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Biomedical subjects

Theresa A Guise

Publications and source records attributed to Theresa A Guise.

At least 19 recordsLinked to original sources
PubMed2006

Dickkopf homolog 1 mediates endothelin-1-stimulated new bone formation.

Tumor-produced endothelin-1 (ET-1) stimulates osteoblasts to form new bone and is an important mediator of osteoblastic bone metastasis. The anabolic actions of ET-1 in osteoblasts were investigated by gene microarray analyses of murine neonatal calvarial organ cultures. Targets of ET-1 action were validated by real-time RT-PCR in murine primary osteoblast cultures. IL-6, IL-11, the CCN (CYR61, CTGF, NOV) family members cysteine-rich protein 61 and connective tissue growth factor, inhibin beta-A, serum/glucocorticoid regulated kinase, receptor activator of nuclear factor kappaB ligand, snail homolog 1, tissue inhibitor of metalloproteinase 3, and TG-interacting factor transcripts were increased by ET-1. ET-1 decreased the transcript for the Wnt signaling pathway inhibitor, dickkopf homolog 1 (Dkk1). Calvarial organ cultures treated with ET-1 had lower concentrations of DKK1 protein in conditioned media than control cultures. High DKK1 concentrations in bone marrow suppress bone formation in multiple myeloma. We hypothesized that the converse occurs in osteoblastic bone metastasis, where ET-1 stimulates osteoblast activity by reducing autocrine production of DKK1. Recombinant DKK1 blocked ET-1-mediated osteoblast proliferation and new bone formation in calvarial organ cultures, whereas a DKK1-neutralizing antibody increased osteoblast numbers and new bone formation. ET-1 directed nuclear translocation of beta-catenin in osteoblasts, indicating activation of the Wnt signaling pathway. The data suggest that ET-1 increases osteoblast proliferation and new bone formation by activating the Wnt signaling pathway through suppression of the Wnt pathway inhibitor DKK1.

Animals↗
PubMed2006

Basic mechanisms responsible for osteolytic and osteoblastic bone metastases.

Certain solid tumors metastasize to bone and cause osteolysis and abnormal new bone formation. The respective phenotypes of dysregulated bone destruction and bone formation represent two ends of a spectrum, and most patients will have evidence of both. The mechanisms responsible for tumor growth in bone are complex and involve tumor stimulation of the osteoclast and the osteoblast as well as the response of the bone microenvironment. Furthermore, factors that increase bone resorption, independent of tumor, such as sex steroid deficiency, may contribute to this vicious cycle of tumor growth in bone. This article discusses mechanisms and therapeutic implications of osteolytic and osteoblastic bone metastases.

Bone Neoplasms↗
PubMed2006

Advances in treating metastatic bone cancer: summary statement for the First Cambridge Conference.

The First Cambridge Conference on Advances in Treating Metastatic Bone Cancer, a symposium held in Cambridge, Massachusetts, October 28 to 29, 2005, was convened to discuss recent advances and research related to the natural history of bone metastases and skeletal complications, bone cancer biology, treatment of myeloma and other solid tumors, and treatment-induced bone loss. The conference format combined brief presentations with extended periods of discussion. The conclusions reached during the 2-day meeting are summarized in this article and presented in more detail in the individual articles and accompanying discussion sessions that comprise the conference proceedings.

Bone Neoplasms↗
PubMed2006

The human Cyr61 gene is a transcriptional target of transforming growth factor beta in cancer cells.

Cyr61 is a multifunctional protein that can stimulate angiogenesis and tumor growth. Its expression by many cancers and breast cancers increases with tumor grade. Cyr61 is closely related to connective tissue growth factor, CTGF. Both proteins regulate skeletal development, suggesting that they could contribute to breast cancer metastases to bone, a process regulated by TGFbeta. We show that Cyr61 transcription is activated by TGFbeta and that the human Cyr61 promoter contains consensus sequences that bind Smad proteins. TGFbeta in the tumor microenvironment may stimulate cancer metastases to sites such as bone by increasing Cyr61 expression and secretion.

Cell Line, Tumor↗
PubMed2006

New insights into the role of T cells in the vicious cycle of bone metastases.

