UMLS:C0178874 - FACTA Search

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Query: UMLS:C0178874 (tumor progression)
40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to find a prognostic marker for the course of disease in head and neck cancer we hypothesized that patients with rapid disease progress would produce increased levels of transforming growth factor alpha (TGF-alpha) and its cell surface receptor, epidermal growth factor receptor (EGFR). Using molecular biological techniques, we examined the incidence of TGF-alpha and EGFR overexpression in 43 patients with tumors of the head and neck. The expression data was correlated with the course of disease in a 4 year follow-up. The tumors were classified into four groups according to the EGFR status: Group 1, no expression for EGFR (15 samples); group 2, expression level 10 for EGFR (18 samples); group 3, expression level 50 for EGFR (7 samples) and group 4, expression level 100 for EGFR (3 samples). Expression for the TGF-alpha protein was only detected in group 4. There was a significant correlation with EGFR/TGF-alpha overexpression in group 4 and survival compared when with group 3 (p < 0.01) and group 1 (p < 0.05). The mean survival for group 1 to 4 was 27, 23, 34 and 10 months, respectively. The analysis of all patients revealed that the patients who expressed EGFR as well as TGF-alpha had the poorest prognosis. Increased production of TGF-alpha and EGFR in tumors of the head and neck may serve both as a marker for tumor progression and as a target for therapy (e.g. inhibition of the autocrine loop, blockage of TGF-alpha binding).
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PMID:Coexpression of epidermal growth factor receptor and TGF-alpha and survival in upper aerodigestive tract cancer. 861 22

The occurrence of different components of the cell growth regulation pathway as expressed in experimental skin carcinogenesis in haired carcinogen-sensitive NMRI, in haired carcinogen resistant DBA/2 mice and in hairless SKH/1 mice was studied by morphological and immunohistochemical methods. The results were compared with respect to neoplastic response, number of tumors, tumor behaviour and to the inducing agent (UV irradiation or chemical carcinogen), in order to increase our understanding of specific alterations in neoplastic development caused by extraneous agents and to determine their possible usefulness as indicators of carcinogen exposure. The expression of growth factors (transforming growth factor alpha and epidermal growth factor), growth factor receptors (epidermal growth factor receptor/c-erbB-1 and c-erbB-2/neu), cell signalling component c-myc, the nuclear transcription factor Harvey-Ras and the tumor suppressor gene p53, were studied in carcinogen- and UV-induced tumor formation in mouse. The results showed increased oncogene expression as well as growth factor expression in the skin during tumor development appearing early in neoplastic and premalignant conditions and becoming more distinct during neoplastic progression. Efforts to delineate specifically initiated cells prior to the appearance of morphologically detectable alterations including dysplasia, papilloma formation and squamous cell carcinomas, were unsuccessful. Increased staining by antibodies to growth factors and oncogenes were also observed in DBA/2 animals resistant to tumor formation. It is concluded that oncogene expression and growth factor protein deposits are associated with carcinogenic effects, partly explaining the mechanism of action of these agents, but the applicability, as such, for the analysis of potential hazardous agents needs further studies.
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PMID:Oncogenes and growth factors as indicators of carcinogen exposure. 867 68

The expression of epidermal growth factor receptor (EGF-R), transforming growth factor alpha (TGFalpha), and epidermal growth factor (EGF) was evaluated in a series of prostate cancer (CaP; n = 55) and benign prostate hyperplasia (BPH; n = 44) specimens using immunocytochemistry (ICC) and Northern blotting. In situ hybridization (ISH), performed on a subgroup of these specimens, proved to be a more informative technique for the assessment of messenger RNA (mRNA) in this heterogeneous tissue. A comparative analysis was made in relation to the proliferative index, assessed using the MIB-1 antibody. Elevated levels of EGF-R and TGFalpha, mRNA, and protein were observed in carcinoma cells compared with benign, secretory epithelium using in situ hybridization and immunocytochemistry. In carcinoma specimens evidence of an autocrine growth loop is provided by a correlation between EGF-R and TGFalpha, mRNA (P < .0001), and protein expression (P < .01). A trend toward increased expression of EGF-R and TGFalpha protein with dedifferentiation and a similar trend in the growth fraction suggest a role in tumor progression. Although there was a correlation between EGF-R and the proliferative index (P < .01), no relationship was found between this latter parameter and TGFalpha immunoreactivity (P > .05), indicating that this growth factor may be linked with other aspects of malignant activity rather than directly stimulating proliferation.
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PMID:Comparative analysis of mRNA and protein expression for epidermal growth factor receptor and ligands relative to the proliferative index in human prostate tissue. 869 13

