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)

Meningiomas show clinical characteristics that vary from very benign to clearly malignant with rapid invasive growth and metastases. This study was undertaken to analyze the expression of members in the insulin-like growth factor (IGF) system in meningiomas showing different degrees of brain invasion. Tissue samples from 16 meningiomas were analyzed for members in the IGF family by mRNA in situ hybridization. The meningiomas comprised three groups: I. Benign meningiomas that did not interfere with the arachnoid plane and showed no edema. II. Benign meningiomas that did not respect the arachnoid plane and tumors that caused edema. III. Aggressive and malignant meningiomas that caused edema and showed brain invasion. IGF-II mRNA was identified in all tumors analyzed, and with a clear increase in expression observed in group III tumors. IGFBP-2 mRNA was detected in equal levels in all tumors. IGFBP-5 mRNA levels were highest in the benign group without edema (I) of meningiomas whereas IGFBP-6 mRNA levels were highest in the group with brain invasion (III). Brain invasiveness in degrees from respect of the arachnoid membrane progressing to frank brain invasion correlated with increases in IGF-II and IGFBP-6 expression. High levels of IGFBP-6 may not inhibit IGF-II actions, which is known to be growth promoting in tumors. Instead, IGFBP-6 appears to have an importance for the characteristics of edema and brain invasion in meningiomas.
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PMID:Expression of IGF-II, IGFBP-2, -5, and -6 in meningiomas with different brain invasiveness. 1212 63

The insulin-like growth factor (IGF) family of ligands, binding proteins and receptors is an important growth factor system involved in both the development of the organism and the maintenance of normal function of many cells of the body. The system also has powerful anti-apoptotic effects. More recently, evidence has accrued to demonstrate that the IGFs play an important role in cancer. Individuals with serum IGF-II levels in the upper quartile of the normal range (and IGF binding protein-3 levels in the lower quartiles) have a relative risk for developing breast, prostate, colon and lung cancer. IGF-II is commonly expressed by tumor cells and may act as an autocrine growth factor; occasionally even reaching target tissues and causing tumor-induced hypoglycemia. The IGF-I receptor is commonly (though not always) overexpressed in many cancers, and many recent studies have identified new signaling pathways emanating from the IGF-I receptor that affect cancer cell proliferation, adhesion, migration and cell death; functions that are critical for cancer cell survival and metastases. In this review, many aspects of the IGF system and its relationship to cancer will be discussed.
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PMID:The insulin-like growth factor system and cancer. 1276 20

The development of the mammary gland requires the coordinated expression of hormones and growth factors. Likewise, some transformed breast cells continue to respond to these same extracellular signals. Thus, understanding the mechanisms that control normal development of tissues can lead to new therapeutic targets. The insulin-like growth factor (IGF) system plays an important role in the normal development and function of the mammary gland. Accumulating evidence suggests that the IGFs are also key regulators of the malignant phenotype. The IGFs stimulate proliferation, promote survival, and enhance metastatic potential of breast cancer cells. Although multiple receptors for the IGFs have been identified, the IGFs primarily exert their biologic effects through ligation of the type I IGF receptor tyrosine kinase (IGF1R). IGF binding to the IGF1R initiates an intracellular signaling cascade that leads to changes in gene expression and cell biology. This review will focus on the evidence that the IGF1R is a relevant treatment target in breast cancer.
Cancer Metastasis Rev 2003 Dec
PMID:The type-1 insulin-like growth factor receptor tyrosine kinase and breast cancer: biology and therapeutic relevance. 1288 9

