Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of aromatase by breast cancer cells and the role of locally produced estrogen in the stimulation of tumor growth has been controversial. The present study was performed to determine the site of aromatization in human breast cancers, using both immunocytochemistry and in situ hybridization. The functional significance of locally produced estrogens on growth of the tumor was addressed by measuring aromatase activity and a marker of proliferation (PCNA score). In addition, histocultures of some tumors were carried out to investigate whether testosterone aromatization could stimulate tumor proliferation. Of the 19 tumors investigated, 10 (52.6%) showed significant immunoreactivity to antiaromatase antibody in the cytoplasm of tumor epithelial cells and in surrounding stromal cells. The presence of aromatase mRNA detected by ISH was also located in tumor epithelial cells and stromal cell, and the pattern of expression was the same as with immunocytochemistry. In the ten tumors that showed immunoreaction to aromatase, the average aromatase activity measured in cryosections was 286.5 +/- 18.6 (SE) fmol estrogen/mg protein.h, whereas in nine tumors with weak aromatase immunoreaction, the enzyme activity was 154.7 +/- 19.3 (SE) fmol estrogen/mg protein-h (P < 0.05). The mean PCNA score was 33.8 +/- 5.1 (SE)% in strongly stained tumors and 20.8 +/- 2.0 (SE)% in weakly stained tumors (P < 0.05). Aromatase activity level and PCNA score were significantly correlated. In histoculture of four tumors, estradiol increased the incorporation of [3H]-thymidine into DNA. In two of these tumors, aromatase activity was high and [3H]-thymidine incorporation into DNA was also stimulated by testosterone. In the other two tumors that had low aromatase activity, no such stimulation occurred with testosterone. The results indicate that aromatase is expressed mainly in tumor epithelial cells and that sufficient amounts of estrogen are synthesized by the tumor to produce a proliferative response. It is concluded that estrogen synthesis by cancer cells could play a important role in promoting growth in a significant proportion of breast tumors.
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PMID:Expression of aromatase protein and messenger ribonucleic acid in tumor epithelial cells and evidence of functional significance of locally produced estrogen in human breast cancers. 877 Sep 32

The immunohistochemical expression of proliferating cell nuclear antigen (PCNA) and p53 was investigated in 9 cases of epithelial dysplasia and 38 cases of squamous cell carcinoma of the oral cavity. The intensity of immunoreactivity for each marker was assessed using a semiquantitative grading system, and was correlated with tumor differentiation, nuclear atypia and the patterns of invasive margins in the underlying connective tissue. PCNA expression, in dysplastic epithelium, was observed in the suprabasal and lower spinous layers; and the labeling grade and intensity of staining increased along with the degree of cellular atypia. In 2 cases of dysplasia, weak positive immunoreactivity for p53 could be seen in a few isolated cells of the basal layer. In squamous cell carcinoma, PCNA expression was correlated with the degree of tumor differentiation and nuclear atypia in well and moderately differentiated carcinoma, but not with the invasive pattern of tumor growth. Immunoreactivity for p53 was positive in 30 cases and showed a distribution pattern very similar to PCNA but with fewer positive cells. Three distinct categories of expression for PCNA and p53 were observed, among them a combination of intense reactivity for both markers was indicative of poor differentiation, higher nuclear atypia and more invasive growth of tumor cells.
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PMID:Proliferating cell nuclear antigen (PCNA) and p53 in epithelial dysplasia and squamous cell carcinoma of oral mucosa--a marker for poor tumor differentiation, increasing nuclear atypia and invasiveness? 892 Jul 67