Overexpression of transforming growth factor alpha (TGF-alpha) and epidermal growth factor receptor (EGFR) occurs in Barrett's esophagus, particularly the specialized type, which is at an increased risk for malignant transformation. We performed this study to evaluate the immunohistochemical expression and prognostic significance of these growth factors, as well as MiB-1, the Ki-67 proliferation-associated nuclear antigen, in Barrett's-associated neoplasia. Monoclonal antibodies for TGF-alpha, EGFR, and MiB-1 were evaluated in 25 cases of Barrett's-associated adenocarcinoma (BAA) and in adjacent areas of Barrett's metaplasia and dysplasia. The data were correlated with the pathologic features (grade, stage, depth of invasion, lymph node metastasis) and the clinical outcome of the patients. Of the BAAs, 100% and 64% were positive for TGF-alpha and EGFR, respectively. TGF-alpha and EGFR expression did not correlate with any of the pathologic features of the tumors. By univariate analysis, a higher degree of EGFR immunostaining was significantly associated with poorer patient survival (P = 0.004). After stratified analysis, however, EGFR expression correlated with poor survival only in patients with pathologic Stage II cancer (P = 0.03). There was significant (P < 0.001) increase in the MiB-1 proliferation index (PI) associated with neoplastic progression: Barrett's metaplasia, 22.0% +/- 6.4; dysplasia, 56.5% +/- 21.6; and BAA, 70.0% +/- 17.7. In a separate comparison of the luminal (upper half) and basal (lower half) crypt MiB-1 PI, dysplastic epithelium revealed a significant increase in the luminal crypt MiB-1 PI in comparison with Barrett's metaplastic epithelium (50.7 +/- 24.6 versus 1.2 +/- 1.9, P < 0.001). EGFR expression might have prognostic value for patients with BAA, particularly those with Stage II cancer. The MiB-1 PI pattern supports the metaplasia-dysplasia-adenocarcinoma pathogenetic sequence in these tumors. Furthermore, the pattern of MiB-1 immunostaining might help to distinguish dysplastic from regenerative metaplastic epithelium of Barrett's esophagus in uncertain cases.
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PMID:Transforming growth factor-alpha, epidermal growth factor receptor, and MiB-1 expression in Barrett's-associated neoplasia: correlation with prognosis. 912 15

Understanding how the regulation of growth factor pathways alters during prostate cancer (PC) progression may enable researchers to develop targeted therapeutic strategies for advanced disease. PC progression involves the shifting of cells from androgen-dependent growth to an androgen-independent state, sometimes with the loss or mutation of the androgen receptors in PC cells. Both autocrine and paracrine pathways are up-regulated in androgen-independent tumors and may replace androgens as primary growth stimulatory factors in cancer progression. Our discussion focuses on growth factor families that maintain homeostasis between epithelial and stromal cells in the normal prostate and that undergo changes as PC progresses, often making stromal cells redundant. These growth factors include fibroblast growth factor, insulin-like growth factors, epidermal growth factor, transforming growth factor alpha, retinoic acid, vitamin D3, and the transforming growth factor beta families. We review their role in normal prostate development and in cancer progression, using evidence from clinical specimens and models of PC cell growth.
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PMID:Growth factor involvement in progression of prostate cancer. 955 81

Angiogenesis is essential for tumor growth and metastasis and depends on the production of angiogenic factors by tumor cells. Neuroblastoma (NB) is a common pediatric tumor of neural crest origin, which is biologically and clinically heterogeneous. Increased tumor vascular index correlates with poor outcome of NB. To determine which angiogenic factors contribute to NB angiogenesis and thereby support tumor progression, we examined the expression of eight angiogenic factors [vascular endothelial growth factor (VEGF), VEGF-B, VEGF-C, basic fibroblast growth factor, angiopoietin (Ang)-1, Ang-2, transforming growth factor alpha, and platelet-derived growth factor (PDGF)] by semiquantitative RT-PCR in 37 NB primary tumors and in 22 NB cell lines. We also analyzed the relationship between angiogenic factor expression and clinicopathological factors as well as patient survival. All eight angiogenic factors examined were expressed at various levels in NB cell lines and tumors, suggesting their involvement in NB angiogenesis. The expression levels of most angiogenic factors were correlated with each other, suggesting their synergy in regulating the angiogenic process. Significantly higher expression levels of VEGF, VEGF-B, VEGF-C, basic fibroblast growth factor, Ang-2, transforming growth factor alpha, and PDGF-A (P < 0.0001-0.026) were found in advanced-stage tumors (stages 3 and 4) compared with low-stage tumors (stages 1, 2, and 4S). Expression of PDGF-A was significantly associated with patient survival (P = 0.04). The redundancy in angiogenic factor expression suggests that inhibition of VEGF bioactivity alone might not be a sufficient approach for antiangiogenic therapy of human NB.
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PMID:High-level expression of angiogenic factors is associated with advanced tumor stage in human neuroblastomas. 1081 14