The circulating level of insulin-like growth factor-binding protein-3 (IGFBP-3) is inversely associated with the risk of prostate cancer (PCa) and its progression and may be modulated by the A/C polymorphism at position -202 in the promoter region of IGFBP-3. This study was conducted to evaluate the role of the A/C polymorphism as a genetic modifier in the etiology of PCa and its disease status. The polymorphism was analyzed by a PCR restriction fragment-length polymorphism technique in 307 PCa patients, 221 benign prostatic hyperplasia (BPH) patients, and 227 male controls. No significant difference in the genotype frequency was found between the PCa or BPH patients and controls (PCa versus control, P = 0.316; BPH versus control, P = 0.964). Regarding the tumor stage, the C allele was more frequently observed in patients having tumors with higher stage (P for trend = 0.002). When the PCa patients with localized disease (stage A + B + C) were considered as reference, those with CC and AC genotype had a significantly increased risk of metastatic disease (stage D) compared with those with AA genotype [age-adjusted odds ratio (aOR) = 3.89, 95% confidence interval (CI) = 1.42-10.64, P = 0.008, and aOR = 1.68, 95% CI = 1.01-2.79, P = 0.044, respectively]. The presence of the C allele appeared to be associated with an increased risk of metastatic PCa with a gene dosage effect (aOR = 1.82, 95% CI = 1.23-2.68, P = 0.002). Similarly, significant findings were also observed when PCa patients were compared between those with organ-confined disease (stage A + B) and those with extra-prostatic extension (stage C + D). Furthermore, the C allele was present more frequently in patients with higher tumor grade. In conclusion, the IGFBP-3 -202 A/C polymorphism was not associated with susceptibility to PCa and BPH in Japanese men, but the presence of the C allele may cumulatively increase the risk for tumor metastasis and for having tumors with a biologically more aggressive phenotype. Because of the significant differences in incidence of clinically evident PCa according to racial backgrounds, the conjecture should be further examined in different racial populations.
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PMID:Insulin-like growth factor-binding protein-3 gene -202 A/C polymorphism is correlated with advanced disease status in prostate cancer. 1290 12

Cancers of the breast, prostate, and lung commonly metastasize to the bone resulting in osteolysis, pathologic fracture, pain and significant clinical morbidity. To date, the reason for such selectivity in the site of metastasis remains largely unknown. The bone is a rich source of many chemokines and growth factors, including: insulin-like growth factor (IGF) I and II, transforming growth factor-beta (TGF-beta), interleukins, and tumour necrosis factor-alpha (TNF-alpha). We propose that exposure of breast cancer cells to the bone microenvironment results in alterations in gene expression that favour the growth and proliferation of tumour cells in the bone. To investigate this hypothesis, MDA-MB-231 breast carcinoma cells were exposed to bone-derived conditioned media (BDCM) generated by culturing fetal rat calvaria for 24 h under serum free conditions. Using cDNA microarray technology, we have identified the insulin-like growth factor family of binding proteins (IGFBPs) as genes whose expression profiles are consistently and significantly altered with exposure to this simulated bone environment in vitro, when compared to untreated controls. Our data suggests that the upregulation of IGFBP-3 seen with exposure to the bone microenvironment is directly linked to an increase in TGF-beta mediated cell proliferation. Furthermore, this process appears to be functioning through an IGF-independent mechanism.
Clin Exp Metastasis 2003
PMID:Role of insulin-like growth factor binding proteins (IGFBPs) in breast cancer proliferation and metastasis. 1459 81

Multiple large case-control studies in the past five years have reported positive associations between high circulating levels of the insulin-like growth factor (IGF)-I and risk for different types of cancer. Correlations certainly do not prove causation, but the reproducibility of this finding implies this is a hypothesis worth further examination through more mechanistic studies. IGF-I binds to the IGF-I receptor, a tyrosine kinase receptor that transduces signals to the nucleus and mitochondrion primarily via the mitogen-activated protein kinase (MAPK) and PI3K/Akt pathways. Examples will be provided to illustrate how IGF-I signaling may contribute to each stage of cancer progression: malignant transformation, tumor growth, local invasion and distant metastases, and resistance to treatment. In addition to direct contributions to each of these stages, IGF-I may promote cancer indirectly, through interactions with oncogenes and tumor suppressors, interactions with other hormones (especially the sex steroids in breast and prostate cancers) and interactions with the IGF binding proteins (IGFBPs). Finally, circulating IGF-I may facilitate cancer development though it likely does not cause cancer to form. Prompted by the accumulating evidence, investigations are also being pursued to modulate the IGF system as a possible means of cancer prevention or treatment.
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PMID:Mechanisms by which IGF-I may promote cancer. 1468 66

