UMLS:C0027627 - FACTA Search

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

Breast cancer cells frequently metastasize to the skeleton, where they induce OCL formation and activity, resulting in extensive bone destruction. However, the mechanisms by which breast cancer cells mediate increased osteolysis remain unclear. To elucidate this point, we investigated how 3 human breast cancer cell lines, MDA-MB-231, MDA-MB-435 and MCF-7, induce OCL formation using a murine osteoblast-spleen cell coculture system and compared their effects with a human colorectal cancer cell line, HCT-15; a human lung cancer cell line, HT-1080; and a normal human breast cell line, HME. The breast cancer cell lines supported OCL formation only when osteoblasts were present in spleen cell cocultures, whilst the non-breast cancer cell lines and the normal breast cell line, HME, had no effect. Fractionation of BCCM by ultrafiltration established that osteoclastogenic activity was associated with factors having m.w. >3 kDa. Breast cancer cell lines produced primarily PTHrP, with lesser amounts of IL-6, IL-11 and TNF-alpha. The effect of BCCM on OCL formation in osteoblast-spleen cell cocultures was partially prevented by a neutralising antibody to human PTHrP and completely prevented by a neutralising antibody to either murine IL-11 or the murine IL-11 receptor; neutralising antibodies to human IL-6, IL-11 or TNF-alpha were without effect. BCCM or human PTHrP induced an increase in murine osteoblast IL-11 mRNA and protein production, effects that were prevented in the presence of a neutralising antibody to human PTHrP. The osteoclastogenic activity of IL-11 was mediated by enhancing osteoblast production of PGE(2) effects, which were abrogated by an inhibitor of cyclooxygenase. PGE(2) apparently enhanced OCL formation by downregulating GM-CSF production by spleen cells since recombinant murine GM-CSF inhibited OCL formation and a neutralising antibody to murine GM-CSF blocked these inhibitory effects. We conclude that breast cancer cells induce OCL formation by stimulating osteoblastic production of IL-11. The subsequent release of PGE(2) followed by inhibition of GM-CSF production by cells within the bone microenvironment plays an important part in mediating the effects of breast cancer cells on OCL formation and their resorptive activity.
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PMID:Breast cancer cells induce osteoclast formation by stimulating host IL-11 production and downregulating granulocyte/macrophage colony-stimulating factor. 1499 70

Parathyroid hormone-related protein (PTHrP) is a key factor in the development of bone metastases, which are a major barrier in treating prostate cancer patients. In this study, we attempted to identify PTHrP-derived peptides immunogenic in human histocompatibility leukocyte antigen (HLA)-A24(+) prostate cancer patients. Among four different PTHrP peptides carrying the HLA-A24 binding motif, both the PTHrP(36-44) and PTHrP(102-111) peptides efficiently induced peptide-specific cytotoxic T lymphocytes from peripheral blood mononuclear cells (PBMCs) of HLA-A24(+) prostate cancer patients. Peptide-stimulated PBMCs showed cytotoxicity against prostate cancer cells in an HLA-A24-restricted manner. Experiments using antibodies and cold inhibition targets confirmed that their cytotoxicity was dependent on PTHrP peptide-specific and CD8(+) T cells. Immunoglobulin G reactive to the PTHrP(102-111) or PTHrP(110-119) peptide was frequently detected in the plasma of prostate cancer patients, suggesting that the PTHrP(102-111) peptide is able to elicit cellular and humoral immune responses in cancer patients. These results indicate that the PTHrP could be a promising target molecule for specific immunotherapy of HLA-A24(+) prostate cancer patients with metastases.
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PMID:Identification of parathyroid hormone-related protein-derived peptides immunogenic in human histocompatibility leukocyte antigen-A24+ prostate cancer patients. 1519 97

