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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate cancer chemoprevention can be described as the administration of natural products and pharmaceutical agents that inhibit one or more steps in the natural history of prostatic carcinogenesis. The principle components of the chemoprevention strategy are closely connected to this natural history and include: (a) agents and their molecular targets; (b) strategic intermediate endpoint biomarkers (IEBs) and their critical pathways; (c) cohorts identified by genetic and acquired risk factors and (d) efficient designs that combine these elements into a cohesive clinical trial. The primary goal is to find effective noncytotoxic agents that modulate the promotion and progression from normal epithelium to dysplasia to high-grade prostatic intraepithelial neoplasia (HGPIN) to locally invasive cancer and metastatic disease. Another important target for chemoprevention is to modulate progression to clinically aggressive disease and to maintain an androgen-sensitive clinical state and delay the emergence of androgen resistance. There is a rationale for use of antiandrogens as the lead class, e.g., 5 alpha receptor inhibitors (5ARI), for chemoprevention of prostate cancer. Nevertheless, the desire to improve the therapeutic index, achieve synergy (5ARI may have only modest anticancer effects) and prevent the emergence of drug (androgen) resistance provide incentives for developing other effective agents and combinations. The availability of more than a dozen classes of noncytotoxic pharmaceutical and natural products already in clinical development create many opportunities for rational combination therapy. Several agent classes have a pharmacodynamic basis for combination with antiandrogens including antiproliferatives, selective estrogen receptor modulators (SERMs), proapoptotic antioxidant micronutrients and selective cyclo-oxygenase (COX)-2 inhibitors. Many other rational pharmacodynamic combinations without antiandrogens are feasible. It is anticipated that in the future, a selective COX-2 inhibitor may be combined with other agent classes such as proapoptotic antioxidant micronutrients, receptor tyrosine kinase modulators, antiangiogenic modulators, antiproliferative/differentiating agents, NFkappaB modulators, IGF-1 modulators and other novel proapototic nonsteroidal drugs. A novel target for rational combinations is the hypermethylation of GST-PI leading to functional silencing of this key anticarcinogen defense enzyme in precursors (HGPIN) and prostate cancer. Factorial designs are well suited for evaluating the individual and combined effects of each agent in a single trial design. There are a number of moderate to high-risk cohorts and clinical models of primary and secondary prevention that can be employed in both short-term developmental (translational) trials for proof of biologic activity and in intermediate sized longer-term chemoprevention trials for proof of efficacy against prostate cancer. Strategic IEBs are needed to more efficiently monitor short-term biologic activity and validate efficacy. The emergence of new powerful tools such as gene chip cDNA microarrays for multiplex gene expression profiling and proteomic analysis of tissue based and secreted proteins will accelerate the identification of new molecular targets, strategic endpoints, cohorts at risk and the design of rational combination trials.
Cancer Metastasis Rev 2002
PMID:Chemoprevention of prostate cancer: current status and future directions. 1254 68

To understand alterations to the urokinase system that may occur in progressively metastatic prostate cancer cells, we assessed urokinase plasminogen activator receptor (uPAR) expression, in vitro motility towards vitronectin, urokinase plasminogen activator (uPA)-induced growth and growth factor regulation of uPAR expression in three cell lines--PC-3 and two derivatives from secondary metastases, PC-3M and PC-3MM2. DU-145 and Tsu-Pr1 cells were included for comparative purposes. uPAR expression increases with metastatic passage in these cell lines and accompanies increased growth and motility responses in the presence of uPA. Growth factors TGFbeta1 and IGF-1 induce uPAR in all three prostate cancer lines; however, PC-3M and PC-3MM2 cells also respond to bFGF. Of the cell lines tested, PC-3MM2 most uniformly respond to added TGFbeta1, IGF-1 and bFGF. These results show that in two progressive derivatives from repeated metastasis of PC-3 cells, constitutive and growth factor-induced uPAR expression is enhanced. This increased uPAR facilitates the properties of growth and motility.
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PMID:Increased levels of urokinase plasminogen activator receptor in prostate cancer cells derived from repeated metastasis. 1505

