여 미세혈관 수를 정량화 하였다. 장액성 종양은 양성 19예, 경계성 3예, 악성 19예였고, 점액성 종양은 양성 2예, 경계성 16예, 악성 14예였다. 결과 : 미세혈관 수, VEGF, Cathepsin D는 점액성과 장액성 모두에서 양성이나 경계성보다 악성에서 현저히 증가하였고, 특히 미세혈관 수는 재발한 1예와 사망한 1예에서 평균보다 높은 수치를 보였다. 그러나 임상인자인 병기, 종양크기 및 환자의 연령과는 통계학적 유의성이 없었다. VEGF 발현과 미세혈관 수 사이에는 유의한 상관 관계가 없으나, Cathepsin D와 VEGF, 신생혈관 수의 발현에는 유의한 상관관계가 있었다. 이는 종양의 혈관형성 에 있어 VEGF 이외에 다른 여러 가지 혈관형성인자 및 성장인자가 관여한다는 것을 보여준다. 결론 : 결론적으로 미세혈관 수, VEGF, 그리고 Cathepsin D의 발현은 난소종양 진행의 유용한 지표로서 여겨지나, 아직 예후에 대한 유의성이 확립되어 있지 않고, 추적기간이 짧아 앞으로 환자의 장기 생존률에 대한 지속적인 연구가 필요할 것으로 사료된다. Objective : Tumor angiogenesis and proteolysis have a role in tumor invasion and metastasis in various types of tumor. But the prognostic significance in ovarian epithelial tumors has not been established. In this study, we evaluate correlation of MVC, VEGF and Cathepsin D expression with progression in ovarian tumor. Methods : Formalin fixed tumor tissues from 41 cases of serous and 50 cases of mucinous tumors were analyzed for the expresssion of VEGF and Cathepsin D by immunohistochemical stain. The authors quantified microvessel counts (MVC) using monoclonal antibody for CD31. The serous tumors included 19 cases of benign, 3 cases of borderline and 19 cases of malignant tumors. The mucinous tumors included 20 cases of benign, 16 cases of borderline and 14 cases of malignant tumors. Results : MVC, VEGF and cathepsin D expression in malignant tumors were significantly higher than those in benign or borderline malignancy of both serous and mucinous tumors. One case of recurrence and another one case of death showed highly counted microvessels. But, there was no significant correlation as to FIGO stage, tumor size or patient’s age. There was no correlation between VEGF expression and MVC, however significant correlation was found between expression of Cathepsin D and VEGF and MVC. These results suggest that other angiogenic factors may affect in the regulation of angiogenesis. Conclusion : MVC, VEGF and Cathepsin D expression seems to be suggested as a useful indicator of progression in ovarian tumors. But, the prognostic significance cannot be fully established and additionally long-term follow up study for patient’s survival rate is needed.

VEGF-C and VEGF-D Expression and its Correlation with Lymph Node Metastasis in Esophageal Squamous Cell Cancer Tissue

Yang, Zeng,Wang, Yong-Gang,Su, Kai Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.1

Background: To explore vascular endothelial growth factor C (VEGF-C) and VEGF-D expression and its correlation with lymph node metastasis in esophageal squamous cell cancer (ESCC) tissue. Materials and Methods: Immunohistochemical methods were applied to detect the levels of VEGF-C and VEGF-D expression in 64 surgicall removal ESCC tissues, tissues adjacent to cancer and normal tissues, and the relationship between VEGF-C and VEGF-D expression and lymph node metastasis was analyzed. Results: Both VEGF-C and VEGF-D were expressed by varying degrees in esophageal cancer tissue, the tissue adjacent to cancer and normal tissue, and the positive expression rate went down successively. The positive expression rates of VEGF-C (59.4%) and VEGF-D (43.8%) in esophageal cancer tissue were significantly higher than in the tissue adjacent to cancer (34.4%, 15.6%) and normal tissue (20.3%, 12.5%), respectively, in which significant differences were manifested (p<0.01). Positive expression rates of VEGF-C and VEGF-D in esophageal cancers with lymph node metastasis were markedly higher than without such metastasis (p<0.01), while those in the tissue with TNM staging I~II were markedly lower than that with TNM staging III~IV (p<0.01). Conclusions: Both VEGF-C and VEGF-D are highly expressed in ESCC tissue, which may be related to the lymph node metastasis of cancer cells. Hence, VEGF-C and VEGF-D can be clinically considered as important reference indexes of lymph node metastasis in esophageal cancer.

