Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0153690 (bone metastases)
 6,382 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor-induced hypercalcemia and tumor-induced osteolysis are essentially due to a marked increase in osteoclast-mediated bone resorption, although the kidneys play an important contributory role in the genesis of tumor-induced hypercalcemia. Parathyroid hormone-like protein plays an essential role in tumor-induced hypercalcemia, and maybe in tumor-induced osteolysis, but other factors could also be responsible for the osteoclast activation secondary to the neoplastic infiltration of the skeleton. Treatment of tumor-induced hypercalcemia essentially consists of volume repletion and administration of potent anti-osteolytic drugs. The bisphosphonate pamidronate is particularly useful for that matter and a dose of 1.0 to 1.5 mg/kg can normalize serum calcium in about 90% of hypercalcemic cancer patients. The apparently low response rate of bone metastases to systemic antineoplastic therapy seems to essentially reflect the relative insensitivity of our current methods for assessing response in tumor-induced osteolysis. Newly developed biochemical markers of bone turnover could be particularly useful for that matter. Bisphosphonates are the most potent of the available inhibitors of osteoclast activity. Prolonged administration of oral pamidronate could reduce by almost one half the complications of tumor-induced osteolysis, and repeated bisphosphonate infusions could induce a dramatic relief of bone pain in one third and a sclerosis of lytic lesions in one fourth of the cases. These data must, however, be confirmed in randomized, blinded trials and many questions remain unanswered concerning the optimal therapeutic schemes. Medical therapy of tumor-induced osteolysis by noncytotoxic means has nevertheless become a reality.
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PMID:Bone metastases and tumor-induced hypercalcemia. 151 Oct 19

In an attempt to analyze the pathological processes which lead to hypercalcemia in patients with multiple bone metastases, 23 advanced breast cancer patients with multiple bone metastases, three hypercalcemic patients with other malignancies and seven early breast cancer patients without any distant metastasis were studied. Of the 23 patients with advanced breast cancer, nine showed serum calcium levels higher than 10 mg/dl. In five of the nine hypercalcemic patients with advanced breast cancer, urinary cyclic AMP excretion was lower than 4 nmol/100 ml of glomerular filtrate (GF), indicating that the secretion of parathyroid hormone was suppressed. However, urinary cyclic AMP excretion was higher than 4 nmol/100 ml of GF in the other four hypercalcemic patients with advanced breast cancer and three hypercalcemic patients with other malignancies. In patients with higher urinary cyclic AMP excretion, fractional excretion of calcium (FECa) showed a negative correlation (r = 0.83, P less than 0.05) with urinary cyclic AMP. Parathyroid hormone immunoreactivity was not detected in any of six patients showing serum calcium levels higher than 11 mg/dl. These results suggest that in about a half of hypercalcemic patients with advanced breast cancer and multiple bone metastasis, there is a factor which increases urinary cyclic AMP and enhances calcium reabsorption in the kidney, but which is different from parathyroid hormone. This factor may facilitate retention of calcium mobilized into the circulation by bone metastases, and lead to hypercalcemia.
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PMID:Stimulation of calcium reabsorption observed in advanced breast cancer patients with hypercalcemia and multiple bone metastases. 298 61

Tumor cells in bone metastases are thought to induce bone resorption primarily by releasing paracrine factors. Parathyroid hormone related protein (PTHrp) has been proposed to mediate osteolytic activity of many tumors. PTHrp is produced by 40% to 60% of breast tumors and is elevated in the serum of up to 50% of patients with breast cancer metastases to bone. Most biologic processes in humans are heterogeneous in nature, so the purpose of this study was to investigate the hypothesis that paracrine factors other than PTHrp could mediate bone resorption by breast tumor cells. Serum-free conditioned medium (CM) was collected from five human breast tumor cell lines and tested for bone resorption-stimulating activity (BRSA) in mouse calvaria organ cultures. CM from all tumor cells studied produced significant bone resorption, comparable to that produced by 10 nM PTH. Small amounts of immunoreactive PTHrp (1.4-12.5 pM) were produced by all breast tumor cell lines. When tested in vitro, equivalent amounts of human PTHrp [1-36] did not produce significant bone resorption. Indomethacin (1 microM) significantly blocked BRSA by CM from all cell lines but did not decrease BRSA by PTHrp. In contrast PTHrp antibody (130 micrograms/ml) completely blocked BRSA by 1 nM PTHrp but did not modify BRSA by CM of breast tumor cells. The results of this study support the hypothesis that breast cancer cells release paracrine factors in vitro that stimulate bone resorption by a mechanism that is partially dependent on prostaglandin synthesis and at least in part different from that of PTHrp.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Parathyroid hormone-related protein: primary osteolytic factor produced by breast tumor cells in vitro? 775 38

