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)

Fifty exocrine pancreatic adenocarcinomas and 57 benign tumors induced in Syrian hamsters by N-nitrosobis(2-oxopropyl)amine (BOP) were examined for the presence of argyrophil cells antiinsulin, -glucagon, -somatostatin, -pancreatic polypeptide (PP), -gastrin/CCK, -vasoactive intestinal polypeptide (VIP), and - neuron-specific enolase (NSE) reactive cells. Argyrophil - and antihormone-reactive cells were found in the normal pancreatic ducts and in the acini, as well as in hyperplastic and atypical ducts/ductules, tubular complexes, benign lesions, and in 80% of ductal adenocarcinomas. Insulin and antiNSE-reactive cells were the most common, followed in decreasing frequency by glucagon, somatostatin, and PP cells. Antigastrin-/CCK-and -VIP-reactive cells were found in two cases. Argyrophil cells were present in about 60% of the tumors with Grimelius staining and in 55% of those with Churukian-Schenk staining. Insulin cells were seen in ductal cancer that had grown into a lymph node and in the lymph node metastases of another cancer. A novel finding was the presence of argyrophil and insulin cells within the lumen of some malignant glandular structures. Coexistence of several peptide cells was found in 52% of the cancers. The presence of argyrophil and hormone-producing cells in induced pancreatic ductal/ductular lesions further strengthens the existence of a close developmental relationship between exocrine and endocrine cells of the pancreas.
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PMID:Immunohistochemical characterization of endocrine cells in experimental exocrine pancreatic cancer in the Syrian golden hamster. 135 11

Tumor metastasis requires highly motile cells that can respond to appropriate stimuli. A2058 human melanoma cells were shown previously to secrete a highly potent autocrine motility factor (AMF) that stimulates chemokinetic movement. We have shown that the insulin polypeptides (IPs; insulin-like growth factors I and II [IGF-I, -II] and insulin) stimulated A2058 cell chemotaxis and chemokinesis. We now report that the IPs and AMF stimulate locomotion in other human malignant cell lines. Insulin (100 nM) induced motility of up to 50% of the magnitude of the AMF response in human carcinoma lines MDA-231 (breast), T24 (bladder), and OVCAR3 (ovarian). The tumorigenic and metastatic 5R Haras-transfected rat embryo fibroblast cell line responded to insulin with both chemotaxis and chemokinesis and was 100% of that seen for AMF. The ED50 for IGF-I in the carcinoma cell lines was in the order of I nM, but the magnitude of the responses at this concentration was 40% of the AMF-stimulated response, with the exception of the A2058 cells, which were maximally stimulated at I nM. IGF-II induced maximal motility of 75 to 130% of the AMF-stimulated response in the carcinoma lines with ED50 of less than or equal to 10 nM. IGF-II-stimulated motility in the carcinoma lines was predominantly chemotactic by modified checkerboard analysis. Cell pretreatment with pertussis toxin inhibited 90-100% of AMF-induced motility, whereas migration to the IPs was not pertussis toxinsusceptible. In growth studies, IGF-I induced mitogenesis up to 140% of basal media control growth. In general, maximal growth stimulation was seen at 100 nM IGF-I, and optimal migration was seen at 10 nM IGF-I. The IGFs are secreted by normal stroma in a number of organs that are common sites for primary and metastatic disease. Therefore, we suggest that IPs may be important homing and mitogenic signals for tumor cells in the process of invasion and metastasis and that the differential motility stimulation and respective mechanisms of action by these physiologically important agents may underlie the diversity of the metastatic process.
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PMID:Heterogeneity of the motility responses in malignant tumor cells: a biological basis for the diversity and homing of metastatic cells. 211 98

