Journal of Pathology and Translational Medicine

Original Article

The spectrum of microvascular patterns in adult diffuse glioma and their correlation with tumor grade: Soni , Vaishali Walke, Deepti Joshi, Tanya Sharma, Adesh Shrivastava, Amit Agrawal; J Pathol Transl Med. 2024;58(3):127-133. Published online May 14, 2024; DOI: https://doi.org/10.4132/jptm.2024.03.11

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Background
Primary brain tumors constitute the leading cause of cancer-related mortality. Among them, adult diffuse gliomas are the most common type, affecting the cerebral hemispheres and displaying a diffuse infiltrative pattern of growth in the surrounding neuropil that accounts for about 80% of all primary intracranial tumors. The hallmark feature of gliomas is blood vessel proliferation, which plays an important role in tumor growth, tumor biological behavior, and disease outcome. High-grade gliomas exhibit increased vascularity, the worst prognosis, and lower survival rates. Several angiogenic receptors and factors are upregulated in glioblastomas and stimulate angiogenesis signaling pathways by means of activating oncogenes and/or down-regulating tumor-suppressor genes. Existing literature has emphasized that different microvascular patterns (MVPs) are displayed in different subtypes of adult diffuse gliomas.
Methods
We examined the distribution and biological characteristics of different MVPs in 50 patients with adult diffuse gliomas. Haematoxylin and eosin staining results, along with periodic acid–Schiff and CD34 dual-stained sections, were examined to assess the vascular patterns and correlate with different grades of diffuse glioma.
Results
The present observational study on adult diffuse glioma evaluated tumor grade and MVPs. Microvascular sprouting was the most common pattern, while a bizarre pattern (type 2) was associated with the presence of a high-grade glioma. Vascular mimicry was observed in 6% of cases, all of which were grade 4 gliomas.
Conclusions
This study supplements the role of neo-angiogenesis and aberrant vasculature patterns in the grading and progression of adult diffuse gliomas, which can be future targets for planning treatment strategies.

Citations

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Sujitha Jayaprakash, Hiu Yan Lam, Ravichandran Vishwa, Bandari BharathwajChetty, Kenneth C-H Yap, Mohammed S. Alqahtani, Mohamed Abbas, Gautam Sethi, Alan Prem Kumar, Ajaikumar B. Kunnumakkara
Chinese Medical Journal.2025; 138(21): 2722. CrossRef
Uptake patterns of Adult-type Non-Enhanced diffuse gliomas on [11C] methionine positron emission tomography
Shoji Yasuda, Naoya Imai, Hirohito Yano, Yuka Ikegame, Soko Ikuta, Takashi Maruyama, Noriyuki Nakayama, Morio Kumagai, Yoshihiro Muragaki, Jun Shinoda, Tsuyoshi Izumo
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Consequences of Hypoxic Events, Necrosis, and Microvascular Density, in Astrocytoma IDH-Mutant, CNS WHO Grade 4
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Review

Molecular Imaging in the Era of Personalized Medicine: Kyung-Ho Jung, Kyung-Han Lee; J Pathol Transl Med. 2015;49(1):5-12. Published online January 15, 2015; DOI: https://doi.org/10.4132/jptm.2014.10.24

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Abstract PDF

Clinical imaging creates visual representations of the body interior for disease assessment. The role of clinical imaging significantly overlaps with that of pathology, and diagnostic workflows largely depend on both fields. The field of clinical imaging is presently undergoing a radical change through the emergence of a new field called molecular imaging. This new technology, which lies at the intersection between imaging and molecular biology, enables noninvasive visualization of biochemical processes at the molecular level within living bodies. Molecular imaging differs from traditional anatomical imaging in that biomarkers known as imaging probes are used to visualize target molecules-of-interest. This ability opens up exciting new possibilities for applications in oncologic, neurological and cardiovascular diseases. Molecular imaging is expected to make major contributions to personalized medicine by allowing earlier diagnosis and predicting treatment response. The technique is also making a huge impact on pharmaceutical development by optimizing preclinical and clinical tests for new drug candidates. This review will describe the basic principles of molecular imaging and will briefly touch on three examples (from an immense list of new techniques) that may contribute to personalized medicine: receptor imaging, angiogenesis imaging, and apoptosis imaging.

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Original Articles

The Expression of Pigment Epithelium-Derived Factor in Bladder Transitional Cell Carcinoma: Tae Jung Jang, Sung Woo Kim, Kyung Seop Lee; Korean J Pathol. 2012;46(3):261-265. Published online June 22, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.3.261

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Abstract PDF

Background

Pigment epithelium-derived factor (PEDF) is an anti-angiogenic factor. The purpose of this study is to examine the involvement of PEDF in the angiogenesis and biological behavior of bladder transitional cell carcinoma (TCC).

Methods

We examined the expression of PEDF in 99 bladder TCCs and ten non-neoplastic tissues, and evaluated microvessel density (MVD).

Results

The positive immunoreactivity for PEDF was seen in normal urothelium in 60% (6/10) and TCC in 13% (13/99). The PEDF expression had a significant correlation with MVD, i.e., a low MVD in 42% (5/12), a middle MVD in 11% (8/76) and a high MVD 0% (0/11) of tumors. The PEDF expression was not significantly correlated with the differentiation and invasion of TCC, but the degree of MVD was significantly higher in both high grade TCC and the pT2 tumors.

Conclusions

The degree of PEDF expression is significantly higher in normal bladder urothelium than bladder TCC; it is inversely correlated with the angiogenesis; and it is not related to the differentiation and progression of TCC. It can therefore be concluded that bladder TCC would initially occur if there is a lack of the PEDF expression.