In previous studies, we have shown that prostate secretory protein (PSP-94) can reduce prostate cancer growth in vivo. In the current study, we identified the amino acid sequence of PSP-94 that is required for eliciting this response. For these studies, we used rat prostate cancer Mat Ly Lu cells overexpressing parathyroid hormone-related protein (PTHrP), which is the main pathogenetic factor responsible for hypercalcemia of malignancy. Synthetic peptides corresponding to amino acids 7-21 (PCK721), 31-45 (PCK3145), and 76-94 (PCK7694) of PSP-94 were synthesized. Only PCK3145 showed a significant reduction in tumor cell proliferation. For in vivo studies, syngenic male Copenhagen rats were inoculated s.c. with Mat Ly Lu cells overexpressing PTHrP into the right flank or into the left ventricle via intracardiac injection, which results in experimental metastases to the lumbar vertebrae causing hind-limb paralysis. Animals were infused with different doses (1, 10, and 100 microg/kg/day) of peptides for 15 days, and the effect of these treatments on tumor volume, skeletal metastases, or development of hind-limb paralysis was determined. Treatment with PCK3145 resulted in a dose-dependent decrease in tumor volume and delay in the development of skeletal metastases. Bone histomorphometry showed that after intracardiac inoculation of tumor cells, the highest dose of PCK3145 (100 microg/kg/day) resulted in reducing skeletal tumor burden, which delayed the development of hind-limb paralysis. Treatment with PCK3145 led to reduction of plasma calcium and PTHrP levels and a significant decrease in PTHrP levels in the primary tumors and in vertebrae of experimental animals. These effects of PCK3145 were due to its ability to promote tumor cell apoptosis. Collectively, the results of these studies have demonstrated the ability of a small peptide derived from PSP-94 to reduce tumor volume and experimental skeletal metastases-results that will be highly beneficial in the continued development of this peptide as a novel therapeutic agent for patients with hormone refractory, late-stage prostate cancer.
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PMID:A synthetic 15-mer peptide (PCK3145) derived from prostate secretory protein can reduce tumor growth, experimental skeletal metastases, and malignancy-associated hypercalcemia. 1528 44

Human tumor cells inoculated into the arterial circulation of immunocompromised mice can reliably cause bone metastases, reproducing many of the clinical features seen in patients. Animal models permit the identification of tumor-produced factors, which act on bone cells, and of bone-derived factors. Local interactions stimulated by these factors drive a vicious cycle between tumor and bone that perpetuates skeletal metastases. Bone metastases can be osteolytic, osteoblastic, or mixed. Parathyroid hormone-related protein, PTHrP, is a common osteolytic factor, while vascular endothelial growth factor and interleukins 8 and 11 also contribute. Osteoblastic metastases can be caused by tumor-secreted endothelin-1, ET-1. Other potential osteoblastic factors include bone morphogenetic proteins, platelet-derived growth factor, connective tissue growth factor, stanniocalcin, N-terminal fragments of PTHrP, and adrenomedullin. Osteoblasts are the main regulators of osteoclasts, and stimulation of osteoblast proliferation can increase osteoclast formation and activity. Thus, combined expression of osteoblastic and osteolytic factors can lead to mixed metastases or to increased osteolysis. Prostate-specific antigen is a protease, which can cleave PTHrP and thus change the balance of osteolytic versus osteoblastic responses to metastatic tumor cells. Bone itself stimulates tumor by releasing insulin-like growth factors and transforming growth factor-beta. Secreted factors transmit the interactions between tumor and bone. They provide novel targets for therapeutic interactions to break the vicious cycle of bone metastases. Clinically approved bisphosphonate anti-resorptive drugs reduce the release of active factors stored in bone, and PTHrP-neutralizing antibody, inhibitors of the RANK ligand pathway, and ET-1 receptor antagonist are in clinical trials. These adjuvant therapies act on bone cells, rather than the tumor cells. Recent gene array experiments identify additional factors, which may in the future prove to be clinically important targets.
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PMID:Tumor-bone cellular interactions in skeletal metastases. 1561 99

Bone metastases lead to hypercalcemia, bone pain, fractures, and nerve compression. They cause increased morbidity and mortality in patients with advanced breast cancer. Animal models reproduce many of the features seen in patients with breast cancer and permit identification of tumor- and bone-derived factors important in skeletal metastasis. These factors provide novel targets for therapeutic interventions. Specific tumor-bone molecular interactions mediated by these factors drive a vicious cycle that perpetuates skeletal metastases. In breast cancer, osteolytic metastases are most common, but mixed and osteoblastic metastases occur in a significant number of patients. Parathyroid hormone-related protein is a common osteolytic factor, and vascular endothelial growth factor and interleukins 8 and 11 also contribute. Osteoblastic metastases can be caused by tumor-secreted endothelin-1 (ET-1), but there are a variety of other potential osteoblastic factors. Stimulation of osteoblasts can paradoxically increase osteoclast function, as bone-synthesizing osteoblasts are the main regulators of bone-destroying osteoclasts. Coexpression of osteolytic and osteoblastic factors can thus produce mixed metastases or increased osteolysis. Cancer treatments, especially sex steroid deprivation therapies, stimulate bone loss. Bone resorption results in the release of bone growth factors, which may unintentionally increase the formation of bone metastases by activating the vicious cycle. Clinically approved bisphosphonates prevent bone resorption and reduce the release of bone growth factors. Parathyroid hormone-related protein-neutralizing antibody, inhibitors of the receptor activator of nuclear factor-kB ligand pathway, and ET-1 receptor antagonists are in clinical trials. These agents act on bone cells rather than tumor cells. Recent experiments identify new potential targets for prevention of bone metastases.
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PMID:Molecular mechanisms of breast cancer metastases to bone. 1580 24