Thirty-one primary canine pancreatic endocrine tumors and their metastases were studied histologically and immunohistochemically for the presence of insulin, glucagon, somatostatin, pancreatic polypeptide (PP), gastrin, and adrenocorticotrophic hormone (ACTH). Tumors were also evaluated for the presence of amyloid. The cytoarchitectural pattern of 25 of 31 primary tumors was predominantly solid, whereas three tumors were mostly glandular, two were unclassified, and one had a gyriform pattern. Cells with insulin immunoreactivity were found in 30 of 31 tumors and were found in all cases in which there was clinical evidence of inappropriate insulin secretion. Insulin was the only hormone demonstrable in three of the 30 tumors, but cells immunoreactive for other hormones were also present in various combinations in most tumors [i.e., glucagon (13 of 30), somatostatin (17 of 30), PP (25 of 30), and gastrin (2 of 30)]. One tumor contained only cells with glucagon and PP immunoreactivity. Amyloid was found in ten of 31 primary tumors but was not detected in metastases. Cells with insulin immunoreactivity were the only cell type consistently present in tumors containing amyloid. Amyloid deposits did not immunoreact with any of the antisera. Seventeen of 31 dogs had metastasis of the pancreatic endocrine tumor to regional lymph nodes, liver, or both. All metastases available for study (15 of 17) contained cells with insulin immunoreactivity and some contained cells with PP or somatostatin immunoreactivity. No statistically significant (P greater than 0.05) differences in tendency to metastasize were found when pancreatic endocrine tumors were compared by region of origin, cytoarchitectural pattern, presence of amyloid, or by number of hormones contained within the tumor.
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PMID:Canine pancreatic endocrine tumors: immunohistochemical analysis of hormone content and amyloid. 288 54

We reviewed our personal experience with insulin-secreting carcinoma of the pancreas to determine the clinical course and the role of surgery in this disease. Seventeen patients with high-grade metastatic carcinoma were treated at our institution between 1957 and 1982. To this series we have added 45 cases of metastatic carcinoma reported in the literature. All patients had symptoms with manifestations of hypoglycemia. Patients with metastatic insulin-secreting carcinoma had an average age of 48.5 years, with male predominance. The average duration of symptoms at presentation was 2.0 years. The tumors were usually single and averaged 6.2 cm. All tumors had metastases, most commonly to the liver and/or lymph nodes. The median disease-free survival after curative resection was 5 years. The recurrence rate was 63%, with the median interval to recurrence 2.8 years, and the median survival with recurrent tumor was 19 months. Palliative resection was associated with a median survival of 4 years, and biopsy only, 11.0 months. Insulin-secreting carcinomas are slow-growing tumors with significant metastatic potential. Surgical resection of primary and metastatic tumors represents the treatment of choice when possible. Long-term follow-up is required.
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PMID:Metastatic insulin-secreting carcinoma of the pancreas: clinical course and the role of surgery. 609 77

Insulin-like growth factor 1 (IGF-1) likely is involved in thyrocyte proliferation via autocrine mechanisms, but limited data are available on its in vivo expression in thyroid neoplasms. This prompted us to explore IGF-1 expression at the protein and mRNA levels and IGF-1 receptor (IGF-1rec) immunoreactivity in normal and neoplastic thyroids (50 adenomas and 53 carcinomas). We documented increased IGF-1 and IGF-1rec immunoreactivity in adenomas (31 of 50 and 40 of 50 cases, respectively) and carcinomas (38 of 53 and 42 of 53 cases) compared with normal thyroid, which only showed minimal immunoreactivity for the ligand and its receptor. A corresponding up-regulation of IGF-1 mRNA was documented in carcinomas, whereas adenomas exhibited down-regulated expression of IGF-1 mRNA. Immunoreactivity for IGF-1 and cognate receptor positively correlated with tumor diameter and wide intrathyroidal extension but not with patients' gender and age or with the stage of the tumors and the occurrence of lymph node metastases. These data emphasize a possible role of the IGF-1 system in thyroid tumorigenesis, as indicated by in vitro studies. In addition, the evaluation of IGF-1 and IGF-1rec immunoreactivity might have clinical implications, because it positively correlates with the aggressiveness of these tumors.
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PMID:Insulin-like growth factor 1 expression in thyroid tumors. 1093 58