직장 결장암의 간전이 환자에서 VEGF-A, C, D 발현의 비교연구

전광식(Kwang-Sik Chun),이경하(Kyung-Ha Lee),송인상(In-Sang Song),김지연(Ji-Yeon Kim),김제룡(Je-Ryong Kim),안문상(Moon-Sang Ahn),이상일(Sang-Il Lee),박종현(Jong-Hyun Park),최송이(Song-E Choi),강대영(Dae-Young Kang),송규상(Kyu-Sang Son 대한외과학회 2009 Annals of Surgical Treatment and Research(ASRT) Vol.76 No.5

Purpose: We aimed to investigate the correlations between expressions of angiogenic cytokines VEGF-A, C, D of primary colorectal cancer and liver metastasis. Methods: We examined paraffin-embedded primary colorectal cancer tissue from 45 patients who had liver resection due to colorectal liver metastasis (metastasis group) and 37 patients who had surgical resection due to colorectal cancer only (control group). In the control group, local recurrence and distant metastasis had not occurred. Immunohistochemical staining for VEGF-A, C and D was performed. We analysed the correlations between expression of VEGF-A, C and D in primary colorectal cancer tissues and clinicopathologic parameters. Results: VEGF-A expressions of primary colorectal carcinoma were not different between the two groups. VEGF-C was more frequently expressed in the metastasis group (P=0.008) but VEGF-D was more expressed in the control group (P=0.003). Patients with VEGF-C negative and VEGF-D positive expression were predominant in the control group (P=0.020). Tumor location, T stage, lymph node metastasis and tumor differentiation were not related with the expressions of VEGF-A, C, D but only preoperative CEA was positively correlated with VEGF-A and C expression. Conclusion: Expressions of VEGF-C in primary tumor were more frequent in metastatic colorectal cancer and expressions of VEGF-D were more frequent in nonmetastatic colorectal cancer. More large-scale prospective studies for VEGF-C and D expression in colorectal cancer are necessary.

조기위암에서 E-cadherin, VEGF-C, VEGF-D의 발현과 Cytokeratin 18로 면역화학염색 한 림프절 전이와의 연관성

김대훈,윤효영,송영진,류동희,민인철,성노현,이상억 대한위암학회 2008 Journal of gastric cancer Vol.8 No.2

목적: VEGF-C와 VEGF-D는 맥관형성성 인자이고, E-cadherin 의 비정상 발현은 위암의 진행에 중요한 역할을 한다. 이 연구의 목적은 조기위암에서 E-cadherin, VEGF-C, -D 그리고 cytokeratin 18번을 이용하여 정확하게 측정된 림프절 전이 와의 연관성을 연구하는데 있다. 대상 및 방법: 1997년 3월부터 2002년 12월까지 49명의 조 기 위암환자들을 대상으로 E-cadherin, VEGF-C와 VEGF-D 면 역화학염색을 시행하였다. 림프절 전이를 정확하게 측정하 기 위하여 49명 환자들의 1,562개의 림프절을 cytokertin 18 을 사용하여 재검사 하였다. 결과: 11 (0.7%)개의 림프절이 12.2% (n=6)의 환자들로부터 새롭게 발견되었다. 정확한 림프절 전이는 점막암에서 3.6%였고, 점막하암에서 38.1%였다. 병기 이동은 3명(6.1%) 의 환자에서 관찰되었다. E-cadherin의 비정상 발현은 36.7% 에서 발견되었고, VEGF-C와 VEGF-D의 발현은 각각 16.3%와 36.7%에서 관찰되었다. E-cadherin의 비정상 발현은 종양의 분화도(P<0.0103)와 Lauren 분류(P<0.0001)와 뚜렷한 연관 성이 있었다. VEGF-C와 VEGF-D는 조기위암에서 림프절 전 이를 포함한 임상병리학적 연관성이 없었다. 그러나 E-cadheirn이 비정상 발현되고 VEGF-C 또는 VEGF-D의 발현이 동 반되는 환자들에서 림프절 전이의 빈도가 높았다(P=0.0031). 결론: 본 연구에서 조기위암에서 림프절 전이와 VEGF-C, VEGF-D의 발현과의 관계를 증명할 수 없었다. 하지만 E-cadherin이 비정상 발현을 하면서 VEGF-C 또는 VEGF-D의 발현 을 동반할 경우 림프절 전이와 연관성이 있었다.