Citations

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Association of pigment epithelium derived factor expression with cancer progression and prognosis: a meta-analysis study
Guo Cheng, Crystal Song
Discover Oncology.2021;[Epub] CrossRef
Level of mitoses in non-muscle invasive papillary urothelial carcinomas (pTa and pT1) at initial bladder biopsy is a simple and powerful predictor of clinical outcome: a multi-center study in South Korea
Ji Eun Kwon, Nam Hoon Cho, Yeong-Jin Choi, So Dug Lim, Yong Mee Cho, Sun Young Jun, Sanghui Park, Young A. Kim, Sung-Sun Kim, Mi Sun Choe, Jung-dong Lee, Dae Yong Kang, Jae Y. Ro, Hyun-Jung Kim
Diagnostic Pathology.2017;[Epub] CrossRef
Endogenous Gastric-Resident Mesenchymal Stem Cells Contribute to Formation of Cancer Stroma and Progression of Gastric Cancer
Eun-Kyung Kim, Hye-Jung Kim, Young-Il Yang, Jong Tae Kim, Min-Young Choi, Chang Soo Choi, Kwang-Hee Kim, Jeong-Han Lee, Won-Hee Jang, Soon-Ho Cheong
Korean Journal of Pathology.2013; 47(6): 507. CrossRef

Microvessel and Lymphatic Vessel Density and VEGFR-3 Expression of Papillary Thyroid Carcinoma with Comparative Analysis of Clinicopathological Characteristics.: Harin Cheong, Hanna Kang, Hyung Kyung Kim, Ji Yoon Bae, Dong Eun Song, Min Sun Cho, Sun Hee Sung, Woon Sup Han, Heasoo Koo; Korean J Pathol. 2010;44(3):243-251.; DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.3.243

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Abstract PDF

BACKGROUND
This study was done to see if there were correlations between anatomic and molecular parameters such as microvessel density (MVD), lymphatic vessel density (LVD), and vascular endothelial growth factor receptor (VEGFR)-3 expression and various clinical parameters for papillary thyroid carcinomas of size > 1.0 cm (PTCs) and size < or = 1.0 cm (papillary thyroid microcarcinomas, PTMCs). PTMCs were divided into two subgroups (0-5 mm and 6-10 mm).
METHODS
We analyzed 197 thyroid carcinomas including 113 PTCs and 84 PTMCs. Tissue samples form 30 patients from each group matched for clinical characteristics were selected for immunostaining.
RESULTS
Although PTCs and PTMCs showed significant differences in clinical characteristics, they did not show significant difference in MVD, LVD, or VEGFR-3 expression. There was a significantly higher LVD in the PTMC subgroup with the larger tumors but no difference in clinical characteristics. LVD was higher in patients > 45 years old (more apparent in the PTC group) and LVD had suggestive correlations with multicentricity and extrathyroidal extension depending on analytic conditions.
CONCLUSIONS
Since LVD showed variable correlations with clinical variables for papillary carcinoma of the thyroid depending on analytic conditions, the individually planned treatments based on overall clinicopathological factors are advised.

Citations

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Freeze-dried bovine amniotic membrane as a cell delivery scaffold in a porcine model of radiation-induced chronic wounds
Daemyung Oh, Daegu Son, Jinhee Kim, Sun-Young Kwon
Archives of Plastic Surgery.2021; 48(4): 448. CrossRef
Polydeoxyribonucleotide Improves Peripheral Tissue Oxygenation and Accelerates Angiogenesis in Diabetic Foot Ulcers
Seoyoung Kim, Junhyung Kim, Jaehoon Choi, Woonhyeok Jeong, Sunyoung Kwon
Archives of Plastic Surgery.2017; 44(06): 482. CrossRef

The Relationship between PTEN Tumor Suppressor Gene and Vascular Endothelial Growth Factor-Mediated Angiogenesis in Breast Cancer.: Jean Kyung Park, Min Jung Jung, Bong Kwon Chun, Bang Hur; Korean J Pathol. 2004;38(2):100-105.

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Abstract PDF: BACKGROUND
PTEN is a novel tumor suppressor gene located at chromosome 10q23.3. Loss of PTEN function has been implicated in the progression of several types of cancer. Angiogenesis is a critical factor in tumor growth and metastasis. We investigated PTEN expression in invasive breast cancers and described its role in the regulation of angiogenesis related to vascular endothelial growth factor (VEGF).
METHODS
Forty-five, surgically resected, formalin-fixed and paraffin embedded breast cancer tissue samples were analyzed for PTEN and VEGF expressions by immunohistochemistry and for microvessel density (MVD) by CD34 immunostaining.
RESULTS
Loss of PTEN expression was found in 35.6% (16/45) of the breast cancer tissues, all of which showed positive VEGF expression. Among 29 cases with normal PTEN expression, 15 (51.7%) were VEGF positive. MVD was significantly higher in tumors with a loss of PTEN expression than in those with normal PTEN expression.
CONCLUSION
A loss of PTEN expression might increase the VEGF-related angiogenesis in breast cancer. There was no correlation between PTEN expression and clinicopathologic parameters. Detection of the loss of PTEN expression may serve as a useful biologic marker for progression in invasive breast cancer.

VEGF Expression and Angiogenesis in Uterine Cervical Carcinomas.: Jin Sook Lee, Kang Suek Suh; Korean J Pathol. 1999;33(2):96-102.

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Abstract: Angiogenesis is a critical factor in the progression of solid tumors, including cervical cancers. The mechanisms responsible for angiogenesis in uterine cervical neoplasia are not well defined. To determine the relationship between angiogenesis and the expression of vascular endothelial growth factor (VEGF) in the cervical neoplasia, the author studied 63 cases of the cervical neoplasia diagnosed between the years 1993 to 1997 at Pusan National University Hospital. The expression of VEGF was semiquantitatively analyzed in paraffin sections by immunohistochemical method. Histologic sections immunostained for factor VIII-related antigen were evaluated for microvessel density. Increased expression of VEGF and microvessel counts was significantly correlated with depth of invasion. Increased microvessel counts were also significantly associated with increased VEGF expression. These results suggest that VEGF is an important angiogenic factor and associated with progression of the cervical neoplasia.

An Immunohistochemical Study of Angiogenesis in Tumor Emboli.: Jo Heon Kim, Chan Choi, Jae Hyuk Lee, Ji Shin Lee, Sung Sun Kim, Chang Woo Han, Sang Woo Juhng; Korean J Pathol. 2007;41(4):252-257.

