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)

Skeletal metastases result from a series of complex steps including activation of osteoclasts and interaction between adhesion molecules on cancer cells and bone matrices. Researchers of this study used pathologic specimens of breast cancer cells from primary and metastatic sites obtained at surgery or autopsy to demonstrate the expression of parathyroid hormone-related protein by immunohistochemistry and beta 3 integrin by in situ hybridization to clarify the role of tumor-derived osteoclast activating factors and adhesion molecules in the development of skeletal metastases. The results of this retrospective study showed a significant difference of parathyroid hormone-related protein and beta 3 integrin expression in cases with and without skeletal metastases. These expressions were enhanced or clonally selected or both in skeletal metastatic sites. Because activation of osteoclastic bone resorption by parathyroid hormone-related protein could facilitate tumor cells to attach to the eroded bone surface through cell adhesion molecules, these 2 factors could make it easier for tumor cells to grow in bone.
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PMID:Development of skeletal metastases. 763 17

Parathyroid hormone-related protein (PTHrP) 1-86 was quantified by immunoassay in extracts of 132 breast cancers, 27 samples of normal breast tissue and four fibroadenomas. PTHrP 1-86, was detected in 68% of primary tumours (range 40-302,000 fmol/g), 33% of normal breast tissues (range 100-1800 fmol/g), and all four fibroadenomas (range 110-11,600 fmol/g). PTHrP displayed molecular heterogeneity on gel filtration chromatography, and 1-86, 1-34 and 37-67 immunoreactivity eluted as 25-27 kDa together with a peak of 19-21 kDA containing only 37-67 activity. Tumour PTHrP 1-86 levels correlated inversely with age (P < 0.05) and were higher in premenopausal women (P = 0.05). The proportion of tumours containing PTHrP was higher in axillary node positive premenopausal women (P < 0.05). These data suggest that oestrogen may regulate expression of PTHrP in breast cancer and that production of PTHrP may be linked to development of axillary node metastases.
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PMID:Parathyroid hormone-related protein (PTHrP) in breast cancer and benign breast tissue. 778 98

The relationship between the expression of parathyroid hormone-related protein (PTHrP) by breast cancer and skeletal metastases, was investigated using a monoclonal antibody against human PTHrP (4B3). The immunohistochemical localization of PTHrP was studied in sections of formalin-fixed, paraffin-embedded tissues from 28 breast cancers obtained surgically between 1980 and 1985. Of the 28 patients, 12 developed skeletal metastases, 8 developed lung metastases, and the other 8 were alive and disease-free at the time of this study. Sixteen of the 28 (57%) tumors showed positive immunoreactivity to 4B3, the PTHrP positive ratio being 83% in the patients who developed skeletal metastases, 38% in those who developed lung metastases, and 38% in those without recurrence, respectively. Thus, a significantly higher proportion of the patients who developed skeletal metastases were positive for PTHrP than the other two groups (P < 0.05). Furthermore, the level of positive staining was strongly related to positivity for estrogen and progesterone receptors (P < 0.01). These results are consistent with the hypothesis that PTHrP might be necessary for metastases to erode bone and grow in skeletal sites, and its expression could be related to certain hormones.
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PMID:The expression of parathyroid hormone-related protein in human breast cancer with skeletal metastases. 800 63

We determined the effect of raised serum levels of midregional (53-84) parathyroid hormone-related protein (PTHrP) on life expectancy in 59 cancer patients with first presentation of hypercalcemia. The patients were stratified according to the serum PTHrP levels measured on day 0 after fluid repletion prior to bisphosphonate therapy. Twenty-nine patients were assigned to group N (PTHrP < or = 21 pmol/L) and 30 to group E (PTHrP > 21 pmol/L). Breast cancers were more common in group N, squamous cell cancers predominated in group E (p < 0.02). More patients with normal PTHrP had skeletal metastases, whereas group E was characterized by a higher incidence of prognostically unfavorable visceral involvement (p < 0.001). Bisphosphonates (pamidronate or BM.210955) were administered on day 0. Within one week, normocalcemia (serum calcium < or = 2.6 mmol/L) was restored in 96% of patients in group N, compared to 70% of patients in group E (p < 0.01). On day 12, 7 patients with elevated PTHrP were still hypercalcemic. Although a comparable number of patients in the two groups received cytostatic treatment after day 12, objective tumor responses were seen only in group N (n = 6; p < 0.05). Calculated from the first occurrence of hypercalcemia, the median survival was 66 days in group N and 33 days in group E (log-rank test: p = 0.0456; Wilcoxon-Breslow test: p = 0.0475). We conclude that in hypercalcemia of malignancy raised serum levels of PTHrP indicate a reduced hypocalcemic response to bisphosphonates, a more advanced tumor state and, therefore, an extremely poor prognosis.
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PMID:Parathyroid hormone-related protein and life expectancy in hypercalcemic cancer patients. 817 89

