Journal of Pathology and Translational Medicine

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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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.

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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
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Polydeoxyribonucleotide Improves Peripheral Tissue Oxygenation and Accelerates Angiogenesis in Diabetic Foot Ulcers
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Archives of Plastic Surgery.2017; 44(06): 482. CrossRef

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.

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.

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 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.

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.

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.

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.

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.

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.

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