Parathyroid hormone-related peptide (PTHrP) is a major factor in the pathophysiology of hypercalcaemia of malignancy. Recent evidence suggests that PTHrP may play an important role in the growth and differentiation of neoplastic as well as non-neoplastic cells. PTHrP was originally detected in normal fetal, but not adult, liver. We have used immunocytochemistry to show that reactive human bile ductules expressing a neuroendocrine phenotype contain immunoreactive PTHrP. These observations raised the possibility that PTHrP immunoreactivity may be useful in the differential diagnosis of primary liver tumours and metastases of adenocarcinoma. A total of 24 primary liver tumours and 22 metastases of adenocarcinoma were studied. All cholangiocarcinomas showed immunopositivity for PTHrP and chromogranin A, while all hepatocellular carcinomas were negative for PTHrP and showed only focal and weak positivity for chromogranin A. Mixed types of primary liver tumour contained PTHrP immunoreactivity only in the areas of cholangiocellular differentiation. Moreover, all metastatic adenocarcinomas were negative for PTHrP and chromogranin A except for two out of five metastatic breast adenocarcinomas. These two patients had bone metastases and hypercalcaemia and thus did not yield differential diagnostic problems with cholangiocarcinoma. None of the patients with cholangiocarcinoma and hepatocellular carcinoma had hypercalcaemia. We conclude that PTHrP is a useful marker for primary cholangiocarcinoma, especially in the differential diagnosis of hepatocellular carcinoma and metastatic adenocarcinoma.
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PMID:Parathyroid hormone-related peptide expression in primary and metastatic liver tumours. 831 35

Parathyroid hormone related protein (PTHrP) is a novel calcium regulating hormone that may have a significant role in the pathophysiology of breast cancer. We have previously demonstrated a relationship between immunohistochemically detectable PTHrP in primary breast tumours and the subsequent development of bone metastases and hypercalcaemia. The aim of this study was to compare the PTHrP status in the primary tumours from three groups of patients with widely varying prognosis. (1) The favourable outcome group; all patients had a favourable prognosis and minimum 3 years disease free follow up (n = 30). (2) The unfavourable outcome group; all patients presented with localized breast cancer but developed distant disease within 3 years (n = 26). (3) The unfavourable presentation group; all had distant disease at first presentation (n = 26). No differences in PTHrP status of the primary tumour amongst the three patient groups were found (66%, 65% and 61% positive respectively). The development of bone with liver metastases and hypercalcaemia was associated with increased positive PTHrP status of the primary tumor.
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PMID:Parathyroid hormone related protein in breast cancers of widely varying prognosis. 849 17

