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)

We analyzed the use of different promoters and the splicing patterns of the exons encoding 5'- and 3'-untranslated sequence amounts of parathyroid hormone-related protein (PTHrP) gene products in breast cancers. Tumor samples from 74 cases of primary breast cancer that had been followed from 1 to 14 years were selected retrospectively according to the occurrence of metastasis: 18 patients developed no metastasis (NM), 56 developed metastases (M), 22 of whom developed metastases in soft tissues (MB-) and 34 of whom developed bone metastases (MB+). The amount of the 1-139 isoform mRNA was much higher in the tumors of patients who later developed metastases (M: 0.29 +/- 0.03) than in those of patients who developed no metastases (NM, 0.13 +/- 0.03; p < 0.01). This isoform mRNA was also more abundant in breast tumors from patients who developed bone metastases (MB+, 0.39 +/- 0.04) than in those of patients who developed metastases in soft tissues (MB-, 0.15 +/- 0.03; p < 0. 0001). By contrast, the amounts of the 1-141 isoform mRNA in these three groups of tumors were similar, but its concentration was higher in the tumors of premenopausal women than in those of postmenopausal women (p < 0.05). Analysis with 5' untranslated regions-specific primers showed transcription from all three putative transcription start sites of PTHrP (P1, P2, and P3). The P3-initiated transcripts were more abundant in patients who developed metastases (M, 0.31 +/- 0.03) than in the nonmetastatic tumors (NM, 0.13 +/- 0.03; p < 0.01). The amount of P3 element did not differ with the site of metastasis (BM+, 0.32 +/- 0.05; BM-, 0. 28 +/- 0.05; NS). The same trend was observed for the P2 element. However, the use of P2-initiated messages was strongly associated with the absence of estrogen receptors from the breast tumors (p < 0. 01). We thus find a close association between the pattern of PTHrP gene expression and the outcome of breast cancer. The P3-initiated start site and the presence of PTHrP 139 mRNA could help identify patients at risk of developing metastases.
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PMID:The parathyroid hormone-related protein (PTHrP) gene: use of downstream TATA promotor and PTHrP 1-139 coding pathways in primary breast cancers vary with the occurrence of bone metastasis. 1002 5

The purpose of this study was to estimate clinical validity of a new available immunoradiometric assay for circulating intact human BGP (N-tact Osteo SP) by measuring this protein in a large number of normal subjects and patients with the most common metabolic bone diseases. One hundred normal subjects were studied in order to obtain our normal ranges (4.9 +/- 1.7 ng/ml). The mean values found in 28 patients with primary hyperparathyroidism (17.5 +/- 22.8 ng/ml, P < 0.001), 15 glucocorticoid-treated patients (1.9 +/- 1.5, P < 0. 001), 10 patients with hypoparathyroidism (1.5 +/- 0.7, P < 0.001), 9 with hyperthyroidism (8.3 +/- 3.8, P < 0.001), 8 with skeletal metastases (7.2 +/- 2.3, P < 0.001), and 4 with humoral hypercalcemia of malignancy (2.42 +/- 1.91, P < 0.005) were significantly different from mean values found in normal subjects. Mean decrease of serum osteocalcin T-score values was significantly greater when evaluated by N-tact Osteo SP assay in 15 steroid-treated patients (-1.4 +/- 1.0) and 19 primary hyperparathyroid (PHPT) patients (3.6 +/- 1.9), compared with the mean values obtained with the Elsa-Osteo assay (-0.67 +/- 1.2, P < 0. 002 and 4.3 +/- 2.8, P < 0.04, respectively). We found significant correlations between the global skeletal uptake of 99mTc-methylendiphosphonate and serum BGP levels assayed by both N-tact Osteo SP (P < 0.01) and Elsa-Ost-Nat assay (P < 0.05). Our results indicate that this new immunoradiometric assay for the intact human osteocalcin has the potential for good discrimination between normal subjects and patients with both low and high bone turnover. Furthermore, our findings emphasize the fact that, in the absence of available standardized commercial assays, one should rely on only one assay because different results are obtained by different assays under different clinical conditions.
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PMID:Clinical validation of a new immunoradiometric assay for intact human osteocalcin. 1020 10