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Abstract PDF: BACKGROUND
Angiogenesis, which is essential for tumor growth, is known to occur in the extravascular stroma. However, vascular structures were noted in intravascular tumor emboli in surgical specimens. This prompted our investigation of the frequency and morphology of angiogenesis in tumor emboli.
METHODS
Hematoxylin-eosin stained specimens were reviewed for tumor emboli, in 21 cases of stomach adenocarcinoma and 22 cases of colon adenocarcinoma. The cases were examined with immunohistochemistry using antibodies against epithelial antigen (cytokeratin), endothelial antigens (CD31, CD34), lymphatic endothelial antigen (D2-40), and proliferation-associated antigen (MIB1).
RESULTS
Endothelial cells were observed in 16 tumor emboli among four (19.1%) of the 21 cases of stomach adenocarcinoma and in 32 tumor emboli among four (18.2%) of the 22 cases of colon adenocarcinoma. The endothelial cells in the tumor emboli showed papillary ingrowth from the vessel wall, formation of vascular lumens, scattered distribution, or surface coating of the emboli. Some of the endothelial cells in the tumor emboli were D2-40-positive, and some were MIB1- positive.
CONCLUSIONS
These findings demonstrated that angiogenesis occurs in intravascular tumor emboli as well as in the extravascular stroma. Angiogenesis in the tumor emboli may reflect an active process and may facilitate tumor growth.

Microvessel Quantitation and Assessment of its Utility by CD34 Staining in Invasive Breast Carcinoma.: Hwa Sook Jeong, Ro Hyun Sung; Korean J Pathol. 1997;31(4):298-307.

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Abstract PDF: Tumor angiogenesis, the development of new blood vessels by tumor, is a widely observed phenomenon associated with the growth of human solid tumors. To investigate how tumor angiogenesis correlates with other prognostic features i.e. menopause status, tumor size, lymph node metastasis, mitosis, angioinvasion, estrogen receptor (ER), p53 protein expression, histologic grade and clinical stage, we counted microvessels by immunohistochemistry using antibody for CD34 antigen in 56 cases of invasive breast carcinoma (27 with and 29 without axillary lymph node metastases) and 20 cases of non-inflammatory benign breast lesion. CD34 antigen is expressed on the surface of hematopoietic progenitor cells and more sensitively expressed than factor VIII in vascular endothelial cells. Microvessel count (MVC) was performed at a single hot field of 200x magnification (0.74 mm2 per field). The results are summarized as follows; 1) The mean MVC of invasive carcinoma and benign breast lesion were 92.0+/-54.4 (range, 7-237) and 20.7+/-16.6 (range, 4-73), respectively (p<0.0001). 2) Although MVC had no correlation with all other prognostic factors i.e. menopause status, tumor size, lymph node metastasis, mitosis count, angioinvasion, ER, p53 protein expression, histologic grade, and clinical stage (p>0.05), MVC had a tendency to increase in tumors with axillary LN metastasis or without ER expression. 3) Without correlation with MVC, ER (+), angioinvasion (-) and higher histologic grade correlate to significantly higher mitosis count (p<0.0005). Also, angioinvasion correlate to a significantly higher histologic grade (p<0.05). In conclusion, angiogenesis is related to tumorigenesis, but MVC may not be related to other clinicopathologic factors.

The Significance of the Expression of p53, E-cadherin, nm23, CD44, and Tumor Angiogenesis in Colorectal Adenocarcinoma.: Sung Suk Paeng, Hee Jin Chang, Jung Il Suh; Korean J Pathol. 1997;31(4):314-325.

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Abstract PDF: Many oncogenes and tumor supressor genes have been identified and studied in colorectal carcinoma. Among them, p53 is a tumor supressor gene and its mutation is frequently noted in human tumors. E-cadherin is a cell adhesion molecule and associated with tumor differentiation. CD44 is a cell surface glycoprotein that plays a role in cell migration and metastasis. nm23 is a gene known to lower metastatic potential of tumors and has been proposed to be a metastasis supressor gene. Tumor angiogenesis is required for the expansion of the primary tumor and metastasis and its degree is related to the potential of malignancy. We studied the expression of p53, E-cadherin, nm23, CD44 and tumor angiogenesis in 36 cases of colorectal adenocarcinomas. They were compared with previously known prognostic factors such as the stage, tumor size, depth of invasion, differentiation, presence of lymphatic or venous invasion, the lymph node and distant metastasis. The results were as follows. 1) The expression of p53 was not significantly associated with any prognostic factors. 2) The expression of E-cadherin was significantly associated with tumor differentiation. In the well differentiated adenocarcinomas, its expression was higher than in the poorly differentiated adenocarcinoma. 3) The expression of nm23 was also significantly associated with tumor differentiation. In carcinoma with lymph node metastasis, the expression of nm23 was reduced, but statistically it was not significant. 4) The expression of CD44 was higher in tumors with lymph node metastasis than in tumors without lymph node metastasis, but it was not statistically significant. 5) The degree of microvessel density was significantly associated with lymphatic invasion. According to the above results, the expression of E-cadherin and nm23 are related to the differentiation of the tumor and tumor angiogenesis is related to the lymphatic invasion of the colorectal adenocarcinoma.

Correlation of Tumor Angiogenesis and nm23-H1 Expression with Lymph Node Metastasis in Proper Muscle Gastric Cancer.: Eun Sook Nam, Gu Kang, Hyung Sik Shin, Young Eui Park; Korean J Pathol. 1997;31(5):410-416.