Fasting blood samples were obtained before definitive surgery or biopsy in 128 patients referred to the department of surgery with suspected or manifest breast cancer. Insulin-like growth factor (IGF)-I, IGF-II and free IGF-I were measured by radioimmunoassay/immunoradiometric assay, while IGFBP-3 proteolysis was evaluated by Western immunoblot. 12 patients had ductal carcinoma in situ benign conditions, while staging revealed metastatic disease in 15 of 16 patients with invasive cancers. IGFBP-3 proteolysis above the normal range was recorded in 19 patients with invasive cancers, but in none of the patients suffering from DCIS/benign conditions. Increased IGFBP-3 proteolysis was most frequently recorded in patients harbouring large tumours and metastatic disease (Stage I: 0/19, 0%; Stage II: 3/45, 7%, Stage III: 9/37, 24%, and Stage IV: 7/15, 47%). IGFBP-3 proteolysis was significantly higher in Stage III (P =0.01) and IV (P< 0.001) patients compared to the other stage groups (P = 0.001). IGF-I and IGF-II correlated negatively to IGFBP-3 proteolysis and age. Plasma levels of IGF-I and -II were significantly lower in patients with elevated IGFBP-3 proteolysis compared to those within the normal range. Our findings reveal alterations in the IGF-system among a substantial number of patients with large primary breast cancers.
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PMID:Plasma insulin-like growth factor binding protein-3 proteolysis is increased in primary breast cancer. 1143 5

Insulin-like growth factors (IGFs) regulate breast cancer cell proliferation, protect cells from apoptosis, and enhance metastasis. In this study, we examined the IGF signaling pathway in two breast cancer cell lines selected for metastatic behavior. LCC6 was selected for growth as an ascites tumor in athymic mice from parental MDA-MB-435 cells (435P). The MDA-231BO cell line was derived from osseous metastases that formed after intracardiac injection of the MDA-MB-231 cell line in athymic mice. Compared to the parental cell lines, IGF-I treatment enhanced IRS-2 phosphorylation over IRS-1 in the metastatic variants. IGF-I stimulated cell migration in the variant cells, but not in the parental cells. To determine the role for IRS-2 in IGF-mediated motility, we transfected MDA-231BO cells with an anti-sense IRS-2 construct. Transfected cells had decreased levels of IRS-2 with diminished IGF-mediated motility and anchorage independent growth when compared to control cells. However, adherence to fibronectin was enhanced in the transfected cells compared to MDA-231BO cells. Our data show that breast cancer cells selected for metastatic behavior in vivo have increased IRS-2 activation and signaling. In these cells, IGF-I enhances cell adhesion and motility suggesting that IRS-2 may mediate these aspects of the malignant phenotype.
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PMID:Regulation of breast cancer cell motility by insulin receptor substrate-2 (IRS-2) in metastatic variants of human breast cancer cell lines. 1170 61

Insulin-like growth factors and their principal receptor, IGF-I receptor (IGF-IR), are frequently expressed in human colon cancers and play a role in preventing apoptosis, enhancing cell proliferation, and inducing expression of vascular endothelial growth factor (VEGF). The role of IGF-IR in regulating angiogenesis and metastases of human colon cancer has not been elucidated. To determine the in vitro and in vivo effects of IGF-IR in human colon cancer growth and angiogenesis, human KM12L4 colon cancer cells were transfected with a truncated dominant-negative form of IGF-IR (IGF-IR dom-neg). IGF-IR dom-neg-transfected cells demonstrated markedly decreased constitutive expression of VEGF mRNA and protein. Subcutaneous injections of IGF-IR dom-neg-transfected cells in nude mice led to significantly decreased tumor growth (p < 0.05) that was associated with decreased tumor cell proliferation, VEGF expression, and vessel count and with increased tumor cell apoptosis (p < 0.05 for all parameters compared with controls). In addition, pericyte coverage of endothelial cells was significantly decreased in tumors from IGF-IR dom-neg-transfected cells. Following this observation, we demonstrated in vitro that vascular smooth muscle cells migrated significantly less in conditioned medium derived from IGF-IR dom-neg-transfected cells compared with medium from control cells. After splenic injections, IGF-IR dom-neg transfectants failed to produce liver metastases, in contrast to parental cells and mock transfectants (p < 0.05). In addition, IGF-IR dom-neg-transfected cells failed to form liver tumors after direct injection into the liver. These studies demonstrate that the IGF-IR plays an important role in multiple mechanisms that mediate the growth, angiogenesis, and metastasis of human colon cancer. IGF-IR is a valid target for the therapy of human colon cancer.
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PMID:Impact of insulin-like growth factor receptor-I function on angiogenesis, growth, and metastasis of colon cancer. 1237 72