The purpose of the present study was to clarify the relationship of parathyroid hormone-related protein (PTHrP) to the oncogenesis and progression of colorectal adenocarcinoma. A total of 108 colorectal tumours, including 12 adenomas, six adenocarcinomas in adenomas, and 90 adenocarcinomas, were studied. Immunohistochemistry, in situ hybridization, and reverse transcription-polymerase chain reaction (RT-PCR) techniques were used to evaluate the expression of PTHrP. Positivity of immunostaining for PTHrP was defined as highly positive (++), slightly positive (+), and negative (-). None of the adenomas of background non-neoplastic mucosal epithelia showed immunostaining of PTHrP. In contrast, PTHrP was expressed in 85 (94.4 per cent) of 90 colorectal adenocarcinomas. Immunoreactivity of PTHrP was greater in poorly differentiated adenocarcinomas than in well-differentiated ones. Furthermore, advancing margins of primary tumours stained more intensely than other sites. Highly positive immunoreactivity of PTHrP, classified by histological invasiveness, was 22.6 per cent within the muscularis propria and 69.5 per cent beyond the muscularis propria. PTHrP expression was significantly correlated with differentiation, depth of invasion, lymphatic invasion, lymph node metastasis, hepatic metastases, and Dukes' classification. In carcinoma, PTHrP mRNA expression was evident in tumour cells by in situ hybridization. PTHrP transcripts were also detected in two resected human colorectal adenocarcinomas by RT-PCR. These findings suggest that PTHrP is related to carcinogenesis, differentiation, progression, and prognosis of colorectal adenocarcinomas.
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PMID:Clinicopathological implications of parathyroid hormone-related protein in human colorectal tumours. 1036 97

A 46-year-old man was diagnosed as Stage IV lung cancer with neck lymph node and bilateral adrenal metastases. He was treated with seven courses of combined chemotherapy (CDDP + etoposide), until he showed extreme hypercalcemia and acute renal failure. The bisphosphonate, pamidronate with elcatonin and prednisolone dramatically lowered his serum calcium level and normalized his renal function. This is a representative case of humoral hypercalcemia of malignancy whose serum calcium could be safely and effectively controlled with pamidronate.
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PMID:[A case of lung cancer with hypercalcemia and renal failure responsive to pamidronate]. 1041 Jan 54

Breast cancer affects approximately one woman in twelve and kills more women than any other cancer. If detected early, patients have a five year survival rate of 66%, but once metastatic disease has developed, there is no effective treatment. About 70% of patients with metastatic disease have bone involvement, while lungs and liver are the other common targets. Bone metastases cause severe pain, pathological fractures and hypercalcaemia and thus are a significant clinical problem. The development of new therapies for metastatic breast carcinoma depends on a better understanding of the mechanism of homing of the tumour cells to bone, liver and lungs and the factors required for their growth in these organs. Research on mechanisms of breast cancer metastasis, particularly to bone, has relied on in vitro studies or on tumour models in which the inoculation route is designed to promote delivery of tumour cells to a specific organ. Metastases in bone are achieved by inoculation into the right ventricle of the heart. To our knowledge there has been no report of a model of metastatic spread from the mammary gland to distant sites which reliably includes bone. In this paper, we describe our recent development of a novel murine model of metastatic breast carcinoma. The new model is unique in that the pattern of metastatic spread closely resembles that observed in human breast cancer. In particular, these murine breast tumours metastasise to bone from the primary breast site and cause hypercalcaemia, characteristics not normally found in murine tumours, but common in human disease. Furthermore, in a preliminary characterisation of this model, we show that secretion of parathyroid hormone-related protein, a role for which has been implicated in breast cancer spread to bone, correlates with metastasis to bone. This model therefore provides an excellent experimental system in which to investigate the factors that control metastatic spread of breast cancer to specific sites, particularly bone. The special advantage of this system is that it involves the whole metastasis process, beginning from the primary site. Existing models consider mechanisms that pertain to growth of tumour once the site has been reached. An understanding of the regulation of these factors by potential therapeutic agents could lead to improvement in therapies designed to combat metastatic disease. For the first time, this development will allow exploration of the molecular basis of site-specific metastasis of breast cancer to bone in a clinically relevant model.
Clin Exp Metastasis 1999 Mar
PMID:A novel orthotopic model of breast cancer metastasis to bone. 1041 Nov 9