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Abstract PDF: We studied clinicopathologic features of 44 cases of PM (proper muscle) gastric cancer, correlated the lymph node metastasis and found the result of immunohistochemical staining for tumor angiogenesis using antibodies to Factor VIII-related antigen and nm23-H1, known as meatastasis inhibitory substance. The results were as follows: 1) The average age of these 44 cases of PM gastric cancer was 55.1 years old (range 35-81). The ratio of male to female was 2.2 : 1. The tumor was located at the antrum of stomach in 72.7% of the cases. The average size of the tumor was 4.1 cm (range 0.6-9). The gross features were comprised of Borrmann type I (6.8%), II (29.6%), III (56.8%), IV (6.8%), respectively. The microscopic type was a diffuse type in 70.5% and an intestinal type in 29.5%. There were lymph node metastasis in 25 of the 44 cases (56.8%). 2) The microvessel count was higher in the lymph node positive group (average 69.3) than in the lymph node negative group (average 45.6) (P=0.004). There was a higher microvessel density in diffuse type, over 4 cm of tumor size, proximally located tumor, older than 50 years, Borrmann type II and IV, but there was no statistically significant correlation. 3) The more decreased expression of nm23-H1 was found in the lymph node positive group (56.0%) than in the lymph node negative group (31.6%), but showed no statistical significance (P=0.0142). There was no significant correlation between the expression of nm23-H1 and the other clinicopathologic factors. We suggest that the microvessel count of the tumor angiogenesis may be a prognostic factor for predicting lymph node metastasis and also help to determine the therapeutic modalities of PM gastric cancer.

Correlation between Tumor Angiogenesis (Microvessel Density), Metastasis and Tumor Cell Proliferation in Colorectal Carcinomas.: Young Chae Chu, Joon Mee Kim; Korean J Pathol. 1997;31(6):517-526.

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Abstract PDF: Tumor angiogenesis has been shown to be associated with metastatic potentials in breast, lung and prostatic carcinomas. The relation between tumor angiogenesis and metastatic potentials in colorectal cancer has not been established to date. We analysed 66 selected patients with colorectal carcinomas (37 with and 29 without nodal metastases) for the microvessel density, tumor proliferation activity, and the clinicopathologic parameters including size, stage, histologic grade, growth pattern, presence of angioinvasion, perineural invasion and lymph node metastasis. For evaluation of microvessel density and tumor proliferative activity, the primary tumors were immunohistochemically stained for CD31 and PCNA. The mean microvessel counts (MVC) per 200X field were 99.27+/-23.28 and 131.35+/-31.48 in node-negative and node-positive patients, respectively. The PCNA index was 39.41+/-5.63% and 56.60+/-7.09% in node-negative and node-positive patients, respectively. MVC and PCNA index were higher in tumors with nodal metastasis (p=0.002, p<0.001), and also correlated each other (sr=0.33, p=0.007). Higher microvessel counts were seen in tumors with advanced stage (p=0.016). Tumor proliferation activity assessed by PCNA immunostaining was significantly higher in tumors with advanced stage, perineural invasion, angioinvasion, poor differentiation and larger size. From these results, MVC and PCNA index in colorectal carcinomas are assumed to be valuable prognostic parameters. Thus assessment of tumor angiogenesis and tumor cell proliferation in colorectal carcinomas may be helpful for the patients in need of aggressive therapy.

Correlation between Tumor Angiogenesis and Metastasis in Invasive Breast Carcinoma.: Nam Hoon Kim, Moon Hyang Park; Korean J Pathol. 1995;29(6):740-745.

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Abstract PDF: Tumor angiogenesis(TA) refers to the growth of new vessels toward and within a tumor. TA is necessary both at the beginning and at the end of the metastatic cascade of events. Recently, experimental evidence suggests that the growth of a tumor beyond a certain size requires angiogenesis. To investigate how tumor angiogenesis correlates with metastases in breast carcinoma, the microvessels were counted (per 200 / field) in the most active areas of neovas-cularization by two investigators. The microvessels within breast carcinoma were highlighted by in imunohistochemical staining for factor VIII-related antigen. Microvessel count(MVC) in node-positive carcinoma(59.66=35) was significantly higher than in node-negative carcinoma(44.76=17)(p=0.009). MVC was also statistically correlated with tumor size and stage, but not with histologic grading, DNA ploidy, or hormonal receptors(estro-gen and progesterone). MVC in invasive breast carcinoma may be one of many prognostic predictors of node-positive breast carcinoma. Assessment of tumor angiogenesis may therefore be valuable in selecting patients with early breast carcinoma for aggressive therapy.

Tumor Angiogenesis and Cathepsin-D Expression in Invasive Ductal Carcinoma of the Breast.: Young Gyung Bae, Dae Hong Suh, Dong Sug Kim, Soo Jung Lee; Korean J Pathol. 1997;31(8):735-744.

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Abstract PDF: This study was conducted to assess the prognostic value of tumor angiogenesis and Cathepsin-D in breast carcinoma, by correlating them with other clinicopathologic prognostic factors. In order to estimate microvessels within the tumor, an immunohistochemical method using monoclonal antibodies for factor VIII-related antigens (DAKO-vWf, F8/86) was used, and they were counted (perx200 field) in the most active areas of neovascularization. For the expression of Cathepsin-D, an immunohistochemical method using monoclonal antibodies (Novocastra, NCL-CDm) was performed. The microvessel count ranged from 8 to 346 per x200 field and the mean (+/-SD) was 72.46+/-54.96. The microvessel count was correlated with the estrogen receptor status, and it was also correlated with the tumor size when it was graded into four groups (1-33, 34-67, 68-100, >100), but was not correlated with other clinicopathologic parameters. Cathepsin-D was expressed in 40% (46/115) of the cases, but it was statistically correlated with the tumor size only. In conclusion, the expression of Cathepsin D and the degree of angiogenesis in breast cancer showed a correlation with the tumor size only. Therefore, they do not appear to be good prognostic parameters, according to the present study.

Sequential Ultrastructural Change of Chorionic Villi in Human Placenta by Gestational Period.: Tae Dong Park, Tae Jung Kwon, Je G Chi; Korean J Pathol. 1993;27(5):468-484.

