Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinase activity was assessed in culture fluids of organ-cultured human skin by gelatin zymography. Both the 92-kD gelatinase/type IV collagenase and the 72-kD gelatinase/type IV collagenase were detected. Production of the 92-kD enzyme was substantially increased in the presence of epidermal growth factor (EGF) and hepatocyte growth factor (HGF) as compared to control but not in the presence of insulin-like growth factor-1 (IGF-1) or keratinocyte growth factor (KGF). This is of interest because our recent studies have shown that EGF and HGF induce the epithelial cells to invade the underlying stroma while normal architecture is maintained in the presence of IGF-1 and KGF. Addition of tissue inhibitor of metalloproteinase-2 to the organ culture fluids blocked expression of the active forms of both enzymes and concomitantly blocked invasion. Epidermal keratinocytes, dermal fibroblasts and dermal endothelial cells were grown in monolayer culture and examined for matrix metalloproteinase production. The 92-kD enzyme accounted for most of the gelatinase activity in keratinocyte culture fluids while the 72-kD enzyme accounted for most of the activity in the dermal fibroblast and endothelial cell culture fluids. Increased production of the 92-kD enzyme was seen in keratinocytes upon exposure to the growth factors that induced invasion (EGF and HGF) while the two factors that did not induce invasion (IGF-1 and KGF) were much less effective. Production of the 72-kD enzyme in fibroblasts and endothelial cells was not upregulated by any of the four growth factors. Taken together, these data indicate that matrix metalloproteinase activity is increased in the epithelium under the influence of invasion-inducing growth factors and contributes to invasion.
Invasion Metastasis 1996
PMID:Growth factor-induced epidermal invasion of the dermis in human skin organ culture: expression and role of matrix metalloproteinases. 883 Jul 61

In a previous report, we observed by light microscopy the extracellular matrix in 51 vulvar squamous carcinomas and found that some tumors has a prominent stromal response in the form of a regional or diffuse zone of extracellular myxoid matrix containing immature collagen and fibroblasts at the tumor-stromal junction. These tumors were associated with clitoral involvement, ulcerative nonexophytic growth pattern, older age groups, poorer survival rate, and more extensive lymph node metastases than when prominent fibromyxoid stromal response (PFSR) was absent. This behavior was demonstrated despite the fact that these tumors were not larger, more deeply invasive, or of higher grade than when PFSR was absent. In the current immunohistochemical study, we examined cytokine, cell adhesion receptor, and tumor suppressor gene expression in 50 vulvar squamous carcinomas using a panel of antibodies to identify any potential role of these proteins in the development of a PFSR. Semiquantification of expression into none, focal (< 25% of cells showing expression), regional (25-50%), and diffuse (> 50%) patterns revealed PFSR to be statistically associated with high CD44, transforming growth factor (TGF) beta 3, and p53 protein expression, but not with fibroblast growth factor, epidermal growth factor, epidermal growth factor receptor, or E-cadherin expression. When expression of CD44 and either stromal or tumor TGF-beta 3 expression was high, i.e., regional or diffuse in distribution, 15 (50%) of 30 cases were associated with PFSR. In contrast, only 1 (7%) of 14 cases was associated with PFSR when expression was high for only one of these two proteins and none of 3 cases was associated with response when expression was low for both proteins (p = 0.005). Furthermore, in cases showing high expression for both TGF-beta 3 and CD44, PFSR was found in 13 (72%) of 18 cases when p53 expression was diffuse compared with 2 (17%) of 12 cases when expression was less (p = 0.01). Since TGF-beta acts mitogenically for fibroblasts and has been shown to be an inhibitor of epithelial cell growth, its high expression in a carcinoma with PFSR would suggest loss of effect on the epithelial component but an intact effect on the stroma. Since CD44 is known to act as a receptor for hyaluronic acid, which is a prominent stromal component and known to play an important role in cell mobility and tumor aggressiveness, its high expression in association with PFSR would suggest a role of CD44 overexpression in altered hyaluronate metabolism with accelerated tumor cell migration and subsequent distal spread. The current study demonstrates that alterations in cytokine and cell adhesion receptor status variably occur in vulvar squamous carcinoma and that such alterations may affect tumor morphology and behavior.
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PMID:Cytokine, cell adhesion receptor, and tumor suppressor gene expression in vulvar squamous carcinoma: correlation with prominent fibromyxoid stromal response. 888 79