Progression through the cell cycle is regulated by cyclins and cyclin-dependent kinases (Cdks). The cyclin kinase inhibitor p21 (also known as WAF1, CIP1, SDI1, and MDA-6) can induce G1 arrest and block entry into S phase by inactivating Cdks or by inhibiting activity of proliferating cell nuclear antigen (PCNA). In normal cells, p21 exists in quaternary complexes with cyclin, Cdk, and PCNA. Transcription of the p21 gene is activated by p53-dependent and -independent mechanisms. Mice deficient in p21 exhibit no apparent phenotype, although p21 function has been demonstrated to be necessary for p53-mediated G1 arrest following irradiation of p21-deficient mouse embryonic fibroblasts. Thus, the function of p21 under normal circumstances appears to be redundant. p21 is expressed in terminally differentiating cells of a variety of tissues in a p53-independent manner. Overexpression of p21 results in G1 arrest and has been shown to suppress effectively tumor growth in vitro and in vivo. We review the recent literature describing the functional characterization of p21. This protein plays a key role in regulating the cell cycle and may have potential gene therapy applications.
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PMID:p21--negative regulator of the cell cycle. 893 60

Scatter factor (SF) (also known as hepatocyte growth factor) is a plasminogen-related growth factor that induces tumor cell motility, invasion, and angiogenesis. Its receptor is a tyrosine kinase encoded by c-met, a protooncogene. Human breast cancer cells express SF and c-met in vivo; but human breast cancer cell lines do not produce SF in vitro. To determine whether SF can modulate the in vivo growth of human breast cancers within a natural mammary environment, we studied the orthotopic growth of SF-transfected (SF+) versus control (SF-) clones of MDAMB231 human mammary carcinoma cells in the mammary fat pads of athymic nude mice. SF+ clones expressed SF mRNA and produced very high titers of SF protein, whereas SF- clones did not express SF mRNA or produce detectable SF protein. Two SF+ clones (21 and 29) showed significantly increased tumor growth rates, reaching 3- to 4-fold larger primary tumor volumes and weights by time of killing (p < 0.001), as well as higher rates of axillary lymph node metastasis (p < 0.02), as compared with two SF- clones (32 and 34). In contrast, in vitro proliferation rates, two-dimensional colony formation, and soft agar colony formation were no greater in SF+ than in SF- clones. We performed further studies to investigate the discrepancy between the in vivo and in vitro growth results. Tumor extracts from SF+ clone (21 + 29) tumors had 50-fold higher SF content than did SF- clone (32 + 34) tumors, confirming high-level SF expression in vivo in SF+ tumors. Immunostaining of tumor sections for proliferating cell nuclear antigen revealed only a modest increase in the proportion of cycling cells in SF+ versus SF- tumors (70% versus 60%, respectively). The terminal deoxytransferase-labeling index was equally low (approximately 1%) in SF+ and SF- tumors, suggesting that apoptosis was not responsible for the slower growth of SF- tumors. However, SF+ tumors had significantly higher tumor microvessel densities than SF- tumors (p < 0.001). Moreover, there were much higher titers of chemotactic activity for microvascular endothelial cells in cell-conditioned media and primary tumor extracts from SF+ clones as compared with SF- clones. As demonstrated using the rat cornea assay, there was more angiogenic activity in SF+ tumor extracts than in SF- extracts. The increased chemotactic and angiogenic activities in SF+ tumor extracts were not explained by secondary alterations in the content of the angiogenic mediator, vascular endothelial growth factor, or the antiangiogenic glycoprotein, thrombospondin-1; and those activities were neutralized using an anti-SF monoclonal antibody. These findings suggest that SF promotes the orthotopic growth of human breast cancers, at least in part, by stimulating tumor angiogenesis.
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PMID:Scatter factor stimulates tumor growth and tumor angiogenesis in human breast cancers in the mammary fat pads of nude mice. 912 Nov 17

Adenoid cystic carcinoma (ACC) is a salivary malignant tumor with poor long-term prognosis, that is known to have predilection for invasion of the adjacent stroma and neural tissues. This carcinoma has shown a high incidence of recurrence and distal metastasis. Invasive carcinomas have been associated with the distributions of extracellular matrices (ECM). Cell proliferation as a marker of tumor growth has been related to poor prognosis in oral carcinomas. Immunohistochemical analysis of 15 cases of ACC was done using antibodies to laminin, type IV collagen, fibronectin, tenascin and anti-proliferating nuclear antigen (PCNA). Laminin and type IV collagen were totally or partially absent in the ACC invasive areas. Tenascin was expressed in the stroma and cytoplasm and was associated with tumor cell proliferation. It can be concluded that basement membrane represents a barrier that is lost during cell invasion and tenascin may be involved in the detachment of cancer cells, increasing the invasive potential of ACC.
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PMID:Extracellular matrices expression in invasion area of adenoid cystic carcinoma of salivary glands. 917 51