Greater than 95% of ovarian cancers originate in the epithelial cells on the surface of the ovary. The current study investigates the expression and action of transforming growth factor alpha (TGFalpha) in ovarian surface epithelium (OSE) and the underlying stroma in both normal and tumorigenic ovarian tissues. Normal bovine ovaries are used in the current study as a model system to investigate normal OSE functions. Transforming growth factor alpha and its receptor, the epidermal growth factor receptor (EGFR), were detected in the OSE from normal ovaries by immunocytochemistry (ICC). Ovarian stromal tissue also contained reduced but positive TGFalpha and EGFR immunostaining. To examine TGFalpha and EGFR gene expression, RNA was collected from normal bovine OSE and ovarian stromal cells. The TGFalpha and EGFR transcripts were detected in both fresh and cultured OSE and stromal cells by a sensitive quantitative reverse transcription polymerase chain reaction (QRT-PCR) assay. Transforming growth factor alpha gene expression was found to be high in freshly isolated OSE, but low in freshly isolated stroma. In contrast, EGFR expression was higher in the stroma compared to the OSE. Both the ICC and QRT-PCR indicate that normal OSE express high levels of TGFalpha in vivo and in vitro. In vitro, normal ovarian stromal cells develop the capacity to express high levels of EGFR. Human ovarian tumors from stage II, stage III, and stage IV ovarian cancer cases were found to express TGFalpha and EGFR protein in the epithelial cell component of the tumor by ICC analysis. The stromal cell component of human ovarian tumors contained little or no TGFalpha/EGFR immunostaining. Observations suggest that tumor progression may in part require autocrine stimulation of the epithelia. Transforming growth factor alpha was found to stimulate the growth of normal bovine OSE and stroma cells to the same level as epidermal growth factor. Two ovarian cancer cell lines, SKOV3 and OCC1, were also stimulated to proliferate in response to TGFalpha. Transforming growth factor alpha was also found to stimulate the expression of two growth factors previously shown to be produced by OSE. Transforming growth factor alpha stimulates both kit ligand/stem cell factor and keratinocyte growth factor production by OSE. The effect of hormones on TGFalpha and EGFR expression by the OSE was also examined. Human chorionic gonadotropin stimulated TGFalpha expression, but not FSH. Both hCG and FSH stimulated EGFR expression by OSE. Combined observations suggest a role of systemic hormones and a locally produced growth factor, TGFalpha, in OSE biology. Insight is also provided into how the OSE may develop abnormal growth characteristics involved in the onset and progression of ovarian cancer.
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PMID:Expression and action of transforming growth factor alpha in normal ovarian surface epithelium and ovarian cancer. 1095 22

We used a murine tumor progression model for the evaluation of potential proliferation markers using positron emission tomography (PET). 5-[(18)F]-2'-deoxyuridine ([(18)F]FdUrd) was synthesized with >98% radiochemical purity and investigated in a pancreatic cancer model, transforming growth factor alpha transgenic mice crossbred to p53 deficient mice. Thymidylate synthase was increased already in premalignant lesions, whereas thymidine kinase 1 mRNA levels were up-regulated 4-fold in the pancreatic cancer specimen of these mice. PET imaging was performed after injection of 1 MBq of [(18)F]FdUrd and 1 MBq of [(18)F]fluoro-deoxyglucose. Animals with pancreatic cancer displayed focal uptake of both tracers. The [(18)F]FdUrd uptake ratio closely correlated with the proliferation index as evaluated in morphometric and fluorescence-activated cell sorter analysis. These results indicate the potential of our tumor model for the evaluation of PET tracers and suggest [(18)F]FdUrd as a tracer for the assessment of proliferation in vivo.
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PMID:In vivo evaluation of 5-[(18)F]fluoro-2'-deoxyuridine as tracer for positron emission tomography in a murine pancreatic cancer model. 1135 95