Recent epidemiological studies have suggested a statistical connection between serum IGF-1 levels in the upper quartile of the normal range and the relative risk of developing certain cancers. Our studies have focused on mouse models where circulating IGF-1 levels are reduced, while tissue expression of IGF-1 is normal. These mice show a lower risk for the development of colon and breast cancers and metastases when compared with control mice, and lend support to the hypothesis that circulating IGF-1 may be linked to cancer cell growth.
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PMID:Circulating IGF-1 and its role in cancer: lessons from the IGF-1 gene deletion (LID) mouse. 1556 20

By virtue of their potent proliferative and anti-apoptotic effects, the insulin-like growth factors (IGFs) have been the subject of long-term scrutiny for their role in tumorigenesis. With regard to prostate cancer in particular, IGF-1 has been shown to stimulate the proliferation of human prostate epithelial cells in culture and to be necessary for normal growth and development of the rat and mouse prostate. Epidemiological studies have established a link between high circulating serum IGF-1 levels and the risk of later developing advanced prostate cancer, and overexpression of IGF-1 in the prostate basal epithelial layer of transgenic mice results in prostate adenocarcinoma that is similar to human disease. Thus, IGF-1 action appears to be important for prostate cancer initiation. On the other hand, decreased IGF action, subsequent to the down-regulation of IGF-1 receptor expression, is associated with advanced, metastatic disease. This decrease in IGF-1 receptor may confer a survival advantage to prostate cancer cells that have entered the circulation by making them resistant to the differentiative effects of IGF-1 at metastatic sites such as bone. The molecular mechanisms that effect IGF-1 receptor down-regulation appear to involve novel oncogenic functions of the Wilms' tumour suppressor, as well as novel actions of the androgen receptor.
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PMID:IGF-1 and prostate cancer. 1556 30

It is a long-standing clinical observation that the bone corresponds to the prevalent site for metastatic growth of prostate cancer. In addition, bone metastases of this malignancy produce a potent blastic reaction, in contrast to the overwhelming majority of other osteotropic neoplasms, whose metastases are generally associated with an osteolytic reaction. Osteoblastic metastases represent almost always the first and, frequently, the exclusive site of disease progression to hormone refractory stage, stage D3. Moreover, the number of skeletal metastatic foci is the most powerful independent prognostic factor associated with a limited response to hormone ablation therapy and poor survival of advanced prostate cancer. It is noteworthy that disease progression to hormone refractory stage occurs almost always in osteoblastic metastases. These clinical observations suggested that the osteoblastic reaction is possibly not an innocent bystander of the metastatic prostate tumour growth, simply suffering its consequences, but it may in fact facilitate the efforts of metastatic cells to expand their population. An extensive line of research in the pathophysiology of osteoblastic metastases has established that the local blastic reaction involves the uPA/plasmin/IGF/IGFBP-3/TGFbs bioregulation system which can stimulate both the growth of osteoblasts and prostate cancer cells. Furthermore, we were the first to characterize osteoblast-derived 'survival factors' able to rescue metastatic prostate cancer cells from chemotherapy-induced apoptosis. These data resulted in the development of a novel concept of an anti-survival factor therapy, namely an anti-IGF-1 therapy, which has provided encouraging preliminary data in a phase II clinical trial with terminally-ill hormone/chemotherapy-resistant prostate cancer patients.
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PMID:Cancer and bone repair mechanism: clinical applications for hormone refractory prostate cancer. 1575 19