점막하 침윤 조기위암에서 Vascular Endothelial Growth Factor (VEGF)-C와 VEGF-D의 발현

김정구(Jeong Goo Kim),최명규(Myung Gyu Choi),박원상(Won Sang Park),이상철(Sang Chul Lee),이동호(Dong Ho Lee),유영경(Young Kyoung You),안창준(Chang Joon Ahn),박조현(Cho Hyun Park) 대한외과학회 2008 Annals of Surgical Treatment and Research(ASRT) Vol.74 No.1

Purpose: Vascular endothelial growth factor (VEGF)-C and VEGF-D are considered novel growth factors that potentially induce lymphangiogenesis and hyperplasia of lymphatic vessels. The aim of this study was to investigate whether the expressions of VEGF-C and VEGF-D are associated with the clinicophathologic factors, and particularly lymphatic invasion and lymph node metastasis, in early gastric cancers that’s invaded the submucosa. Methods: Using immunohistochemical staining, we studied the VEGF-C and VEGF-D expressions in the gastric cancer specimens from 83 patients who underwent curative gastrectomy. Results: The VEGF-C and VEGF-D immunoreactivity was mainly located in the cytoplasm of the tumor cells. There was a positive VEGF-C expression in 27 of 83 cases (32.5%). The VEGF-D positivity rate was lower than the VEGF-C positivity rate. VEGF-D was positive in 20 of 83 cases (24.0%). A VEGF-C positive expression was associated with lymphatic invasion (P=0.018) and lymph node metastasis (P=0.001). However, the expression of VEGF-D had no correlation with any of the clinicopathologic factors, including lymphatic invasion and lymph node metastasis. Conclusion: The VEGF-C expression may have a role in lymph node metastasis of gastric cancer cells. The VEGF-C expression in tumor specimens may be a reliable marker for lymph node metastasis of early gastric cancer that’s invaded the submucosa.

구강점막 편평상피세포암에서 림프관형성 유전자 발현

박영욱,김성곤,김소희,김한석,김민근,Park, Young-Wook,Kim, Seong-Gon,Kim, So-Hee,Kim, Han-Seok,Kim, Min-Keun 대한악안면성형재건외과학회 2009 Maxillofacial Plastic Reconstructive Surgery Vol.31 No.6

Background and Purpose: Vascular endothelial growth factor (VEGF)-C, VEGF-D and their tyrosine kinase receptor, VEGF receptor (VEGFR)-3 are recently known to have lymphangiogenic activities in various tumor types. Oral mucosal squamous cell carcinoma (OMSCC) easily metastasizes to cervical lymph nodes, so we determined the expression levels of VEGF-C, VEGF-D and VEGFR-3 in oral squamous cell carcinoma. Materials and Methods: We performed Western blot analyses with 4 OMSCC cultured tumor cell lines (SCC9, KB, YD-10B, YD-38), and with 7 surgical specimens of OMSCC for the detection of VEGF-C, VEGF-D and VEGFR-3 proteins. Expression of VEGF-C mRNA as well as mRNA for VEGFR-3 in 4 OMSCC cell lines (KB, SCC-4, SCC-9, YD-10B) was investigated by RT-PCR. We also measured VEGFC/VEGF-D protein concentrations in the media and protein concentration of VEGFR-3 in cell lysates of 4 OMSCC cell lines (SCC9, KB, YD-10B, YD-38) using commerical ELISA kits. Finally, we performed immunoprecipitation for the detection of VEGF-C in cell lysates of 4 OMSCC cells (KB, SCC-4, SCC-9, YD-10B) and real-time RT-PCR for the quantification of VEGF-C mRNA. Results: In the result of Western blotting with cell lysates of 4 OMSCC cells, we could not detect the protein expression of VEGF-C, VEGF-D, and VEGFR-3. But, all tumor tissues demonstrated VEGF-C and VEGFR-3. VEGF-C mRNA was detected at various levels in 4 OMSCC cell lines. Moreover, OMSCC cells secreted VEGF-C, not VEGF-D and VEGFR-3 was also detected in cell lysates of OMSCC by ELISA. Immunoprecipitation and real-time RT-PCR revealed VEGF-C was also expressed in 4 OMSCC cell lines. Conclusion: Taken together, tumor cells of OMSCC secrete VEGF-C, not VEGF-D. And VEGFR-3 is expressed tumor cells as well as OMSCC tumor tissues, needs further study.