Parathyroid hormone-related protein (PTHrP) is associated with the syndrome of humoral hypercalcemia of malignancy. A high incidence of positive staining for PTHrP is observed in breast cancer and positivity is more frequent in patients who develop bone metastases. We assessed the presence of PTHrP mRNA by using the polymerase chain reaction in 38 normocalcemic breast cancer patients with long-term follow-up (minimum, 5 years) selected for the presence or absence of later bone metastasis development. In all the patients except one, the PTHrP gene was expressed in the breast tumor. The level of amplified PTHrP complementary DNA was inversely related to age (P < 0.02) and positively related to the proportion of invaded nodes (P < 0.02) but was not related to the other usual prognostic factors. The level of PTHrP mRNA was not different between the group of patients without recurrence or metastases (n = 11) and the group of patients who later developed metastases in soft tissues (n = 10). By contrast, patients who subsequently developed bone metastases (n = 17) showed higher PTHrP gene expression than patients in the other two groups (P < 0.001). This study suggests that strong PTHrP gene expression in breast tumors is associated with the onset of bone metastases.
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PMID:Polymerase chain reaction analysis of parathyroid hormone-related protein gene expression in breast cancer patients and occurrence of bone metastases. 822 37

A two-site immunoradiometric assay (IRMA) of parathyroid hormone-related protein (PTHrP) was employed to react with circulating concentrations of PTHrP in 14 patients with hepatocellular carcinoma (HCC) and hypercalcemia (> 10.6 mg/dl). Eleven of them had unresectable lesions and three received transcatheter arterial chemo-embolization (TACE) treatment. Patients had no evidence of bony metastases and only one had evidence of a parathyroid lesion (by bone scan and serum parathyroid hormone level, respectively). The urinary cAMP level was increased in all patients, but the serum 1,25-dihydroxyvitamin D and plasma cAMP levels varied. Twelve patients had elevated alpha-fetoprotein (AFP) (> 400 ng/ml) and two of them had mildly elevated AFP levels (11 and 147 ng/ml). Their PTHrP concentrations were elevated (7.1 to 33.2 pmol/l), compared with normal levels obtained in our laboratory (< 3.5 pmol/l). A significant decrease in plasma PTHrP (from 27.4 to 5.2 pmol/l), serum calcium concentrations (from 16.3 to 9.4 mg/dl) and AFP levels (from 64,787 to 3129 ng/ml) was observed on the day following TACE treatment. These results, by using an improved technique, extend the findings that hypercalcemia in patients with HCC is associated with increased renal reabsorption of calcium and increased bone resorption of PTHrP generated by HCC.
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PMID:Hypercalcemia and parathyroid hormone-related protein in hepatocellular carcinoma. 829 94

Hypercalcemia is relatively frequent in malignancy with or without osteolytic bone metastases. It is thought that neoplastic cells may secrete substances which not only stimulate osteoclastic activity but are also capable of modifying the absorption, excretion, and resorption of calcium and phosphate ions. Since 1987, we have studied 24 breast cancer patients with hypercalcemia (22 with bone metastases and two without). The group of 22 patients with bone metastases were divided into two subgroups. The first consisted of 10 patients with high serum levels of humoral factors, such as parathyroid hormone-related protein (PTHrP), and/or prostaglandin E2 (PGE2) and/or interleukin 1 (IL-1), and high levels of bone markers, such as alkaline phosphatase, bone Gla protein and urinary hydroxyproline. The second subgroup consisted of 12 patients with high levels of bone markers alone. Bone histologic analysis showed an osteoclastic activation surrounding metastatic tumor tissue in six out of 10 patients of the first subgroup, while an evident osteolysis caused by the tumor cells was noted in seven out of 12 patients of the second subgroup. The two patients without bone metastases showed normal biochemistry and bone histologic examination. The authors, having tried to explain the pathogenesis of hypercalcemia, emphasize the importance of humoral factors secreted by tumor cells as a direct or indirect cause of hypercalcemia. The origin of hypercalcemia remains unclear in two patients without bone metastases.
Clin Exp Metastasis 1993 Sep
PMID:Hypercalcemia in breast cancer. 837 11