Ectopic acromegaly represents less than 1% of the reported cases of acromegaly. Although clinical improvement is common after treatment with somatostatin (SMS) analogs, the biochemical response and tumor size of the growth hormone-releasing hormone (GHRH)-producing tumor and its metastases are less predictable. Subject A 36-year-old male was referred because of a 3-year history of acromegaly related symptoms. He had undergone lung surgery in 1987 for a "benign" carcinoid tumor. Endocrine evaluation confirmed acromegaly Plasma IGF-1: 984 ng/ml (63-380), GH: 49.8 ng/ml (<5). MRI showed a large mass in the left cerebellopontine angle and diffuse pituitary hyperplasia. Pulmonary, liver and bone metastases were shown by chest and abdominal CT scans. Ectopic GHRH secretion was suspected. Methods Measurement of circulating GHRH levels by fluorescence immunoassay levels and immunohistochemical study of the primary lung tumor and metastatic tissue with anti-GHRH and anti-somatostatin receptor type 2 (sst2A) antibodies. Results Basal plasma GHRH: 4654 pg/ml (<100). Pathological study of liver and bone biopsy material and lung tissue removed 19 years earlier was consistent with an atypical carcinoid producing GHRH and exhibiting sst2A receptor expression. Treatment with octreotide LAR 20-40 mg q. month resulted in normalization of plasma IGF-1 levels. Circulating GHRH levels decreased dramatically. The size of the left prepontine cistern mass, with SMS receptors shown by a radiolabeled pentetreotide scan, decreased by 80% after 18 months of therapy. Total regression of pituitary enlargement was also observed. No changes were observed in lung and liver metastases. After 24 months of therapy the patient is asymptomatic and living a full and active life.
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PMID:Ectopic growth hormone-releasing hormone secretion by a metastatic bronchial carcinoid tumor: a case with a non hypophysial intracranial tumor that shrank during long acting octreotide treatment. 1737 89

Metastasis is the primary cause of death from breast cancer. Cell migration and invasion play important roles in neoplastic metastasis. The insulin-like growth factor (IGF-1) stimulates cell migration through activation of PI-3K/Akt signaling pathway. IGF-1 induces the tumorigenicity of many types of cancer cells and is critical for metastatic cell spread in estrogen receptor (ER)-negative breast-cancer cells. Matrix metalloproteinase-2 (MMP-2) is a key enzyme in the degradation of extracellular matrices and its expression has been dysregulated in breast cancer invasion and metastasis. Resveratrol exhibited potential anticarcinogenic activities in several studies. However, the inhibitory effects of resveratrol on the expression of MMP-2, migration and invasion of breast-cancer cell have not been demonstrated yet. In the present study, we investigated the anti-invasive mechanism of resveratrol in human breast cancer MDA-MB 435cells. Here, we showed that IGF-1 is a potent stimulant of the migration of ER-negative human breast-cancer cells. Resveratrol could inhibit IGF-1-mediated cell migration of MDA-MB 435 in vitro. The inhibitory effect of resveratrol was mediated in part through the suppression of the activation of PI-3K/Akt signaling pathway. Furthermore, IGF-1-mediated expression of MMP-2 was significantly inhibited by resveratrol in concomitance with alteration of cell invasion.
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PMID:Resveratrol inhibits migration and invasion of human breast-cancer cells. 1839 72

Androgen refractory cancer of the prostate (ARCaP) cells contain androgen receptor (AR) and synthesize and secrete prostate specific antigen (PSA). We isolated epithelia-like ARCaP(E) from parental ARCaP cells and induced them to undergo epithelial-mesenchymal transition (EMT) by exposing these cells to soluble factors including TGFbeta1 plus EGF, IGF-1, beta2-microglobulin (beta2-m), or a bone microenvironment. The molecular and behavioral characteristics of the resultant ARCaP(M) were characterized extensively in comparison to the parental ARCaP(E) cells. In addition to expressing mesenchymal biomarkers, ARCaP(M) gained 100% incidence of bone metastasis. ARCaP(M) cells express receptor activator of NF-kappaB ligand (RANKL), which was shown to increase tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts in culture, and when metastatic to bone in vivo. We provide evidence that RANKL expression was promoted by increased cell signaling mediated by the activation of Stat3-Snail-LIV-1. RANKL expressed by ARCaP(M) cells is functional both in vitro and in vivo. The lesson we learned from the ARCaP model of EMT is that activation of a specific cell signaling pathway by soluble factors can lead to increased bone turnover, mediated by enhanced RANKL expression by tumor cells, which is implicated in the high incidence of prostate cancer bone colonization. The ARCaP EMT model is highly attractive for developing new therapeutic agents to treat prostate cancer bone metastasis.
Clin Exp Metastasis 2008
PMID:Epithelial to mesenchymal transition (EMT) in human prostate cancer: lessons learned from ARCaP model. 1853 13