위암의 내시경하 생검 조직에서 CD105 (Endoglin), D2- 40, Vasc ular Endothelial Growth Fac tor- A와 D의 발현을 통한 침습성의 예측

김성수(Sungsoo Kim),이태진(Tae Jin Lee),김범규(Beom Kyu Kim),차성재(Sung Jae Cha),박성준(Sung Jun Park),장인택(In Taek Chang),박성일(Sung Il Park) 대한외과학회 2007 Annals of Surgical Treatment and Research(ASRT) Vol.72 No.5

Purpose: CD105 (endoglin) has been shown to be a more useful marker to identify the proliferating endothelium involved in tumor angiogenesis than are the panendothelial markers. The monoclonal antibody D2-40 is a specific lymphatic endothelial marker. Methods: We investigated CD105, lymphatic vessel marker (D2-40), vascular endothelial growth factor (VEGD)-A and the VEGF-D expressions as possible prognostic markers in the endoscopic biopsy tissue of stomach cancer patients. The pre-operative endoscopic biopsies and surgical biopsies from 73 patients were immunostained for CD105, D2-40, VEGF-A and VEGF-D. Positively stained microvessels were counted in densely vascular foci (hot spots) at a ×200 field in each specimen. Results: The microvessel density (MVD) and lymphatic vessel density (LVD), according to the CD105 and D2-40 expressions of the endoscopic biopsies, showed a statistically significant correlation with the surgical biopsies. The MVD via CD105 a showed statistically significant correlation with the histologic differentiation, T-stage, nodal metastasis and stage in the endoscopic biopsies and surgical biopsies, respectively. The lympathic vessel density (LVD) via D2-40 showed a statistically significant correlation with T-stage, nodal metastasis and stage in the endoscopic biopsies. The expressions of VEGF-A and VEGF-D showed a statistically significant correlation with the MVD and LVD. Conclusion: The MVD, as determined by the CD105 expression and the LVD as determined by the D2-40 expression may be useful markers for predicting the invasiveness with using a pre-operative endoscopic biopsy of stomach cancer.

피부종양에서 HOX D3와 혈관성장인자(VEGF-C)의 발현

김형동 ( Hyung Dong Kim ),조문균 ( Moon Kyun Cho ),박영립 ( Young Lip Park ),이종석 ( Jong Suk Lee ),황규왕 ( Kyu Uang Whang ) 대한피부과학회 2007 大韓皮膚科學會誌 Vol.45 No.4

Background: The anatomical relation between a malignant tumor and its vascular and lymphatic bed is an important influencing metastasis. Hox D3 is required for these expressions of integrin αvβ3 and urokinase plasminogen activator (uPA), which contribute to endothelial cell adhesion, invasion, and migration during angiogenesis. Recent studies in different tumor types have shown that vascular endothelial growth factor-C (VEGF-C), which displays a high specificity for lymphatic endothelium, is involved in tumor-induced lymphagiogenesis and lymphatic metastatic spread. Objective: This study was designed to measure the expression of HOX D3 and VEGF-C in different skin cancers. Methods: The expression of HOX D3 and VEGF-C was examined by immunohistochemical staining of 40 skin cancer tissue samples, including 8 keratoacanthomas, 8 extramammary paget`s disease, 8 basal cell carcinomas, 8 squamous cell carcinomas and 8 malignant melanomas. Results: Immunohistochemical analysis of 40 skin cancer tissue samples revealed a high expression of HOX D3 and VEGF-C in the more aggressive and invasive skin tumors, including squamous cell carcinomas and malignant melanomas. On the other hand, low expression was seen in the less-invasive skin tumors, including keratoacanthomas, extramammary paget`s disease and basal cell carcinomas. Also the degree of expression of HOX D3 and VEGF-C showed a statistically-significant correlation with each skin tumor (p<0.05). Conclusion: These findings provide evidence that the upregulation of HOX D3 and VEGF-C might be involved in the promotion of angiogenesis and lymphagiogenesis in skin tumors and play an important role in metastasis. (Korean J Dermatol 2007;45(4):354~361)

BMB Reports : Loss of phospholipase D2 impairs VEGF-induced angiogenesis

( Chang Sup Lee ),( Jaewang Ghim ),( Parkyong Song ),( Pann Ghill Suh ),( Sung Ho Ryu ) 생화학분자생물학회(구 한국생화학분자생물학회) 2016 BMB Reports Vol.49 No.3

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. [BMB Reports 2016; 49(3): 191-196]