A series of 198 female breast cancer biopsies were analysed immunohistochemically for the expression of epidermal growth factor (EGF), with special emphasis on its prognostic significance. A total of 67/198 tumours (33.8%) were EGF-positive, 24 (12%) of which showed strong expression of EGF. EGF was usually expressed in the cytoplasm of the cancer cells but, in 22 cases, the normal ducts adjacent to the cancer showed positive staining as well. Strong EGF expression was related to distant metastases at diagnosis (P = 0.04). Oestrogen(ER)- and progesterone-receptor(PR)-negative tumours showed EGF positivity with equal frequency (P = 0.05 in both). Axillary lymph node status, histological type, tumour size, histological grade, S-phase fraction, mitotic index or cancer recurrence did not show any statistical correlation with EGF expression. Tumour size (P = 0.007), axillary lymph node involvement (P = 0.003) and ER content (P = 0.03) were independent prognostic factors in multivariate survival analysis, whereas EGF positivity, as an independent factor, had no effect on survival. In univariate analysis, however, EGF positivity predicted a more favourable outcome in axillary-lymph-node-positive tumours (P = 0.04). The results suggest that immunohistochemical assessment of EGF expression has hardly any clinical significance in addition to the well-established prognostic factors in breast cancer.
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PMID:Prognostic value of epidermal growth factor expression in breast cancer. 899 43

Transforming growth factor-alpha (TGF-alpha), a potent growth factor belonging to the epidermal growth factor family, exerts its role in the proliferation and differentiation of normal and neoplastic cells by binding to epidermal growth factor receptor (EGFR). Coexpression of TGF-alpha and EGFR in carcinomas is believed to confer growth advantage to tumor cells. To evaluate their role in such indolent tumors as gastrointestinal (GI) carcinoids, we investigated the immunohistochemical expression of TGF-alpha and EGFR in 25 GI carcinoids (nine foregut, 13 midgut, and three hindgut) and studied the correlation of their expression with the secretory and clinicopathologic profiles of these tumors. TGF-alpha was expressed in 18 (72%) of these tumors, and whereas 16 of 17 tumors showed immunopositivity for the extracellular domain of EGFR, none expressed its intracellular domain. Ten TGF-alpha-positive tumors were positive for serotonin, seven for somatostatin, three for calcitonin, and one tumor each for gastrin, glucagon, pancreatic polypeptide, vasoactive intestinal peptide, and growth hormone-releasing factor, respectively. Seven TGF-alpha-positive tumors were multihormonal, eight were monohormonal, and three were completely nonreactive for the regulatory substances studied. Except for its correlation with 5-hydroxytryptamine (serotonin) expression by the tumor cells, expression of TGF-alpha showed no significant association with other pathologic attributes, for example, the site of origin, size, depth of intramural penetration, metastases, and the secretory profiles of the tumors. These findings indicate that although TGF-alpha is expressed by a high proportion of GI carcinoids, the absence of its intact receptor molecule (EGFR) on the tumor cells renders it functionally ineffective as a growth factor. Thus, unlike in carcinomas of the GI tract, TGF-alpha appears to play no role in the growth and progression of GI carcinoids, which perhaps explains the indolent behavior and slow biological progression of GI carcinoids.
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PMID:Immunohistochemical expression of transforming growth factor alpha and epidermal growth factor receptor in gastrointestinal carcinoids. 906 Jun 3