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Abstract PDF: A study was performed to observe the sequential morphological change of the human placental barrier by means of light microscopy, immunohistochemistry, scanning electron microscopy and transmission electron microscopy. The examined placentas ranged in age from 4 weeks gestation to the full-term(40 weeks). Sixty seven placental specimens were obtained immediately after delivery. With the progression of gestation, the microvilli on the surface of syncytinum tended to be fewer, shorter and blunter. The syncytiotrophoblasts were getting thinner with formation of vasculo-syncytial membrane. The cytotrophoblasts formed a continuous layer which progressively disappeared but still present in the mature villi. In view of presence of intermediate cells and remnant of desmosomes, the cytotrophoblasts appeared to form the syncytiotrophoblasts. In early pregnancy, capillary formation took place by the aggregation and differentiation of the proliferation and aggregation of endothelial cells and pericytes. Myofibroblasts in villous stroma were examined by desmin immunohistochemical staining, and detected from 19 weeks to the full-term. During last period of pregancy definitive smooth muscle cells could be demonstrated, suggesting that the presence of myofibroblasts or smooth muscle cells are closely related to the placental maturity. Scanning electron microscopy of the early placenta showed numerous syncytial sprouts representing stages in the formation of new villi, but in the late period of gestation syncytial sprouts were diminished. It is concluded that the syncytiotrophoblast is originated from the cytotrophoblast in early pregnancy as the placental barrier is formulated. Moreover, myofibroblasts and smooth muscle cells in villous stroma play important role in placental maturation.

Tumor Angiogenesis and Stage in Ovarian Carcinoma.: Eun Sook Chang, Hyun Chang Joo, Tae Sung Lee; Korean J Pathol. 1999;33(8):596-602.

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Abstract PDF: Tumor angiogenesis has been found to have prognostic significance in many tumor types for predicting an increased risk of metastasis. We assessed tumor vascularity in 28 cases of borderline malignancy and 71 cases of carcinoma of the ovary which had been resected and diagnosed, using the highly specific endothelial cell marker CD34. The numbers of microvessels were counted in 200 magnification in three highly vascularised areas. The numbers of microvessels in carcinomas were higher than that in the borderline malignancy of serous and mucinous tumors. The number of microvessels of mucinous carcinomas was significantly higher than that of serous carcinomas. There were neither significant differences in the number of microvessels according to histological tumor types (p=0.075) nor significant differences in the number of microvessels according to FIGO stages (p=0.072). But in serous carcinomas, the number of microvessels was higher in the FIGO III-IV stage than in the FIGO I-II stage (p=0.017). This study showed higher neovascularization in malignant tumor than borderline malignancy, and in the advanced stage (FIGO III-IV) than less advanced stage (FIGO I-II) of serous carcinomas.

The Effect of Tamoxifen and Pentosan Polysulfate on the Microvessel Density and Cell Proliferation of Dimethylbenzanthracene-Induced Rat Mammary Carcinoma.: Chan Heun Park, Zhe Piao, Kwang Gil Lee; Korean J Pathol. 1996;30(2):94-105.

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Abstract PDF: Antiestrogen tamoxifen (TMX) is thought to elicit its therapeutic effect by competing with endogenous estrogens for the estrogen receptor. Several more recent studies asserted that the antitumor effect of TMX is not due solely to the inhibition of estrogen receptor-mediated action, but due partly to its capacity to inhibit angiogenesis and impair neovascularization. Despite extensive research and clinical experience with this drug, its exact mode of action in inducing tumor regression is still not clear. The present study is aimed toward the investigation of the effects of TMX on dimethylbenzanthracene- induced rat mammary carcinomas with respect to the tumor response to the drugs, histological changes, cell proliferative acitivity and angiogenesis inhibition, and if TMX has antiangiogenic action, to compare it with that of pentosan polysulfate (PPS), an already known antiangiogenic substance. Female Sprague-Dawley rats, aged 50 days, were divided into normal control, test control (tumor induction by dimethylbenzanthracene), TMX (TMX administration after tumor induction), and PPS (PPS administration after tumor induction) groups. Tumor response to the drug administration was classified according to changes of tumor volume as follows; complete response (CR), partial response (PR), no response (NR), and progressive disease (PD). The response rate of rat mammary carcinomas to the drug administration was significantly higher (p<0.05) in the TMX and PPS groups as compared with the test control group. There was, however, no statistical significance between the TMX and PPS groups. Necrosis was considerably frequent in tumors of the TMX and PPS groups. Hyaline change of the stroma was strikingly more common and marked in the TMX group and it was associated with atrophy of epithelial cells of the tumor glands. Proliferating cell nuclear antigen (PCNA)- labeling index of the tumors was significantly higher (p<0.05) in the tumors with NR and PD of the TMX group when compared with those with PR of the same group, which suggested a higher cell proliferative activity in these response groups. In the PPS group, however, there was no significant difference in PCNA index according to response. Microvessel density of the tumors was significantly lower (p<0.05) in the PPS group as compared with the test control and TMX groups and it was not related with response. The TMX group, however, did not show any significant difference in microvessel density when compared with the test control group. Microvessel density was significantly higher (p<0.05) in tumors with PD than those with PR in all 3 groups, which suggested a positive relation of increase in tumor size and angiogenesis. Based on these results it is thought that TMX and PPS inhibit growth of chemically-induced rat mammary carcinomas. It seems that the antitumor action of PPS is related with its antiangiogenic capability, but that of TMX does not have a relationship with angiogenenesis inhibition.

Role of Angiogenesis and Expression of Vascular Endothelial Growth Factor in Mouse Skin Carcinogenesis .: Aeree Kim, Byoung Kook Kim, Hosu Chun, Ju Han Lee, Jong Sang Choi; Korean J Pathol. 2002;36(2):106-111.