PURPOSE OF REVIEW: Bone metastases interact with the bone microenvironment. Cancer cells modulate the functions of osteoblasts and osteoclasts to induce new bone formation or bone resorption, leading to secondary stimulation of tumor development. Recent findings suggest the involvement of T cells in this process. RECENT FINDINGS: Bone metastatic cancer cells produce factors such as parathyroid hormone-related protein, interleukin-7, and interleukin-8 that can recruit or activate T cells. T cells are involved in bone remodeling and can induce osteoclastic resorption. Bone resorption releases transforming growth factor-beta, however, which could suppress T-cell antitumor immune responses. Bisphosphonate antiresorptive drugs are the approved treatment for solid tumor bone metastases. They have recently been found to activate the cytolytic activity of gammadelta T cells. Thus, inhibitors of transforming growth factor-beta or antiresorptive therapies may be effective enhancers of antitumor immune responses in bone. SUMMARY: T cells at the site of bone metastases may be functionally suppressed by factors in the bone microenvironment. Instead of acting against tumor cells, they may increase bone resorption, making bone a privileged site for tumor growth.

Bone Neoplasms↗
PubMed2006

Adrenomedullin is a cross-talk molecule that regulates tumor and mast cell function during human carcinogenesis.

We have previously demonstrated that adrenomedullin (AM) plays a critical role as an autocrine/paracrine tumor cell survival factor. We now present evidence that AM is an important regulator of mast cell (MC) function and that this modulation is potentially involved in tumor promotion. AM induced histamine or beta-hexosaminidase release from rat and human MCs through a receptor-independent pathway. AM was chemotactic for human MCs and stimulated mRNA expression of vascular endothelial growth factor, monocyte chemoattractant protein-1, and basic fibroblast growth factor in this cell type. Differentiated but not undifferentiated human MCs responded to hypoxic insult with elevated AM mRNA/protein expression. Using confocal microscopy, we identified AM-producing MCs in tumor infiltrates of human breast and lung cancer patients. In mixed culture assays the AM-producing human MC line HMC-1 augmented both anchorage-dependent and -independent growth of human lung cancer A549 cells, an effect that was suppressed by MC-targeted siRNA AM knockdown. Finally, HMC-1 cells induced in vivo angiogenesis as assessed by directed in vivo angiogenesis assay analysis; neutralizing anti-AM monoclonal antibody blocked this ability. Our collective data suggest a new role for AM as a cross-talk molecule that integrates tumor and MC communication, underlying a unique promotion mechanism of human cancers.

Adrenomedullin↗
PubMed2005

Tumor-derived interleukin-8 stimulates osteolysis independent of the receptor activator of nuclear factor-kappaB ligand pathway.

Bone is a common site of cancer metastasis. Breast, prostate, and lung cancers show a predilection to metastasize to bone. Recently, we reported that the chemokine interleukin 8 (IL-8) stimulates both human osteoclast formation and bone resorption. IL-8 mRNA expression was surveyed in a panel of human breast cancer lines MDA-MET, MDA-MB-231, MDA-MB-435, MCF-7, T47D, and ZR-75, and the human lung adenocarcinoma cell line A549. IL-8 mRNA expression was higher in cell lines with higher osteolytic potential in vivo. Human osteoclast formation was increased by MDA-MET or A549 cell-conditioned medium, but not by MDA-MB-231. Pharmacologic doses of receptor activator of nuclear factor-kappaB (RANK)-Fc or osteoprotogerin had no effect on the pro-osteoclastogenic activity of the conditioned medium; however, osteoclast formation stimulated by conditioned medium was inhibited 60% by an IL-8-specific neutralizing antibody. The data support a model in which tumor cells cause osteolytic bone destruction independently of the RANK ligand (RANKL) pathway. Tumor-produced IL-8 is a major contributor to this process. The role of secreted IL-8 isoforms was examined by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, which detected distinct IL-8 isoforms secreted by MDA-MET and MDA-231 cells, suggesting different pro-osteoclastogenic activities of the two IL-8-derived peptides. These data indicate that (a) osteoclast formation induced by MDA-MET breast cancer cells and A549 adenocarcinoma cells is primarily mediated by IL-8, (b) cell-specific isoforms of IL-8 with distinct osteoclastogenic activities are produced by tumor cells, and (c) tumor cells that support osteoclast formation independent of RANKL secrete other pro-osteoclastogenic factors in addition to IL-8.

Adenocarcinoma↗
PubMed2005

Breast cancer metastasis to bone: mechanisms of osteolysis and implications for therapy.