Although several neoplasms may produce osteoblastic metastases, carcinoma of the prostate is by far the most common. Biochemical and histologic studies indicate that osteolysis also is a manifestation of prostate carcinoma. Furthermore, factors such as parathyroid hormone-related peptide, which mediate osteolysis in other cancers, also appear to be operative in the bone breakdown induced by prostate carcinoma. However, the most unique skeletal effect of this tumor is its consistent capacity to stimulate osteoblasts to deposit new bone. Several bone growth factors have been detected in prostatic tissue and may contribute to this process. These include transforming growth factor-beta, fibroblast growth factor, and bone morphogenetic proteins. The author isolated an amino-terminal fragment (ATF) of the protease urokinase (uPA) from the conditioned medium of the prostate carcinoma cell line PC-3 and demonstrated that this fragment has mitogenic activity for osteoblastic cells. The activity appears to reside in an epidermal growth factor-like growth factor domain (GFD) within the ATF. Subsequently, the author cloned the rat uPA receptor (uPAR). uPAR is known to bind the ATF and can permit the uPA molecule to exhibit focal proteolysis. It was shown that the ATF also can induce c-myc, c-jun, and c-fos in osteoblastic cells. This effect of ATF can be mimicked by the GFD and suggests that this signalling pathway in osteoblasts is via the uPAR. Consequently, the uPA molecule may contribute to growth factor effects in osteoblasts via the NH2-terminal fragment and to tumor invasiveness via its COOH-terminal proteolytic domain. This scenario is supported by results from studies with uPA-overexpressing prostate carcinoma cells in rats. Additional studies will be required to further define the mechanisms of interaction of prostate carcinoma and other cancers with bone but each site of molecular interaction may provide a therapeutic window for curtailing the effects of these tumors on the skeleton.
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PMID:Mechanisms of the development of osteoblastic metastases. 936 25

Tumor cells have been found in autologous hematopoietic cell transplants used after high-dose chemotherapy. To specifically eliminate contaminating mammary tumor cells during ex vivo expansion of CD34+ hematopoietic progenitor cells, we used recombinant immunotoxins (ITs) directed against cell-surface antigens expressed on mammary carcinoma cells. ITs were expressed from fusion cDNAs combining a single-chain antibody fragment (scFv) directed against the Erb-B2 or epidermal growth factor (EGF) receptors with a truncated Pseudomonas exotoxin A fragment devoid of its cell-binding domain. CD34+ hematopoietic progenitor cells did not express Erb-B2 and EGF receptors as detected by Western blotting. Ex vivo expansion of total hematopoietic cells or of colony-forming cells from CD34+ progenitors in the presence of stem-cell factor (SCF), interleukin-1 (IL-1), IL-3, IL-6, and erythropoietin (Epo) was not affected when ITs were added to the cultures. In contrast, MDA-MB 453 and MCF-7 mammary carcinoma cells were depleted in a dose- and time-dependent manner by more than 3 log in coculture with CD34+ cells over a period of 7 days in the presence of 100 to 1,000 ng/mL of anti-Erb-B2 IT. This included elimination of the subpopulations with regrowth potential. Similarly, addition of either anti-Erb-B2 or anti-EGF receptor ITs to primary breast cancer cells isolated from patients with metastatic disease resulted in elimination of cytokeratin-positive cells in seven of seven samples. ITs are highly efficient and convenient to use for the depletion of mammary tumor cells during ex vivo expansion of hematopoietic progenitor-cell autografts.
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PMID:Purging of mammary carcinoma cells during ex vivo culture of CD34+ hematopoietic progenitor cells with recombinant immunotoxins. 947 51

Bladder cancers frequently exhibit an increased number of epidermal growth factor receptors (EGFR) in comparison to normal urothelium. The EGFR could potentially be a target for toxic conjugates. The aim of our study was to compare the expression of EGFR in metastases with concurrent or primary tumour in the urinary bladder using immunohistochemical techniques and a monoclonal antibody. Tumour material from 20 patients was investigated. The majority (13/20) of the metastases were homogeneously stained and showed a moderate to strong membranous staining for EGFR. The expression of EGFR in primary bladder tumours and metastases was similar. There was no indication that tumour tissue exposed to chemotherapy or radiation had a decreased number of EGFR. Targeting of the EGFR thus seems potentially applicable to metastatic disease.
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PMID:Expression of epidermal growth factor receptor in urinary bladder cancer metastases. 953 79

