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Biomedical subjects

John M Chirgwin

Publications and source records attributed to John M Chirgwin.

12 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

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

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↗
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 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↗
PubMed2003

Transforming growth factor-beta in osteolytic breast cancer bone metastases.

Breast cancers frequently metastasize to the skeleton and cause bone destruction. Tumor cells secrete factors that stimulate osteoclasts. The consequent osteolytic resorption releases active factors from the bone matrix, in particular transforming growth factor-beta (TGF-beta). The released factors then stimulate tumor cell signaling, which causes breast cancer cells to make increased amounts of osteolytic factors, such as parathyroid hormone-related protein (PTHrP), interleukin-11 (IL-11), and vascular endothelial growth factor (VEGF). Therefore, tumor cell-bone cell interactions cause a vicious cycle in which tumor cells stimulate bone cells to cause bone destruction. As a consequence, the local microenvironment is enriched with factors that fuel tumor growth in bone. Transforming growth factor-beta is of particular importance because it increases breast cancer production of PTHrP. Parathyroid hormone-related protein then stimulates osteoblasts to express RANK (receptor activator of nuclear factor kappa B) ligand, which in turns enhances osteoclast formation and activity. Breast cancer osteolytic metastasis can be interrupted at four points in the vicious cycle: by neutralizing PTHrP biologic activity, by blocking the TGF-beta signaling pathway in the tumor cells, by inhibiting PTHrP gene transcription, and by inhibiting bone resorption.

Animals↗
PubMed2002

Transforming growth factor-beta stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways.

Transforming growth factor (TGF)-beta promotes breast cancer metastasis to bone. To determine whether the osteolytic factor parathyroid hormone-related protein (PTHrP) is the primary mediator of the tumor response to TGF-beta, mice were inoculated with MDA-MB-231 breast cancer cells expressing a constitutively active TGF-beta type I receptor. Treatment of the mice with a PTHrP-neutralizing antibody greatly decreased osteolytic bone metastases. There were fewer osteoclasts and significantly decreased tumor area in the antibody-treated mice. TGF-beta can signal through both Smad and mitogen-activated protein (MAP) kinase pathways. Stable transfection of wild-type Smad2, Smad3, or Smad4 increased TGF-beta-stimulated PTHrP secretion, whereas dominant-negative Smad2, Smad3, or Smad4 only partially reduced TGF-beta-stimulated PTHrP secretion. When the cells were treated with a variety of protein kinases inhibitors, only specific inhibitors of the p38 MAP kinase pathway significantly reduced both basal and TGF-beta-stimulated PTHrP production. The combination of Smad dominant-negative blockade and p38 MAP kinase inhibition resulted in complete inhibition of TGF-beta-stimulated PTHrP production. Furthermore, TGF-beta treatment of MDA-MB-231 cells resulted in a rapid phosphorylation of p38 MAP kinase. Thus, the p38 MAP kinase pathway appears to be a major component of Smad-independent signaling by TGF-beta and may provide a new molecular target for anti-osteolytic therapy.

Bone Neoplasms↗