The most common skeletal complication of breast cancer is osteolytic bone metastasis. Bone metastases are present in 80% of patients with advanced disease and cause significant morbidity. They are most often osteolytic, but can be osteoblastic or mixed. Tumor cells, osteoblasts, osteoclasts and bone matrix are the four components of a vicious cycle necessary for the initiation and development of bone metastases. Tumor cell gene expression is modified by interaction with bone-derived factors. For example, parathyroid hormone related protein (PTHrP), a tumor cell factor, is upregulated by bone-derived transforming growth factor beta (TGFbeta). Tumor cell factors, in turn, act upon bone cells to cause dysregulated bone destruction and formation. PTHrP increases osteoblast expression of RANK (receptor activator of NFkappaB) ligand which, in turn, activates osteoclasts. PTHrP-independent osteolytic factors, such as interleukin [IL]-11 and IL-8, also contribute to the vicious cycle. Other tumor-bone interactions, such as stimulation of tumor-homing through the CXCR4 chemokine receptor by its bone-derived ligand stromal-derived factor-1 (SDF-1), may be responsible for the site-specific predilection of breast cancer for bone. These factors and their roles in fueling the vicious cycle may identify novel targets for therapies to prevent metastasis.

Animals↗
PubMed2005

Molecular mechanisms of breast cancer metastases to bone.

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.

Animals↗
PubMed2004

Guide to bone health and disease in cystic fibrosis.

Cystic fibrosis (CF) is the most common genetic disease within the Caucasian population and leads to premature respiratory failure. Approximately 60,000 individuals are currently living with CF in North America and Europe, 40% of whom are adults. The life span of these patients has increased from approximately 2 to 32 yr of age over the last three decades. Bone disease has emerged as a common complication in long-term survivors of CF. Some studies have observed that 50-75% of adults have low bone density and increased rates of fractures. Prevention and treatment of CF-related bone disease must address the myriad risk factors (decreased absorption of fat-soluble vitamins due to pancreatic insufficiency, altered sex hormone production, chronic lung infection with increased levels of bone-active cytokines, physical inactivity, and glucocorticoid therapy) for poor bone health. This review is a condensed and updated summary of the Guide to Bone Health and Disease in Cystic Fibrosis: A Consensus Conference, a statement that evolved from a meeting convened by the Cystic Fibrosis Foundation in May 2002 to address the pathogenesis, diagnosis, and treatment of bone disease in CF. The goal of this conference was to develop practice guidelines for optimizing bone health in patients with CF.

Bone Diseases↗
PubMed2004

Osteoporosis in men with prostate carcinoma receiving androgen-deprivation therapy: recommendations for diagnosis and therapies.

BACKGROUND: Androgen-deprivation therapy (ADT) is prescribed with increasing frequency for men with prostate carcinoma. There is growing concern about the effects of such therapy on the skeleton. In the current review, the authors addressed the current research, diagnostic methods, and treatment recommendations for bone loss and osteoporosis in men with prostate carcinoma who received ADT. METHODS: Data were obtained from electronic literature searches (for the years 1986 through 2002) and from abstracts and meeting proceedings. All randomized and nonrandomized clinical trials, retrospective studies, and cross-sectional studies of osteoporosis in men with prostate carcinoma who received ADT with or without other therapies were reviewed. RESULTS: The findings confirmed that ADT resulted in significant bone loss in men with prostate carcinoma. Bone mineral density (BMD) of the hip, as measured by dual-energy X-ray absorptiometry (DXA), is considered the preferred site of assessment in older men. Spinal BMD is equally important, although careful interpretation of spinal DXA values is required, because of coexisting facet joint disease and extravertebral calcification. Osteoporosis is diagnosed when BMD is > 2.5 standard deviations below a reference mean. Men with prostate carcinoma who were treated with ADT had average BMD measurements below those of eugonadal men. Rates of bone loss ranged from 2% to 8% in the lumbar spine and from 1.8% to 6.5% in the femoral neck during the initial 12 months of continuous ADT. Retrospective data indicated an increased risk of fracture in men with prostate carcinoma who were treated with ADT. CONCLUSIONS: For men with prostate carcinoma who are at high risk for osteoporosis and fractures, clinical management should be dictated by the results of radiographic and DXA skeletal assessment.

Age Distribution↗
PubMed2004

Endothelins in bone cancer metastases.