Hypercalcemia is a frequent complication of breast cancer which causes significant morbidity and mortality. Most commonly, it occurs in patients with multiple skeletal metastases. However, in a significant minority of patients, calcium levels become elevated in the absence of skeletal disease. In both instances, hypercalcemia is the result of pathological bone resorption caused by the secretion of cytokines that stimulate osteoclast differentiation and activity. One of these cytokines is parathyroid hormone-related protein (PTHrP). PTHrP is also secreted by normal breast cells during lactation to increase bone resorption and liberate skeletal calcium stores for the purposes of milk production. Therefore, the pathophysiology of hypercalcemia in breast cancer patients mimics the physiological processes that normally regulate calcium metabolism during lactation. Current therapy for hypercalcemia in breast cancer patients relies on the inhibition of bone resorption by a class of drugs known as bisphophonates. Newer therapies in development target cytokines involved in the recruitment and activation of osteoclasts by tumor cells.
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PMID:Hypercalcemia in breast cancer: an echo of bone mobilization during lactation? 1602 22

Calcium homeostasis is a tightly regulated process involving the co-ordinated efforts of the skeleton, kidney, parathyroid glands and intestine. Neoplasms can alter this homeostasis indirectly through the production of endocrine factors resulting in humoral hypercalcaemia of malignancy. Relatively common with breast and lung cancer, this paraneoplastic condition is most often due to tumour production of parathyroid hormone-related protein and ensuing increased osteoclastic bone resorption. Although control of hypercalcaemia is generally successful, the development of this complication is associated with a poor prognosis. The metastasis of tumour cells to bone represents another skeletal complication of malignancy. As explained in the 'seed and soil' hypothesis, bone represents a fertile ground for cancer cells to flourish. The molecular mechanisms of this mutually beneficial relationship between bone and cancer cells are beginning to be understood. In the case of osteolytic bone disease, tumour-produced parathyroid hormone-related protein stimulates osteoclasts that in turn secrete tumour-activating transforming growth factor-beta that further stimulates local cancer cells. This 'vicious cycle' of bone metastases represents reciprocal bone/cancer cellular signals that likely modulate osteoblastic bone metastatic lesions as well. The development of targeted therapies to either block initial cancer cell chemotaxis, invasion and adhesion or to break the 'vicious cycle' is dependent on a more complete understanding of bone metastases. Although bisphosphonates delay progression of skeletal metastases, it is clear that more effective therapies are needed. Cancer-associated bone morbidity remains a major public health problem, and to improve therapy and prevention it is important to understand the pathophysiology of the effects of cancer on bone. This review will detail scientific advances regarding this area.
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PMID:Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone. 1617 92