Breast cancers commonly cause osteolytic metastases in bone, a process that is dependent upon osteoclast-mediated bone resorption. Recently the osteoclast differentiation factor (ODF), better termed RANKL (receptor activator of NF-kappaB ligand), expressed by osteoblasts has been cloned as well as its cognate signaling receptor, receptor activator of NFkappaB (RANK), and a secreted decoy receptor osteoprotegerin (OPG) that limits RANKL's biological action. We determined that the breast cancer cell lines MDA-MB-231, MCF-7, and T47D as well as primary breast cancers do not express RANKL but express OPG and RANK. MCF-7, MDA-MB-231, and T47D cells did not act as surrogate osteoblasts to support osteoclast formation in coculture experiments, a result consistent with the fact that they do not express RANKL. When MCF-7 cells overexpressing PTH-related protein (PTHrP) were added to cocultures of murine osteoblasts and hematopoietic cells, osteoclast formation resulted without the addition of any osteotropic agents; cocultures with MCF-7 or MCF-7 cells transfected with pcDNAIneo required exogenous agents for osteoclast formation. When MCF-7 cells overexpressing PTHrP were cultured with murine osteoblasts, osteoblastic RANKL messenger RNA (mRNA) levels were enhanced and osteoblastic OPG mRNA levels diminished; MCF-7 parental cells had no effect on RANKL or OPG mRNA levels when cultured with osteoblastic cells. Using a murine model of breast cancer metastasis to bone, we established that MCF-7 cells that overexpress PTHrP caused significantly more bone metastases, which were associated with increased osteoclast formation, elevated plasma PTHrP concentrations and hypercalcaemia compared with parental or empty vector controls.
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PMID:Breast cancer cells interact with osteoblasts to support osteoclast formation. 1049 98

Parathyroid hormone-related protein (PTHrP) is a key factor behind humoral hypercalcemia of malignancy (HHM). It is produced in most breast tumors and may be an important local mediator of skeletal metastases due to breast cancer. PTHrP may mediate local bone destruction in the absence of increased circulating PTHrP. Calcitonin (CT) is used for treatment of HHM, but there are data showing that CT can increase PTHrP expression and secretion in vitro. We have therefore studied the effect of CT on PTHrP gene expression and secretion in MCF-7 breast cancer cells. PTHrP mRNA decreased significantly after 4, 8, and 16 h incubation with 10 nM salmon calcitonin (sCT) when compared with the respective controls. PTHrP mRNA also decreased significantly and dose-dependently after incubation with sCT at 0.1 to 10 nM for 16 h. The PTHrP levels in the conditioned medium also decreased in a similar dose-dependent manner. The adenylate cyclase agonist forskolin lowered the PTHrP mRNA dose-dependently. In cells exposed to varying concentrations of sCT for 15 min, the cAMP levels increased dose-dependently. In conclusion, sCT can suppress PTHrP gene expression in MCF-7 breast cancer cells. The suppressive effect is probably exerted mainly via the cAMP-protein kinase A pathways.
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PMID:Calcitonin-suppressed expression of parathyroid hormone-related protein in breast cancer cells. 1054 24