We studied the association between epidermal growth factor (EGF) binding capacity and histopathologic features or prognosis in human renal cell carcinoma (RCC) by Scatchard analysis in 67 patients. EGF binding capacity was significantly greater in metastatic than in nonmetastatic tumors, and in nuclear grade 3 than nuclear grade 1 tumors. Multivariate analysis revealed that tumor stage, nuclear grade, EGF binding capacity, and tumor size significantly correlated with overall survival. These results suggest that EGF binding may be an important determinant of prognosis in patients with RCC.
Invasion Metastasis 1997
PMID:Relationship of epidermal growth factor binding capacity to histopathologic features and prognosis in human renal cell carcinoma. 956 Oct 28

Many oncogenes and tumor suppressor genes are involved in multistep carcinogenesis. Cripto is an epidermal growth factor (EGF) related gene which shares homology with EGF and TGFalpha. The aim of this study was to evaluate the role of abnormal p53 and cripto oncogene expression in endometrial carcinogenesis and progression using a hyperplasia carcinoma sequence model. Ninety-six primary endometrial adenocarcinomas and 30 hyperplastic tissues of which 7 were atypical (AH), were immunohistochemically examined for the presence of cripto and abnormal p53 protein. Immunopositivity was compared in hyperplastic and carcinoma tissues and analysed for conventional clinicopathological prognostic variables such as grade, depth of myometrial invasion, lymphovascular invasion, lymph node metastases and clinical stage. Cripto immunoreactivity was strong in most cases of AH, and endometrial carcinomas revealed 71% overall and 41% strong positivity, while hyperplasias without atypia were weakly stained. There was no correlation between cripto expression and clinicopathological prognosticators. Abnormal p53 was not observed in hyperplasias but AH and carcinomas expressed 14% and 25% overall positivity, respectively. There was a statistically significant correlation between the stage of the disease and abnormal p53 accumulation. Our results suggest that both cripto and p53 may play a role in endometrial carcinogenesis while abnormal p53 expression is an important parameter for disease progression.
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PMID:Abnormal expression of cripto and p53 protein in endometrial carcinoma and its precursor lesions. 964 Dec 41

Gliomas are characterized by their extensive invasion into the brain parenchyma. Recently it has been shown that normal brain cells can produce laminin, fibronectin and collagen type IV when confronted by invading glioma cells. Laminin stimulates cell migration of several human glioma cell lines in vitro. This migration can be inhibited by adding blocking monoclonal antibodies (MAbs) against the most expressed integrin subunits, alpha3 and beta1. Previous studies have shown that glioma cell migration, invasion and growth are stimulated by epidermal growth factor (EGF). However, MAb directed against the EGF receptor (EGFR) did only partly inhibit the invasive process in vitro. Since laminin has regional peptide homology with EGF (EGF-like repeats), the present work was aimed at studying how two human glioma cell lines exposed to antibodies to the EGFR, reacted to laminin stimulated migration. Furthermore, we wanted to study which role the EGFR and the laminin receptor integrin subunits alpha3 and beta1 play during glioma cell invasion. EGFR expression of two glioma cell lines, AN1/lacZ and U-251/lacZ was studied by flow cytometry and immunofluorescence microscopy. A cell migration assay was used to study effects of MAbs against EGFR on migration from laminin-stimulated tumor spheroids. Tumor cell invasion was evaluated by using an in vitro co-culture model, where normal fetal brain cell aggregates were confronted with multicellular tumor spheroids. The results show that both cell lines expressed EGFR, AN1/lacZ 4-fold more than U-251/lacZ. MAb against EGFR inhibited the laminin-stimulated migration only from AN1/lacZ spheroids. MAbs against alpha3 and beta1 integrin subunits inhibited glioma cell invasion in vitro. The present work indicates possible connections between laminin-stimulated cell migration and the EGFR expression on glioma cells. These elements contribute to the characteristic features of glioma cells and may be an important part of the complex relationships between growth factors, integrins and extracellular matrix during glioma cell invasion.
Invasion Metastasis 1997
PMID:Epidermal growth factor and laminin receptors contribute to migratory and invasive properties of gliomas. 987 21


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