The variability of different primary tumors in the susceptibility to metastatic bone disease is poorly understood. Factors that determine the viability of metastatic cells are also poorly understood, but may depend in part upon gene expression of PTHrP and the vitamin D receptor. In contrast, much more is known of the manner in which metastatic disease affects bone remodeling to induce osteolytic bone disease. Mechanisms include a generalized increase in activation frequency at sites close to metastatic tissue, an imbalance between the amount of bone formed and that resorbed within resorption cavities, and uncoupling of bone formation from bone resorption. The greatest morbidity from metastatic bone disease arises from osteolytic disease and gives rise to hypercalcemia, bone pain, and fractures. Because osteolysis is primarily mediated by the activation of osteoclasts, there has been a great deal of interest in the use of agents which primarily affect bone metabolism to alter the natural history of metastatic bone disease. Nonsteroidal antiinflammatory agents and cytotoxic agents are capable of inducing responses in bone, but are limited by their toxicity when effective doses are utilized. The use of calcitonin in the long-term suppression of osteolysis has also been disappointing. The bisphosphonates are, however, capable of inducing sustained decreases in osteoclast activity and numbers in patients with osteolytic bone disease. There are now several studies which have examined the effects of the bisphosphonates on skeletal morbidity in breast cancer. Both clodronate and pamidronate decrease the incidence of hypercalcemia, bone pain, and pathological fractures, but do not significantly alter mortality.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Bone and cancer: pathophysiology and treatment of metastases. 857 90

We present herein the case of a 60-year-old man found to have a rare type of cloacogenic anal carcinoma. The disease was advanced and aggressive with local invasion to the prostate as well as distant lymph node metastases to the neck and paraaortic region on presentation. Therefore, a palliative abdominoperineal resection was performed, 10 weeks following which the patient developed humoral hypercalcemia. Despite treatment with hydration, furosemide, steroids, and calcitonin, serum calcium continued to rise and the patient died on the 95th postoperative day. Laboratory findings revealed a decreased parathyroid hormone (PTH) level and marked elevation of parathyroid hormone-related protein (PTHRP). The detection of the PTHRP in the tumor extract and the positive immunohistochemical staining for this in the tumor cells suggested that the humoral hypercalcemia was definitely caused by its associated tumor production. Although hypercalcemia is not an uncommon complication of solid cancers in their late stage, only three other cases of rectal cancer with hypercalcemia have ever been reported. To our knowledge, this is the first documentation of cloacogenic anal carcinoma accompanied by PTHRP-induced severe humoral hypercalcemia.
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PMID:Cloacogenic anal carcinoma presenting with humoral hypercalcemia: report of a case. 864 24

Breast cancer almost invariably metastasizes to bone in patients with advanced disease and causes local osteolysis. Much of the morbidity of advanced breast cancer is a consequence of this process. Despite the importance of the problem, little is known of the pathophysiology of local osteolysis in the skeleton or its prevention and treatment. Observations in patients with bone metastases suggest that breast cancer cells in bone express parathyroid hormone-related protein (PTHrP) more frequently than in soft tissue sites of metastasis or in the primary tumor. Thus, the role of PTHrP in the causation of breast cancer metastases in bone was examined using human breast cancer cell lines. Four of eight established human breast cancer cell lines expressed PTHrP and one of these cell lines, MDA-MB-231, was studied in detail using an in vivo model of osteolytic metastases. Mice inoculated with MDA-MB-231 cells developed osteolytic bone metastasis without hypercalcemia or increased plasma PTHrP concentrations. PTHrP concentrations in bone marrow plasma from femurs affected with osteolytic lesions were increased 2.5-fold over corresponding plasma PTHrP concentrations. In a separate experiment, mice were treated with either a monoclonal antibody directed against PTHrP(1-34), control IgG, or nothing before tumor inoculation with MDA-MB-231 and twice per week for 26 d. Total area of osteolytic lesions was significantly lower in mice treated with PTHrP antibodies compared with mice receiving control IgG or no treatment. Histomorphometric analysis of bone revealed decreased osteoclast number per millimeter of tumor/bone interface and increased bone area, as well as decreased tumor area, in tumor-bearing animals treated with PTHrP antibodies compared with respective controls. These results indicate that tumor-produced PTHrP can cause local bone destruction in breast cancer metastatic to bone, even in the absence of hypercalcemia or increased circulating plasma concentrations of PTHrP. Thus, PTHrP may have an important pathogenetic role in the establishment of osteolytic bone lesions in breast cancer. Neutralizing antibodies to PTHrP may reduce the development of destructive bone lesions as well as the growth of tumor cells in bone.
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PMID:Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. 883 2


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