The propensity for breast cancer cells to metastasize to bone and to induce osteolysis has long been recognized. Characteristics of both the tumor cells and the bone microenvironment contribute to this phenomenon. The presence of tumor in bone is associated with activation of osteoclasts, resulting in excessive bone resorption and subsequent osteolysis. Breast cancer cells and other tumor types influence osteoclastic bone resorption by increasing the number of osteoclasts and enhancing their resorptive activity. Parathyroid hormone-related peptide, in addition to its role in humorally mediated hypercalcemia, is secreted by metastatic breast cancer cells in bone in which it acts as a paracrine factor to stimulate osteoclasts. As bone matrix is broken down by activated osteoclasts, a rich supply of mitogenic factors is released, including insulin-like growth factors, bone morphogenetic proteins, and fibroblast growth factors. Transforming growth factor (TGF)-beta, one of the most abundant of the bone-derived factors, promotes increased production of parathyroid hormone-related peptide by tumor cells, establishing a "vicious cycle" leading to progressive tumor growth and bone destruction. Bisphosphonates interrupt this cycle by inhibiting osteoclasts, in part by inducing osteoclast apoptosis. In several animal models of breast cancer metastasis to bone, bisphosphonates decrease the number of new bone metastases and inhibit progression of existing lesions. A single 3 microg intravenous injection of zoledronic acid (Zometa; Novartis Pharmaceuticals Corp, East Hanover, NJ), a new highly potent bisphosphonate, prevented destruction of trabecular bone in an orthotopic mouse mammary tumor model. Tumor volume in bone was decreased by zoledronic acid in a dose-dependent manner in the same model, and tumor cell apoptosis was increased by zoledronic acid in bone metastases in the 4T1 murine model of mammary carcinoma metastasis. Zoledronic acid at a dose of 1.0 microg/d for 10 days also reduced bone lesion area in a nude mouse model with existing bone metastases. Although bisphosphonates, including zoledronic acid, are able to induce apoptosis in tumor cells in vitro, studies in animal models to date have generally not shown a reduction in nonosseous tumor. Therefore, bisphosphonate-associated tumor reduction in bone is most likely mediated by osteoclast inhibition or is related to high local concentrations of bisphosphonates in the bone compartment.
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PMID:Preclinical studies with zoledronic acid and other bisphosphonates: impact on the bone microenvironment. 1134 63

Background: Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTH-rP) are two potent hypercalcemic hormones that act on the same targets. Autonomous secretion of the former is involved in primary hyperparathyroidism (PHPT), whereas the latter is responsible for humoral hypercalcemia of malignancy (HHM). Methods: From 250 consecutive, hypercalcemic serum samples sent to our laboratory for assessment of intact PTH, we were able to obtain clinical information, as well as an additional plasma sample for PTH-rP measurement, in 134 patients. At the time of sampling, patients could be classified into seven groups: cancer without known bone metastases (CaNoMeta, n=36), cancer with bone metastases (CaMeta, n=9), no evidence of cancer (noEvCa, n=71), sarcoidosis (Sarc, n=3), end-stage renal disease (ESRD, n=12), vitamin D overdose (VIT-D, n=2), and hyperthyroidism (Thyr, n=1). Results: In the CaNoMeta group, 29/36 patients had elevated PTH-rP levels, 9/36 patients had inappropriately elevated PTH levels, and 5/36 had elevated levels of both hormones. In the CaMeta group, three of the nine patients had inappropriately elevated PTH levels, two of them with concomitantly elevated PTH-rP levels. In the NoEvCa group, 63/71 patients had an inappropriate elevation of PTH levels and were diagnosed as having PHPT. Four of the 71 patients had elevated levels of both PTH and PTH-rP; three of them were in poor health and died within a short period of time. All of the ESRD patients had very high PTH and normal PTH-rP levels, except for one woman with high PTH-rP and undetectable PTH levels; she died from what later turned out to be a recurrent bladder carcinoma. In the Sarc, Vit-D, and Thyr groups, both PTH and PTH-rP levels were normal. Conclusions: (1) Elevated PTH-rP levels are a common finding in cancer patients without bone metastases. Intact PTH, however, should always be measured in hypercalcemic patients with malignancy because concurrent primary hyperparathyroidism is not rare. (2) Primary hyperparathyroidism accounts for hypercalcemia in 90% of patients without evidence of cancer whose PTH-rP levels may also be found to be elevated in a few cases, even some with surgically demonstrated parathyroid adenoma.
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PMID:Diagnostic approach to hypercalcemia: relevance of parathyroid hormone and parathyroid hormone-related protein measurements. 1139 97