MECHANISMS OF BONE LOSS: In patients with bone metastases, bone loss is the consequence of a dissociated process combining excessive bone resorption and inhibited bone formation. This destructive process occurs in response to soluble factors secreted by metastatic cells (PTH-rP, cytokines) which activate osteoclasts. These cells also secrete proteases (cathepsin K, metalloprotease MMP-9) which degrade the bone's collagen network. Excessive bone resorption is also favored by direct interaction between the metastatic cells and stromal cells in the bone marrow in response to the activation of membrane receptors (integrins a4 beta 1 and a4 beta 7). Finally, metastatic cells secrete non-identified soluble factors capable of inhibiting osteoblast proliferation in vitro. EFFECT OF BONE LOSS ON THE METASTASIS: Bone is a major reservoir of growth factors (mainly TGF beta and IGF-1). Positive feedback mechanism operates at the site of osteolysis where TGF beta released by bone tissue induces a paracrine stimulation of PTH-rP production by metastatic cells. IGF-1 released by the bone favors grow of metastatic cells present in the marrow. In addition, IGF-1 as well as collagen proteolytic fragments may stimulate recruitment of new metastatic cells at the site of the bone metastasis. This creates a vicious circle of mutual stimulation between bone destruction and tumor proliferation.
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PMID:[Bone hyperresorption in bone metastases]. 1074 42

Parathyroid hormone-related protein (PTHrP) is the major mediator of the humoral hypercalcemia of malignancy and of malignant osteolysis associated with skeletal metastases of common epithelial cancers. PTHrP secretion is regulated by the extracellular calcium concentration ([Ca(2+)](o)) in several types of normal and malignant cells. Because the [Ca(2+)](o)-sensing receptor (CaR) is a key mediator of [Ca(2+)](o)-regulated hormone secretion [e.g., of parathyroid hormone (PTH) by parathyroid chief cells], we investigated the expression of the CaR and PTHrP in normal and neoplastic glial cells and studied the effects of [Ca(2+)](o) on PTHrP secretion. Our results show that primary embryonic human astrocytes (HPA) express CaR mRNA and protein as detected by RT-PCR and Western analysis, respectively. Furthermore, astrocytomas and meningiomas also express the CaR at similar levels as assessed by RT-PCR and Northern and Western blot analyses. HPA and astrocytomas express transcripts encoding all three known isoforms of PTHrP [PTHrP(139), PTHrP(141), and PTHrP(173), comprising 139, 141, and 173 predicted amino acid residues, respectively] as assessed by RT-PCR, whereas meningiomas express only the first two of these. Finally, elevated levels of [Ca(2+)](o) and other polycationic CaR agonists dose dependently stimulate PTHrP secretion from HPA, astrocytomas, and meningiomas, although both basal and high [Ca(2+)](o)-stimulated rates of PTHrP secretion are approximately 2. 5-fold higher in HPA than in the glial tumors studied here. Therefore, our results show that HPA, astrocytomas, and meningiomas express both the CaR and PTHrP and that CaR agonists stimulate PTHrP secretion.
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PMID:Regulation of secretion of PTHrP by Ca(2+)-sensing receptor in human astrocytes, astrocytomas, and meningiomas. 1094 19

Parathyroid hormone-related protein (PTHrP) is now well established as the major, if not the sole mediator of the humoral hypercalcaemia of malignancy. This is the phenomenon of elevated blood calcium in the absence of bony metastases in patients with certain solid tumours, most commonly squamous cell carcinoma (SCC) of the lung, but also occurring in SCC at other sites including skin, and other cancers including melanoma. Although discovered because of its hormonal action in cancer, there is at present no indication that PTHrP acts as a circulating hormone in normal animals or in humans after birth, with the possible exception of the period during lactation. Along with its significant effects on calcium metabolism in cancer patients, PTHrP is widely expressed in mammalian tissue, and evidence to date indicates that the major physiological role of PTHrP is as a paracrine factor affecting growth and development of cells in several tissues.
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PMID:Parathyroid hormone-related protein and skin cancer. 1099 65


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