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Abstract PDF: BACKGROUND
Angiogenesis is crucial for many biological processes such as embryogenesis, cyclic changes in the endometrium and wound healing. It is also critical for the growth, invasion and metastasis of solid tumors. Vascular endothelial growth factor (VEGF) acts as a mitogen for endothelial cells and is expressed by the presence of various tumor cells. The objective of this study is to evaluate if angiogenesis is involved in the mouse skin carcinogenesis and if VEGF is related to angiogenesis.
METHODS
We induced premalignant and malignant lesions on mouse (BALB/c) skin using the two stage chemical carcinogenesis moedl, DMBA (7,12-dimethylbenzanthracene) initiation and TPA (tetra decanoyl-phorbol-acetate) promotion. And we analysed the microvessel densities (MVD) and expression of VEGF in various stages of premalignant and malignant lesions by immunohistochemical studies.
RESULTS
Squamous papillomas, keratoacanthoma, dermatofibroma, and squamous cell carcinomas were developed in 20 weeks. There were no differences in the incidence of benign and malignant tumors between 10-week and 20-week promotion groups. There were significant increases in MVD from normal and hyperplastic skin through premalignant lesion to invasive squamous cell carcinoma (p<0.0005). But the degree of VEGF expression neither correlated with neither MVD nor the tumor groups.
CONCLUSIONS
Increased angiogenesis begins from the hyperplastic stage. VEGF produced by tumor cells may not play major roles in the angiogenesis in the two stage chemical carcinogenesis model of the mouse skin.

Thrombospondin-1 and -2 Expressions in Hepatocellular Carcinomas: an Association with Tumor Angiogenesis and p53 Overexpression.: Jae Sin Chung, Ho Sung Park, Hyun Jin Son, Myoung Jae Kang, Woo Sung Moon; Korean J Pathol. 2005;39(4):215-221.

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Abstract PDF: Background
: It has been suggested that thrombospondin (TSP) is a p53-dependent negative regulator of tumor angiogenesis. TSP expression and localization in hepatocellular carcinomas (HCCs) and its association with overexpression of p53 protein were investigated. Methods : TSP-1 and -2 expressions were examined in 40 HCC specimens by immunohistochemical staining and in 4 HCC cell lines by Western blotting. In addition, p53 protein expression and microvessel density (MVD) were correlated with the TSP expression. Results : Strong immu- nopositivity for TSP-1 was observed in fibroblasts, vascular endothelial cells, and some vas- cular smooth muscle cells of the stroma in 18 cases (45%), and in tumor cells in 3 cases (7.5%) of 40 cases of HCC. Immunoreactivity for TSP-2 was observed in only the sinusoidal lining cells of the tumor in 15 cases (46%), and in tumor cells in 2 cases (6%) of 32 cases of HCC. TSP-1 expression was inversely correlated with MVD (p=0.028), but TSP-2 expression did not show any correlation with MVD. Although p53 was overexpressed in 17 cases, there was no significant correlation between TSP and p53 expressions. None of the HCC cell lines expressed TSP-1 or -2. Conclusions : These findings indicate that TSP-1 is mainly derived from nonparenchymal cells, and may decrease tumor angiogenesis in HCC.

Tumor Angiogenesis in Renal Cell Carcinoma.: Ji Shin Lee, Jong Jae Jung, Chang Soo Park; Korean J Pathol. 1999;33(11):1055-1060.

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Abstract PDF: Angiogenesis is essential for the growth of solid tumors. Microvessel counts, which represent a measure of tumor angiogenesis, have been correlated with the overall survival of patients with a variety of malignancies. However, the significance of angiogenesis in renal cell carcinoma remains controversial. To determine whether angiogenesis correlates with prognosis of patients with renal cell carcinoma, we counted the microvessels within the primary tumors and compared their numbers with patients' prognosis. Tumor specimens from 42 patients were investigated. Microvessels were stained with anti-CD34 and anti-factor VIII-related antigen monoclonal antibodies. Significant correlation between microvessel counts for two antibodies was observed (r=0.875, p<0.01), although microvessel counts for CD34 were approximately two times higher. Microvessel counts were higher in clear cell than in non-clear cell carcinoma (p<0.05). These results suggest that immunostaining with anti-CD34 antibody may provide a more sensitive and accurate measure of tumor angiogenesis. There was no correlation between microvessel counts and nuclear grade, or TNM stage. In univariate analyses, nuclear grade and TNM stage were significantly associated with patient survival (p<0.01). But further studies on tumor angiogenesis of renal cell carcinoma are needed before it can be adopted as a prognostic marker.

The Expression of Matrix Metalloproteinase-9 and Tumor Angiogenesis in Human Osteosarcoma.: Jinyoung Yoo, Ji Han Jung, Hyun Joo Choi, Seok Jin Kang, Anhi Lee, Eun Joo Seo, Sang In Shim, Chang Suk Kang; Korean J Pathol. 2005;39(6):418-423.

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Abstract PDF: BACKGROUND
Matrix metalloproteinase-9 (MMP-9) is a matrix-degrading enzyme that's believed to play a crucial role not only for tumor invasion and metastasis, but also for a variety of stromal reactions, including neovascularization. The aim of this study was to investigate the expression of MMP-9 and to compare its expression with the angiogenesis activity in human osteosarcoma.
METHODS
Archival tumor tissue samples from 20 patients with osteosarcoma were analyzed by performing immunohistochemistry for the expression of MMP-9 and CD34. The vascularity was measured as the average microvascular density (MVD) of the CD34-positive vessels. The clinical information was obtained through searching the computerized retrospective database from the tumor registry.
RESULTS
MMP-9 was expressed in 90% (18/20) of the tumors we examined. The MVD ranged from 10.5 to 179.7 with a mean of 64.9. There was no significant correlation between the MMP-9 expression and the MVD (p=.613). The MMP-9 expression was not associated with any of the clinicopathologic variables, whereas the MVD showed an increasing tendency according to the metastasis status (p=.073).
CONCLUSIONS
We demonstrated that MMP-9 activation is likely to occur in human osteosarcoma. However, there was no direct involvement of MMP-9 with tumor angiogenesis. It is noteworthy that MVD may aid physicians to predict the presence of distant metastasis in osteosarcoma patients.

Expression of Nitric Oxide Synthase Isotypes in Advanced Gastric Carcinoma.: Kyong Mee Kwon, Young Chae Chu, Tae Sook Hwang; Korean J Pathol. 2002;36(6):374-371.