Uveal melanoma is the most common primary intraocular malignant tumor in adults with 30% to 50% of patients that ultimately succumb to metastatic disease, mainly to the liver. (Shields et al. 1991) Although new diagnostic and therapeutic tools have been developed during the most recent years, only the eye conservation rate has been achieved, while the survival rate remains poor. The reason for this liver-homing is largely unknown, but it is conceivable that hepatic environmental factors may be implicated in the growth, dissemination, and progression of this malignancy. The insulin-like growth factor (IGF-1) that binds to the IGF-1 receptor (IGF-1R) is mainly produced in the liver. It has been shown to be crucial for tumor transformation, maintenance of malignant phenotype, promotion of cell growth, and prevention of apoptosis. (Baserga 1995) The hepatocyte growth factor/scatter factor (HGF/SF) is another growth factor produced in the liver and exerts its biological effects through binding to the plasma membrane receptor c-Met. The activation of this receptor by HGF/SF ligand can induce proliferation, motility, adhesion, and invasion of tumor cells. (Cruz et al. 2003) Metastasis is a process involving many components, including tumor cell adhesion, migration, extracellular matrix (ECM) proteolysis, and invasion. The tumor cells undergo intravasation, disperse via the vascular and the lymphatic systems, and finally extravasate to invade the secondary sites. In all these steps, proteolytic enzyme systems are involved, including the matrix metalloproteinase (MMP) system and the plasminogen activation system. The migration of a malignant cell through the ECM and the basement membrane requires proteolytic activities. (Stetler-Stevenson et al. 1993). Efforts to target the IGF-I system has been made with different types of cancer but not with uveal melanoma.
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PMID:Uveal melanoma and macular degeneration: molecular biology and potential therapeutic applications. 1908 34

Ectopic secretion of growth hormone-releasing-hormone (GHRH) is a rare cause of acromegaly-representing less than 1% of patients. A 25-year-old woman was admitted to the hospital with acromegaly and a 6 x 6 cm infrahepatic mass. Sellar magnetic resonance imaging indicated diffuse pituitary enlargement consistent with hyperplasia. The infrahepatic mass was resected, and the histopathological diagnosis was a well-differentiated invasive neuroendocrine carcinoma of the duodenum with metastases to local lymph nodes. The tumor cells contained cytoplasmic immunoreactivity for GHRH. Because increased IGF-1 concentrations persisted after the operation, the patient was treated with octreotide long-acting repeatable (LAR) injections of 20 mg/month. Growth hormone and IGF-1 levels normalized. After 6 years of surveillance, a left paraaortic mass was detected by uptake of indium 111 octreotide. Surgical exploration revealed metastatic neuroendocrine carcinoma in a 2.5-cm lymph node. Postoperatively, the IGF-1 concentration was mildly elevated. Octreotide LAR therapy is being continued at 10 mg/month. This case suggests that octreotide treatment may have a beneficial effect on disease course and can be maintained for as long as 7 years in a patient with acromegaly due to a GHRH-secreting neuroendocrine carcinoma.
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PMID:Ectopic growth hormone-releasing hormone secretion by a neuroendocrine tumor causing acromegaly: long-term follow-up results. 1930 Nov 54


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