The receptor for the type 1 insulin-like growth factor (IGF-IR) was identified as a major regulator of the malignant phenotype and a target for cancer therapy. In the present study, a novel IGF-IR mutant consisting of the entire extracellular domain of the receptor (IGFIR(933)) was genetically engineered and expressed in highly metastatic H-59 murine lung carcinoma cells. We show here that the cells expressed a truncated heterotetramer (beta(m)-alpha-alpha-beta(m)) that was secreted into the medium and could neutralize the effects of exogenous IGF-I, thus diminishing IGF-I-induced signaling and blocking IGF-I-mediated cellular functions such as cell proliferation, invasion, and survival. In vivo, tumor incidence and growth rate were markedly reduced in mice inoculated s.c. with H-59/IGFIR(933) cells. Moreover, after the intrasplenic/portal inoculation of these cells, there was a 90% reduction in the incidence of hepatic metastases and a significant increase in the long-term, disease-free survival of the mice compared with controls. Our results identify the IGFIR(933) as a potent antitumorigenic and antimetastatic agent with potential applications for cancer gene therapy.
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PMID:Loss of tumorigenicity and metastatic potential in carcinoma cells expressing the extracellular domain of the type 1 insulin-like growth factor receptor. 1515 88

Extracranial multiple metastases from meningeal hemangiopericytoma have been reported only rarely. The authors describe the case of a 61-year-old woman, who was previously diagnosed as having primary meningeal hemangiopericytoma with its multiple metastases to the liver, lumbar spine, etc. and who suffered from a sudden attack of hypoglycemia. Considering the history of her present illness, this hypoglycemic shock was most likely brought on by the remarkable metastatic tumors to the liver. Recent literature pertinent to hypoglycemia suggests that insulin-like growth factor-II (IGF-II) produced by tumor is strongly suspected to be involved in the development of hypoglycemia.
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PMID:[Multiple extracranial metastases from a meningeal hemangiopericytoma and severe hypoglycemia: a case report]. 1522 44

In this review we bring forward what is currently known about the role of type I insulin-like growth factor receptor (IGF-1R) in mediating breast cancer invasion and metastasis. We begin by addressing how activated IGF-1R could allow pre-cancerous cells to become invasive. To this effect, we discuss clinical reports suggesting that activation of IGF-1R could stimulate ductal carcinoma in situs to become invasive. In the same light, we review basic research from our laboratory showing that IGF-1R differentially regulates the expression of breast cancer progression genes when pre-malignant breast epithelial cells were stimulated with insulin-like growth factor-I (IGF-I) over time. The discussion then turns toward the ability of IGF-1R to stimulate invasion of breast cancer cells that have acquired a malignant phenotype. At this stage of breast cancer, it appears that IGF-I stimulates cells to invade in part by inducing urokinase plasminogen activator. Finally, we consider the potential role of IGF-1R in regulating breast cancer metastases by facilitating angiogenesis and lymphangiogenesis. In support of this idea, there is evidence for IGF-1R in both of these processes through the induction of vascular endothelial growth factors (VEGF(165) and VEGF(121)). Thus, IGF-1R affords breast cancer cells many opportunities to become invasive and eventually metastatic. We conclude that disrupting IGF-1R signaling has many important implications in the treatment and management of breast cancer.
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PMID:Role of IGF-1R in mediating breast cancer invasion and metastasis. 1568 76

This review examines the rationale for targeting the insulin-like growth factor (IGF)-I receptor in the therapy of human tumours and their metastases. The rationale is based on two crucial findings: 1) in experimental animals, normal cells are only partially affected by the deletion of the IGF-I receptor, whereas tumour cells undergo apoptosis when the IGF-I receptor is downregulated; and 2) cells with a deleted IGF-I receptor are refractory to transformation by viral and cellular oncogenes. This review focuses on the mechanisms underlying the experimental findings, and discusses the possibility of extrapolating the results obtained in animals to the cure of human tumours.
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PMID:The insulin-like growth factor-I receptor as a target for cancer therapy. 1608 41


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