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Abstract PDF: BACKGROUND
Increased expression of nitric oxide synthase (NOS) isotypes is present in human tumor cell lines and solid tumor tissues. Hypoxia upregulates NOS expression, and nitric oxide (NO) induces mitogenesis among endothelial cells. NO has been known to induce vascular endothelial growth factor (VEGF) expression in carcinoma cells and to induce neovascularization in tumors.
METHODS
The expression and cellular localization of 3 isotypes of NOS was detected by immunohistochemistry in 73 advanced gastric carcinoma tissues along with adjacent normal gastric mucosa; and the relationship to known clinicopathologic parameters, microvascular density, and VEGF expression was analysed.
RESULTS
Forty-four (60.3%), 56 (76.7%), and 52 (71.2%) of the 73 cases revealed eNOS, nNOS, and iNOS expression, respectively. Intestinal type adenocarcinomas tended to have higher activity of eNOS (p=0.000) and nNOS (p=0.001) activities than did the diffuse type adenocarcinomas. All isotypes of NOS (eNOS, p=0.001; nNOS, p=0.005; iNOS, p=0.044) tended to be highly expressed when the tumor was differentiated. There was no significant relationship between any of the 3 NOS isotypes and microvascular density, whereas VEGF was closely related with microvascular density (p=0.000). The expression of VEGF was not related to with any of the NOS isotype expressions.
CONCLUSIONS
From the above results, we speculated that NO may be implicated in the early stage of the gastric carcinogenesis rather than the growth and progression stages, and NO does not appear to affect angiogenesis or VEGF expression in the advanced gastric carcinoma.

Immunohistochemical Analysis of TGF-beta Expression and Angiogenesis in Infiltrating Duct Carcinoma of the Breast.: Tae Jin Lee, Nam Bok Cho, Eun Sub Park, Jae Hyung Yoo, Sung Jun Park; Korean J Pathol. 1996;30(7):557-569.

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Abstract PDF: Forty cases of infiltrating duct carcinoma of the breast were examined immunohistochemically for expression of TGF-beta and angiogenesis in order to analyze significant correlation with prognostic parameters including tumor size, axillary lymph node metastasis, clinical stage, histologic grade, estrogen receptor and progesterone receptor status. The TGF-beta expression was observed in tumors center and advancing edges of tumors. To determine microvessel density for angiogenesis, we stained endothelial cells for Factor VIII related antigen and counted microvessel within tumor. The results were as follows: 1) The strong immunohistochemical expression of TGF-beta and higher counts of microvessels were observed in advancing edges of tumors (p<0.05). 2) The TGF-beta expression in the advancing edges of tumors was closely related to clinical stage and presence of axillary lymph node metastasis (p<0.05). 3) The mean microvessel counts were significantly higher in tumors from patients with axillary lymph node metastasis and increased with increasing clinical stage (p<0.05). 4) The TGF-beta expression was not related to histologic grade, estrogen receptor and progesterone receptor status(p>0.05). Therefore, the results suggested that the TGF-beta expression and angiogenesis in infiltrating duct carcinoma of the breast may play an important part in prognostic factors, closely related to the lymph node metastasis and clinical stage.

A Study of Correlation between Stage and Angiogenesis f Uterine Cervical Squamous Cell Carcinoma.: Eung Seok Lee, In Sun Kim; Korean J Pathol. 1998;32(4):283-289.

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Abstract PDF: A variety of malignant neoplasms have been shown to induce neovascularization, and in some cases the degree of vascularization appears to correlate with an aggressive behavior and risk of metastasis. We compared the degree of vascularization in 11 benign and 33 cancerous lesions of the cervix. The microvessels were identified by immunohistochemistry using antibody to Factor VIII-related antigen in 44 hystrectomy specimens. Three highly vascularized microscopic fields were selected and counted the number of microvessels in 400 magnification. The proportion of the endothelial cell area was also quantified by using the CAS 200 image analysis system. All 33 cases of carcinomas demonstrated a significantly higher microvessel count and an endothelial cell area than those of the benign lesions (p<0.01). There were no significant difference in microvessel count and endothelial cell area among carcinoma in situ, microinvasive carcinoma and invasive carcinoma (p>0.05). Microvessel count and an endothelial cell area in invasive cancers were not correlated with tumor size, depth of invasion, or histologic type (p>0.05).This study showed cervical cancer induces neovascularization in an early stage but it is difficult to predict prognosis and metastasis with microvessel count and an endothelial cell area.

VEGF Expression and Microvessel Density in Oral Squamous Cell Carcinomas.: Ji Jun Lim, Sam Pyo Hong, Jae Il Lee, Seong Doo Hong, Chang Yun Lim; Korean J Pathol. 2000;34(3):190-198.

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Abstract PDF: Angiogenesis is an essential process in tumor growth and metastasis. VEGF has been considered a leading candidate inducing tumor angiogenesis. VEGF expression was significantly correlated with clinical stage, lymph node matastasis, and prognosis of cancers of various parts of body. However, little has been known about the correlation between VEGF expression and clinicopathologic parameters in oral squamous cell carcinoma. The aim of this study was to correlate VEGF expression with the clinicopathological parameters and microvessel density. Forty six oral squamous cell carcinomas were analyzed using immunohistochemical method with primary antibodies to VEGF and CD31. VEGF expression was detected in 33 (71.7%) of the 46 cases. The microvessel density was significantly correlated with VEGF expression (P=0.002). There was no correlation between microvessel density and tumour size, clinical stage, and lymph node metastasis, respectively. VEGF expression did not correlate with the histological grade of tumour differentiation, tumour size, and clinical stages. The VEGF-positive rate seemed to be higher in patients with cervical lymph nodal metastasis than in those without it, but it was not statistically significant. In conclusion, the overexpression of VEGF in the oral squamous cell carcinoma seemed to be associated with a more aggressive course of the disease. Further study is necessary to define the role of VEGF in oral squamous cell carcinoma.