In this study we investigated the immunohistochemical expression of the p53 protein in 44 ductal pancreatic adenocarcinomas and its relation to cell proliferation, apoptosis and necrosis, three factors affecting tumor growth. The results were evaluated against survival and other clinical parameters of the patients. p53-positivity was found in 18/44 (41%) of the tumors. A positive p53 status was significantly associated with a high extent of necrosis (> or = 10% of tumor tissue)(p = 0.04, Fisher's exact test), with a high immunohistochemical expression of PCNA (p = 0.04, Fisher's exact test) and with a high mitotic count (p = 0.05, two-tailed t test). No statistically significant association was found between p53-positivity and high or low extent of apoptosis as evaluated by in situ labeling of the 3'-ends of the DNA fragments (p = 0.34, Fisher's exact test). Patient survival was not associated with the p53 expression of the tumors or separately with tumor cell proliferation, apoptosis or necrosis. The results suggest that an altered p53 function, as reflected by p53 overexpression, affects tumor growth by promoting cell proliferation and necrosis, but does not show a significant association with the extent of apoptosis in operated pancreatic adenocarcinoma.
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PMID:Association between p53 overexpression, cell proliferation, tumor necrosis and extent of apoptosis in operated pancreatic adenocarcinoma. 936 91

Tyr-Phe and Met limitation in vitro inhibited cell proliferation and proliferating cell nuclear antigen (PCNA) expression to a greater extent than serum limitation. Tyr-Phe and serum limitation arrested cells in the G0/G1 phase; Met limitation blocked cells in the G0/G1 and S phases. Tyr-Phe limitation progressively decreased cyclin D1 expression to 30% of control within four days and did not affect expression of cyclin D3 or cyclin-dependent kinase (CDK2, CDK4, and CDK5) expression, Met limitation decreased cyclin D3 expression to 25% of control and CDK2 expression to 32% of control by Day 4 and did not affect expression of cyclin D1, CDK4, and CDK5. Serum limitation inhibited cyclin D1 and cyclin D3 expression to 24% of control after four days and did not effect CDK expression. Expression of two CDK inhibitors, p21WAF1/Cip1 and p27Kip1, was not changed by amino acid or serum limitation. Dietary restriction of Tyr-Phe in mice bearing subcutaneous B16BL6 melanoma tumors decreased tumor growth rate compared with mice fed a normal diet. Tumors from Tyr-Phe-restricted mice exhibited decreased PCNA expression, G0/G1 phase cell cycle arrest, and reduced cyclin D1 expression. These data indicate that decreased tumor growth in vivo associated with dietary restriction of Tyr and Phe is cell cycle specific.
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PMID:Tyrosine and phenylalanine restriction induces G0/G1 cell cycle arrest in murine melanoma in vitro and in vivo. 942 72

Immunohistochemistry (IHC) has provided major insights about the classification of brain tumors by identifying cellular markers of phenotype and about tumor growth potential with nuclear markers of proliferation. In situ hybridization (ISH) research shows promise for diagnostic applications in tumor classification. The avidin-biotin conjugate IHC procedure is highlighted for diagnostic use on routinely processed clinical specimens. The immunophenotypes of brain tumors are tabulated in reference to their common IHC markers. Tumors that have been correctly classified by their IHC phenotypes include the giant-cell glioblastoma, primary brain lymphoma, and central neurocytoma. Phenotypes that may be more definitively detected by ISH, such as pituitary hormone, immunoglobulin light chain, and collagen messages are described. IHC of nuclear proliferation markers correlates with grade of malignancy, predicts tumor growth potential, and is prognostic for patient survival. The incorporation of bromodeoxyuridine, the expression of proliferating cell nuclear antigen, and the expression of Ki-67 antigen detected by MIB-1 antibody are compared in regard to their cell cycle activity and labeling index determinations. Fluorescence in situ hybridization (FISH) of brain tumor interphase nuclei and chromosomes is described. Abnormal FISH signals of specific chromosomes are associated with different types of brain tumors, with different grades of malignancy, and with mesenchymal drift of glioma cells in culture.
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PMID:Insights about brain tumors gained through immunohistochemistry and in situ hybridization of nuclear and phenotypic markers. 960 6