Glioblastomas rarely metastasize outside the CNS. We biologically characterized a case of secondary glioblastoma associated with extracranial progression and distant metastasis. A 42-year-old male patient was subjected to craniotomy for a left temporal tumor (astrocytoma grade II) and subsequently underwent another 3 craniotomies due to tumor recurrences. At the third craniotomy, extracranial progression was noted, and the tumor was classified as a glioblastoma. In order to pinpoint the genes expressed differentially in the intracranial primary tumor and the metastatic tumors, we used cDNA microarray. The patterns of gene expression in these 2 samples were highly similar, suggesting that the mechanism of metastasis was direct infiltration of tumor cells into extracranial blood vessels. Insulin-like growth factor binding protein-2 was overexpressed in both primary and metastatic tumors. Immunohistochemical studies of DNA-dependent protein kinase, which participates in the repair of DNA, was strongly positive in the samples obtained at the first and second operations, but the positive rates were markedly reduced in the specimens obtained at the third and fourth operations. These results suggest that insulin-like growth factor binding protein-2 and deficiency of DNA-dependent protein kinase proteins promoted tumor progression in the present case.
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PMID:Biologic characterization of a secondary glioblastoma with extracranial progression and systemic metastasis. 1262 29

Insulin-like growth factors (IGF) and their receptors (IGF-1R) constitute a complex biologic system implicated in diverse regulatory levels of cell proliferation, viability, differentiation and metabolism. Extensive epidemiologic data have implicated the IGF/IGF-1R pathway in the establishment of human malignancies, consistent with experimental data on the role of this signaling cascade in promoting cell transformation, resistance to apoptosis, metastases and other aspects of the biology of human cancers. However, historically, the IGF/IGF-1R pathway has not been viewed as an attractive target for therapeutic intervention. The widespread IGF-1R expression in normal tissues and its close homology to the insulin receptor had led to the assumption that IGF-1R inhibition would cause unacceptable toxicities in vivo. Even though neutralizing antibodies against human IGF-1R have been efficacious against xenograft tumors, a lack of reactivity against the host rodent receptor has confounded the assessment of its therapeutic index. Furthermore, the lack of a clear understanding of the relevant significance for neoplastic cells in the function of IGF-1R versus other growth factor receptors provided an additional disincentive for the study of this pathway. However, recent reports from the authors' group and others have shown that small molecule inhibitors of tyrosine kinase activity of IGF-1R can be safely and efficaciously administered in vivo in clinically relevant orthotopic models of human neoplasias, such as multiple myeloma. This article reviews the data that validated IGF-1R as a therapeutic target for a broad spectrum of malignancies and provides in vivo proof-of-concept for the use of selective IGF-1R kinase inhibitors as primary antitumor therapy or in synergistic combination as chemosensitizers. These results have not only provided the rationale for clinical trials of small molecule IGF-1R inhibitors, but have also rekindled interest in other therapeutic modalities (e.g., monoclonal antibodies) aimed at suppressing the function of this critical pathway for tumor cell pathophysiology.
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PMID:Treatment of hematologic malignancies and solid tumors by inhibiting IGF receptor signaling. 1600 56


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