Tumour-induced hypercalcaemia (TIH) is a frequent complication of advanced cancer but has been rarely reported in patients with malignant melanoma, and its pathogenesis remains unexplored. We studied eight patients with TIH and melanoma. We determined the incidence and pathogenesis of this complication and the effects of bisphosphonate therapy. The incidence of TIH in 751 patients with melanoma was 1.1%. All patients had liver and bone metastases at the time of hypercalcaemia. All patients had osteolytic lesions, most often multiple. The median survival was 30 days (range 4-136 days). After rehydration, the mean (+/- SEM) corrected calcium was 3.42 +/- 0.17 mmol/l. Parathyroid hormone levels were adequately suppressed and vitamin D concentrations were normal. Serum osteocalcin, a marker of bone formation, was low, except in the two patients with renal insufficiency, whereas fasting urinary calcium and hydroxyproline were increased, indicating inhibition of bone formation and stimulation of bone resorption. Increased parathyroid hormone-related protein secretion was noted in only one patient. Three of four patients became normocalcaemic after bisphosphonate therapy for a median duration of 2 weeks. In conclusion, hypercalcaemia is a rare complication of melanoma. It occurs in the context of far advanced disease and is essentially due to aggressive lytic bone metastases with an uncoupling in bone turnover. Bisphosphonates can offer short-term palliation.
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PMID:Hypercalcaemia of melanoma: incidence, pathogenesis and therapy with bisphosphonates. 1159 84

Parathyroid hormone-related peptide (PTHrP) has a high homology with the N-terminal portion of the parathyroid hormone (PTH). The gene of PTHrP is complex and can generate by alternative splicing at least three mature peptides containing 139, 141 and 173 amino acids. PTHrP acts via a common receptor with PTH but also via specific receptors. In physiological circumstances, PTHrP is produced locally in many normal tissues where it has autocrine/paracrine functions, particularly during embryonic development, growth regulation and differentiation of many cellular types. PTHrP has endocrine action on bone and kidney. The humoral hypercalcemia of malignancy is mainly mediated by PTHrP. Most hypercalcemic patients with solid tumors have increased plasma PTHrP, whereas PTHrP is not detectable in healthy subjects. During treatment with bisphosphonates, elevated plasma levels of PTHrP are associated with a weak response. PTHrP has also a significant role in the pathophysiology of bone metastases. PTHrP can induce a local osteolysis near the bone metastases, which favours their progression and thus participates in the autocrine regulation of tumor growth. In breast cancer, PTHrP is detected in about 60% of primary tumors and in more than 70% of bone metastases, whereas only 17% of nonbone metastases express PTHrP. A higher expression of PTHrP and its mRNA 1-139, is positively correlated with an invasive tumor phenotype and the development of bone metastases. PTHrP is an effector of transforming growth factor (TGFbeta) in the development and progression of osteolytic bone metastases. TGFbeta, which is released in bone matrix during osteolytic resorption, enhances tumor cells PTHrP production. Then, PTHrP stimulates bone resorption and develops tumor cells metastatic potential. Thus a feedback loop exists between carcinoma cells and the bone microenvironment, leading to a vicious circle.
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PMID:[PTHrP and breast cancer]. 1174 1

Parathyroid hormone-related peptide is a regulatory protein implicated in the pathogenesis of bone metastases, particularly in breast carcinoma. Parathyroid hormone-related peptide is widely expressed in primary prostate cancers but there are few reports of its expression in prostatic metastases. The aim of this study was to examine the expression of parathyroid hormone-related peptide and its receptor in matched primary and in bone metastatic tissue from patients with untreated adenocarcinoma of the prostate. Eight-millimetre trephine iliac crest bone biopsies containing metastatic prostate cancer were obtained from 14 patients from whom matched primary tumour tissue was also available. Histological grading was performed by an independent pathologist. The cellular location of mRNA for parathyroid hormone-related peptide and parathyroid hormone-related peptide receptor was identified using in situ hybridization with (35)S-labelled probe. Expression of parathyroid hormone-related peptide and its receptor was described as uniform, heterogenous or negative within the tumour cell population. Parathyroid hormone-related peptide expression was positive in 13 out of 14 primary tumours and in all 14 metastases. Receptor expression was evident in all 14 primaries and 12 out of 14 metastases. Co-expression of parathyroid hormone-related peptide and parathyroid hormone-related peptide receptor was common (13 primary tumours, 12 metastases). The co-expression of parathyroid hormone-related peptide and its receptor suggest that autocrine parathyroid hormone-related peptide mediated stimulation may be a mechanism of escape from normal growth regulatory pathways. The high frequency of parathyroid hormone-related peptide expression in metastases is consistent with a role in the pathogenesis of bone metastases.
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PMID:Parathyroid hormone related peptide and receptor expression in paired primary prostate cancer and bone metastases. 1187 91


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