Most evidence indicates that osteoblastic bone metastases are due to tumor-produced factors that stimulate the osteoblast. This review supports a causal role for ET-1. Based on our results, we propose a model to explain the tumor cell and bone interactions that are responsible for the osteoblastic response (Figure 2). Tumor cells housed in bone produce factors, such as ET-1, stimulate osteoblast activity. This results in the abundant and disorganized new bone formation that is characteristic of osteoblastic metastases. The effects of ET-1 to stimulate bone formation are mediated by ETA receptors on the osteoblast. ETA receptor inhibition successfully blocked osteoblastic bone metastases in a mouse model. These receptor antagonists are currently in clinical trials for advanced prostate cancer and bone metastases (Stephenson, 2001; Carducci et al., 2002; 2003). Therefore, the molecular mechanisms responsible for osteoblastic metastases are complex and involve bi-directional interactions between tumor cells and bone. Elucidation of the interactions at a molecular level can identify therapeutic targets for osteoblastic metastases. Although ET-1 and ETA receptors are potential targets for this devastating complication of cancer (Remuzzi et al., 2003), they are certainly not the only ones. The rapid pace of metastasis research, will not only expand our therapeutic armamentarium against bone metastases, but will also provide insight into achieving the ultimate goal: the prevention of cancer metastases to bone.

Animals↗
PubMed2004

Mechanisms and treatment for bone metastases.

Alterations in bone architecture and mineral metabolism are common complications of malignancy. Cancers such as breast, prostate, and lung can affect the skeleton either indirectly through the elaboration of factors that act to disrupt normal calcium homeostasis at the level of the kidney and bone; or directly via secondary spread of tumor to bone. Although the pathophysiology of these skeletal complications is diverse, it is clear that the osteoclast and osteoblast are not just bystanders but are active participants in the development and progression of hypercalcemia and bone metastasis. Our understanding of the molecular mechanisms of metastasis leading to tumor cell escape, homing, adhesion, and secondary growth in a hospitable environment are evolving. Treatment modalities aimed at not only reducing tumor burden but altering the skeletal response to tumor have shown benefit. Newer generation bisphosphonates are quite effective in controlling hypercalcemia of malignancy and have been shown to delay progression of skeletal metastases. Clearly, cancer-associated bone morbidity remains a major public health problem. 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.

Animals↗
PubMed2003

A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases.

Osteoblastic bone metastases are common in prostate and breast cancer patients, but mechanisms by which tumor cells stimulate new bone formation are unclear. We identified three breast cancer cell lines that cause osteoblastic metastases in a mouse model and secrete endothelin-1. Tumor-produced endothelin-1 stimulates new bone formation in vitro and osteoblastic metastases in vivo via the endothelin A receptor. Treatment with an orally active endothelin A receptor antagonist dramatically decreased bone metastases and tumor burden in mice inoculated with ZR-75-1 cells. Tumor-produced endothelin-1 may have a major role in the establishment of osteoblastic bone metastases, and endothelin A receptor blockade represents effective treatment.

Bone Neoplasms↗
PubMed2003

Role of endothelin-1 in osteoblastic bone metastases.

BACKGROUND: Certain solid tumors metastasize to bone and cause an osteoblastic response. The mechanisms by which tumor cells stimulate this new bone formation are not completely understood. METHODS: The authors identified three breast cancer lines that cause osteoblastic metastases in female nude mice and provided evidence that tumor-produced endothelin-1 (ET-1) mediates the osteoblastic response. RESULTS: Tumor conditioned media, as well as exogenous ET-1, stimulated osteoblast proliferation and new bone formation in cultures of mouse calvariae. These effects were blocked by antagonists of the endothelin A (ET(A)), but not ET(B), receptors. Mice inoculated with the ZR-75-1 breast cancer line and treated with a selective ET(A) receptor antagonist (ABT-627) had significantly fewer osteoblastic bone metastases and less tumor burden compared with untreated mice. In contrast, there was no effect of ABT-627 on osteolytic bone metastases caused by ET-1-negative breast cancer, MDA-MB-231. ABT-627 had no effect on growth in vitro or at the orthotopic site of ZR-75-1 or MDA-MB-231 cells. CONCLUSIONS: Collectively, the data suggested that tumor-produced ET-1 mediates osteoblastic bone metastases by stimulating osteoblast proliferation and new bone formation. ET(A) receptor blockade may be useful for prevention and the treatment of osteoblastic bone metastases due to breast or prostate cancer.

Animals↗
PubMed2003

Role of bisphosphonates in prostate cancer bone metastases.

Bisphosphonate inhibitors of bone resorption have a variety of positive actions against prostate cancer cells in vitro and in preclinical animal models. In patients, they can reduce skeletal-related events and bone pain, as well as reduce the adverse effects of androgen deprivation therapy on skeletal integrity. The preclinical and clinical data to support this are reviewed here. Further clinical trials are required to determine whether bisphosphonates decrease tumor burden or increase patient survival or quality of life, and whether such adjuvant treatments will be cost-effective.

Androgen Antagonists↗