Growth factors and estrogen receptor (ER) signaling cooperate to play essential roles in cell proliferation, differentiation and tumor progression in mouse reproductive organs. Treatment of neonatal mice with diethylstilbestrol (DES) induces an estrogen-independent persistent proliferation and cornification of the vaginal epithelium, which results in cancerous lesions later in life. However, the mechanisms of the estrogen-dependent and -independent pathways essentially remain unknown. We characterized the expression of epidermal growth factor (EGF)-like growth factors (EGF, transforming growth factor alpha (TGF-alpha), heparin-binding EGF-like growth factor (HB-EGF), betacellulin (BTC), amphiregulin (APR), epiregulin (EPR) and neuregulin (NRG) 1) and erbB receptors (EGF receptor (EGFR), erbB2/neu, erbB3 and erbB4) in the vaginae of mice treated either neonatally (0-4 day) or as adults (55-59 day) with estrogens. EGFR and erbB2 were activated in the vaginal epithelium of mice by estrogen treatment. This activation was also encountered in vaginae from neonatally DES-exposed mice, along with the expression of EGF, TGF-alpha, HB-EGF, BTC, APR, EPR and NRG1. Immunohistochemical analysis indicated that erbB2 was primarily expressed in vaginal epithelium. Finally, we found that serine 118 and 167 located in the AF-1 domain of ERalpha were phosphorylated in these vaginae. AG825, AG1478 or ICI 182,780 administration blocked proliferation of vaginal epithelium induced by neonatal DES exposure. Thus, signal transduction via EGFR and erbB2 could be related to the estrogen-induced vaginal changes and persistent erbBs phosphorylation and sustained expression of EGF-like growth factors, leading to ERalpha activation that may result in cancerous lesions in vaginae from neonatally DES-exposed mice later in life.
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PMID:Estrogen-independent activation of erbBs signaling and estrogen receptor alpha in the mouse vagina exposed neonatally to diethylstilbestrol. 1464 53

Two of the most promising new targets in the treatment of colorectal cancer are the epithelial growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF). Agents that inhibit the EGFR or bind to VEGF have demonstrated clinical activity as single agents and in combination with chemotherapy in phase II and phase III clinical trials. The most promising of these agents are cetuximab, which blocks the binding of EGF and transforming growth factor alpha (TGF-alpha) to EGFR, and bevacizumab, which binds free VEGF. Cetuximab and irinotecan have been evaluated in two clinical studies in the USA (IMCL CP02-0141 and IMCL CP02-9923). Study IMCL CP02-0141 evaluated the antitumor activity of single-agent cetuximab in patients with irinotecan-refractory, EGFR-positive metastatic colorectal carcinoma. There were 6 partial responses in 57 treated patients, for a response rate of 10.5%. Study IMCL CP02-9923 evaluated the combination of cetuximab and irinotecan in a total of 139 patients enrolled at 27 study sites. In this trial 22.5% of patients with progressive disease on irinotecan achieved an objective response (19% by investigator assessment) showing that the combination of cetuximab and irinotecan has antitumor activity in this population. A large randomized phase II trial evaluating similar study populations in Europe confirmed these findings, demonstrating response rates for cetuximab/irinotecan and cetuximab alone of 22.9% and 10.8%, respectively. The other promising agent bevacizumab is a humanized variant of the anti-VEGF monoclonal antibody. VEGF is produced by healthy and neoplastic cells. Its activities are mediated by two receptor tyrosine kinases. VEGF signaling is often a rate-limiting step in physiologic and pathologic angiogenesis. Bevacizumab has been studied as an antiangiogenic cancer therapeutic as a single agent and in combination with chemotherapy in patients with stage III and IV colon cancer. In addition to its direct antiangiogenic effects, bevacizumab may allow more efficient delivery of chemotherapy by altering tumor vasculature and decreasing the elevated interstitial pressure common in tumors. In this regard, some of the most robust phase II data using bevacizumab are from a randomized study of chemotherapy [fluorouracil (5-FU) and leucovorin (LV)] with or without bevacizumab in metastatic colorectal cancer. In this study, treatment with bevacizumab plus 5-FU/LV resulted in higher response rates, longer median time to disease progression, and longer median survival. Recently, a phase III, multicenter, double-blind, randomized, placebo-controlled trial was designed to investigate the addition of bevacizumab to first-line irinotecan, 5-FU, and LV chemotherapy (IFL). The trial showed a higher response rate, longer time to tumor progression, and prolonged overall survival in patients with metastatic colorectal cancer. It was the first large, randomized, phase III survival trial to assess the importance of targeting VEGF and tumor angiogenesis for the treatment of human cancer. Integration of novel agents targeting VEGF and EGFR with irinotecan-based chemotherapy has shown clinical activity in patients with metastatic colorectal cancer. The goal in the future will be to predict which specific chemotherapy and targeted agent combination will most likely benefit individual patients.
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PMID:Integration of novel agents in the treatment of colorectal cancer. 1530 12

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