A Study on the Tumor Angiogenesis and Expression of Cytokine and Growth Factors in the Prostatic Carcinoma.: Sung Chul Lim, Ho Jong Jeon; Korean J Pathol. 1996;30(8):671-679.

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Abstract PDF: There is considerable experimental evidence to indicate that tumor growth is dependent on angiogenesis. However, we do not understand how the angiogenic activity is initiated by a given tumor. There is a clear distinction between a stage without neovascularization, which correlates with a paucity of metastases, and a stage in which increasing neovascularization correlates with a rising rate of metastasis. The authors therefore asked whether the extent of angiogenesis in human prostatic carcinoma is correlated with the tumor grades or some growth factors. To investigate how tumor angiogenesis correlates with tumor aggressiveness, the authors counted microvessels within the various grades of invasive prostatic carcinomas of 44 patients and the nodular hyperplasias of 10 patients. Highlighting of the vessels by immunohistochemical staining for factor VIII-related antigen and assessment of the tumor aggressiveness by the degree of expression of some growth factors(transforming growth factor-alpha, and beta, epidermal growth factor), tumor necrosis factor-alpha and tumor grading(Gleason's score) were done. As a result, both microvessel counts and the expression of growth factors and tumor necrosis factor correlated with tumor grades. In conclusion, the number of microvessels per 200 X fields in the areas of most intense neovascularization in a prostatic carcinoma may be a predictor of the patient's prognosis. Therefore, assessment of tumor angiogenesis may prove valuable in selecting patients with prostatic carcinoma, especially small needle biopsy, for aggressive therapy.

Tumor Angiogenesis and Vascular Endothelial Growth Factor Expression in Cervical Intraepithelial Neoplasia.: Hye Jean Park, Hye Jin Park, Hye Sung Moon, Woon Sup Han, Sun Hee Sung; Korean J Pathol. 2000;34(7):524-530.

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Abstract PDF: Angiogenesis is an essential requirement for development, progression, and metastasis of malignant tumors. Vascular endothelial growth factor (VEGF) is one of the important angiogenic factors. Recently the role of angiogenesis has been known in premalignant lesions. This study was performed to determine whether the angiogenesis and VEGF expression were increased in association with histological grade of cervical intraepithelial neoplasia (CIN) and to see the relationship between the angiogenesis and VEGF. Immunostainings for factor VIII and VEGF were performed on 52 cases of cervical neoplasia (12 cases of CIN I, 11 cases of CIN II, 15 cases of CIN III, 7 cases of microinvasive squamous cell carcinoma, and 7 cases of invasive carcinoma) and 5 cases of normal cervix. The results showed a significant increase of microvessel count from normal cervix through CIN grades to invasive squamous cell cacinoma. VEGF expression was increased in proportion to the CIN grades. There was no significant correlation between microvessel count and VEGF expression. In conclusion, the tumor angiogenesis is an early event in tumorigenesis of uterine cervix. In addition, no significant relationship between the microvessel count and VEGF expression in CIN suggests the possibility of other growth factors affecting mainly angiogenesis of premalignant lesion of uterine cervix.

Expression of Transforming Growth Factor-beta1 and Its Effects on the Extracellular Matrix Formation and Angiogenesis in Gastric Carcinoma.: Young Hee Choi, Young Euy Park; Korean J Pathol. 1998;32(9):647-654.

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Abstract: Malignant cells in culture express elevated levels of transforming growth factor-beta1 (TGF-beta1) mRNA and secrete an abundant amount of the TGF-beta1 protein. An attempt was made to define the role of the TGF-beta1 secreted from tumor cells, as a possible humoral factor which functions in a paracrine manner to stimulate the production of collagen and angiogenesis in gastric carcinoma. The expression of the TGF-beta1 by immunohistochemical stain (n=70) in gastric adenocarcinoma tissues was studied. Angiogenesis was evaluated by immunohistochemical staining of tumor vessels, using polyclonal antibody to factor VIII related antigen and counting the three most active areas of neovascularization. The extracellular matrix was counted as area density by using an image analyzer following Masson-Trichrome staining. The prominent reactivity for TGF-beta1 was associated with invasion depth (r=0.2, p<0.05), increased number of microvessel (r=0.49, p<0.05) and increased area density of extracellular matrix (r=0.36, p<0.05), respectively. In summary, TGF-beta1 may have a role in tumor invasion and metastasis by increased angiogenesis and deposits of extracellular matrix.

The prognostic significance of tumor angiogenesis, proliferating cell nuclear antigen(PCNA), and the Ki-67 index in carcinoma of the uterine cervix.: Chan Pil Park, Seung Yon Lee, Moon Hyang Park; Korean J Pathol. 1997;31(1):1-14.

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Abstract PDF: Angiogenesis, the induction of new capillaries and venules, is associated with tumor growth. This study was designed to determine whether cervical carcinomas are angiogenic, and to investigate whether tumor angiogenesis can serve as a prognostic factor in cervical carcinoma. Surgical specimens of 47 cervical carcinomas were immunohistochemically stained specifically for endothelial cells with factor VIII-related antigen to identify all vessels. Microvessels were counted from photographs of 200x microscopic fields. In addition, thirty-seven cases were studied by immunohistochemical means using the monoclonal antibodies for PCNA and for Ki-67 to determine tumor cell proliferation rates in cervical carcinomas. The microvessel count(MVC), the PCNA labelling index, and the Ki-67 index were calculated and compared with known prognostic factors and disease free survival rates in cervical carcinomas. A wide range in the MVC count(range 12-100 mean=38.2+/-19.2), the PCNA labeling index(8-69% mean=33.6+/-15.2%), and in the extent of Ki-67 staining(0-43% mean=10.3+/-10.5%) was observed, indicating considerable variation of tumor angiogenic activity and tumor growth rates. This study showed statistically significant correlations in disease free survival rates with both lymph node status and the microvessel count. However, there was no significant difference in disease free survival rates between tumor stage, age, the PCNA labelling index, and the Ki-67 index.

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