This review focuses on the promising roles of prostate secretory protein of 94 amino acids (PSP-94) and one of its derived peptides (PCK3145) as potential therapeutic modalities for prostate cancer and its associated complications. Evaluation of these compounds was carried out in vitro and in vivo using syngeneic models of rat prostate cancer. Overproduction of parathyroid hormone-related protein (PTHrP) results in the development of hypercalcemia of malignancy in several malignancies including prostate cancer. In order to evaluate the effect of PSP-94 and PCK3145 on prostate cancer progression, the rat Dunning R3227 MatLyLu cell line transfected with full-length cDNA encoding PTHrP (MatLyLu-PTHrP) was used. As the main pathogenetic factor of hypercalcemia of malignancy, overexpression of PTHrP was aimed at mimicking the hypercalcemic nature seen in patients suffering from late-stage cancer. In vitro studies showed that PSP-94 and PCK3145 can cause a dose-dependent inhibition in the growth of MatLyLu-PTHrP cells. For in vivo studies, male Copenhagen rats were inoculated either s.c. into the right flank or directly into the left ventricle via intracardiac (i.c.) inoculation with MatLyLu-PTHrP cells. In these models, s.c. injection of MatLyLu cells results in the development of primary tumor growth, whereas i.c. inoculation routinely results in the development of experimental skeletal metastases in the lumbar vertebrae causing hind-limb paralysis. Administration of PSP-94 and PCK3145 into tumor-bearing animals resulted in a dose-dependent inhibition of primary tumor growth, and tumoral and plasma PTHrP levels, and in the reduction of plasma calcium levels. Additionally, treatment with PSP-94 or PCK3145 caused an inhibition of skeletal metastases resulting in a significant delay in the development of hind-limb paralysis. Interestingly, equimolar concentrations of PCK3145 were shown to be more effective in delaying the development of experimental skeletal metastases as compared to PSP-94. One of the possible mechanisms of action of these modalities is through the induction of apoptosis which was observed by both in-vitro and in-vivo analyses of MatLyLu-PTHrP cells and tumors. Several intracellular mechanisms can also be involved in inhibiting PTHrP production and anti-tumor effects of PSP-94 and PCK3145. Collectively, these studies warrant the continued clinical development of these agents as therapeutic agents for patients with hormone-refractory prostate cancer.
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PMID:Prostate secretory protein of 94 amino acids (PSP-94) and its peptide (PCK3145) as potential therapeutic modalities for prostate cancer. 1622 45

Prostate cancer (CaP) is unique among all cancers in that when it metastasizes to bone, it typically forms osteoblastic lesions (characterized by increased bone production). CaP cells produce many factors, including Wnts that are implicated in tumor-induced osteoblastic activity. In this prospectus, we describe our research on Wnt and the CaP bone phenotype. Wnts are cysteine-rich glycoproteins that mediate bone development in the embryo and promote bone production in the adult. Wnts have been shown to have autocrine tumor effects, such as enhancing proliferation and protecting against apoptosis. In addition, we have recently identified that CaP-produced Wnts act in a paracrine fashion to induce osteoblastic activity in CaP bone metastases. In addition to Wnts, CaP cells express the soluble Wnt inhibitor dickkopf-1 (DKK-1). It appears that DKK-1 production occurs early in the development of skeletal metastases, which results in masking of osteogenic Wnts, thus favoring osteolysis at the metastatic site. As metastases progress, DKK-1 expression decreases allowing for unmasking of Wnt's osteoblastic activity and ultimately resulting in osteosclerosis at the metastatic site. We believe that DKK-1 is one of the switches that transitions the CaP bone metastasis activity from osteolytic to osteoblastic. Wnt/DKK-1 activity fits a model of CaP-induced bone remodeling occurring in a continuum composed of an osteolytic phase, mediated by receptor activator of NFkB ligand (RANKL), parathyroid hormone-related protein (PTHRP) and DKK-1; a transitional phase, where environmental alterations promote expression of osteoblastic factors (Wnts) and decreases osteolytic factors (i.e., DKK-1); and an osteoblastic phase, in which tumor growth-associated hypoxia results in production of vascular endothelial growth factor and endothelin-1, which have osteoblastic activity. This model suggests that targeting both osteolytic activity and osteoblastic activity will provide efficacy for therapy of CaP bone metastases.
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PMID:Role of Wnts in prostate cancer bone metastases. 1644 63

Hypercalcemia is one of the most common paraneoplastic syndromes, where it may result from the presence of osteolytic metastases or from humoral effect of factors produced by tumor cells. One of such factors is the parathyroid hormone-related protein (PTH-rP). This protein is usually produced by solid tumors, especially by squamous cell carcinomas. In the case of squamous cell carcinoma of the skin hypercalcemia is very rare and symptomatic hypercalcemia is unusual. We present a case of acute hypercalcemic crisis as a consequence of overproduction of PTH-rP in a patient with spinocellular squamous cell carcinoma of the skin, which was proved by immunohistochemical staining of the tissue samples from the neoplastic lesion, metastases in bone and in lung, and also from kidney and liver.
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PMID:[Acute hypercalcaemic crisis in the course of PTH-rP producing squamous cell carcinoma of the skin--a case report]. 1652 24

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