The plasma levels of free estradiol are very low in postmenopausal women. However, concentrations of estrogens within breast tissue have been reported to be higher than in plasma and similar to plasma concentrations in premenopausal women. One mechanism by which this may occur is for breast cells to synthesize estrogens themselves and produce high concentrations locally. Thus, tumor aromatase may be a significant source of estrogen which stimulates tumor growth. To address the question of the importance of this pathway, we have investigated the expression of aromatase within the normal breast and breast cancers. Because conventional biochemical assays for measuring aromatase activity require relatively large amounts of tissue, we developed an immunocytochemical method using a monoclonal antibody to determine the expression of aromatase. The method can be applied to sections of tumors embedded in paraffin blocks as routinely prepared for pathology. Since we have previously shown that mRNA for aromatase (P450 arom) and the protein are expressed in the same cells of the human placenta, we used in situ hybridization of sequence specific probes to P450 arom mRNA in breast tissue as one method to verify the specificity of the immunocytochemical detection of the enzyme. Both immunocytochemistry and in situ hybridization identified aromatase enzyme and mRNA expression in the epithelial cells of the terminal ductal lobula units (TDLU) and surrounding stromal cells of the normal human breast, and in the tumor epithelial cells and stromal cells of breast cancers. In addition, evidence for the functional significance of tumor aromatase was indicated by a correlation between aromatase activity and expression of proliferating cell nuclear antigen (PCNA) in the tumor, and by increased thymidine incorporation into DNA in response to testosterone in tumors in histoculture which had high aromatase activity but not in those with low activity. The findings suggests that estrogen produced locally is important in enhancing proliferation of the tumor.
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PMID:Aromatase expression in the human breast. 979 22

It was retrospectively examined whether the tumor growth fraction determined by PCNA score in the advanced cancer of larynx could be used as a prognostic factor. There was used immunohistochemical method to evaluate the PCNA score of positive cells in paraffin embedded tissues of laryngeal carcinoma obtained from 90 patients. They were treated by surgery in the Department of Otolaryngology at the Medical University in Cracow, Poland in 1987 and 1988. The follow-up period was not shorter than 5 years. In the examined material there were 59 patients with tumor T3 and 31 with T4. Neck dissection on one or on both sides was performed on patients. The metastases in regional lymph nodes was found in 26 patients. Histologic grading (G1 = 18, G2 = 52 and G3 = 20 patients) and number of mitosis was assessed. The PCNA score was defined by counting positive cells and presented as percentage of a cells. It ranged from 2.1 to 73.0% with the average value of 34.5%. The PCNA score below this level was defined as a low PCNA score (49 patients) and above this level as a high PCNA score (41 patients). There was a correlation between PCNA score and survival of the patients. 35 patients (71.4%) with low PCNA score survived and 15 (36.6%) with high PCNA score (P < 0.05). Similarly the high PCNA score influenced the number of metastases in lymph nodes. They occurred in low and high PCNA score respectively at nine (18.4%) and 17 patients (41.5%) (P < 0.05). There was not found any correlation between PCNA score and tumor differentiation, its size and mitosis number. The PCNA may be a prognostic factor for the patients with advanced cancer of larynx.
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PMID:The prognostic value of proliferating cell nuclear antigen (PCNA) in the advanced cancer of larynx. 979 97


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