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Russell S Taichman

Publications and source records attributed to Russell S Taichman.

17 recordsLinked to original sources
PubMed2007

Osteoblasts support B-lymphocyte commitment and differentiation from hematopoietic stem cells.

Early B lymphopoiesis in mammals is induced within the bone marrow (BM) microenvironment, but which cells constitute this niche is not known. Previous studies had shown that osteoblasts (OBs) support hematopoietic stem cell (HSC) proliferation and myeloid differentiation. We now find that purified primary murine OBs also support the differentiation of primitive hematopoietic stem cells through lymphoid commitment and subsequent differentiation to all stages of B-cell precursors and mature B cells. Lin(-)Sca-1(+)Rag-2(-) BM cell differentiation to B cells requires their attachment to OBs in vitro, and this developmental process is mediated via VCAM-1, SDF-1, and IL-7 signaling induced by parathyroid hormone (PTH). Addition of cytokines produced by nonosteoblastic stromal cells (c-Kit ligand, IL-6, and IL-3) shifted the cultures toward myelopoiesis. Confirming the role of OBs in B lymphopoiesis, we found that selective elimination of osteoblasts in Col2.3Delta-TK transgenic mice severely depleted pre-pro-B and pro-B cells from BM, preceding any decline in HSCs. Taken together, these results demonstrate that osteoblasts are both necessary and sufficient for murine B-cell commitment and maturation, and thereby constitute the cellular homolog of the avian bursa of Fabricius.

Animals↗
PubMed2007

Expression and activation of alpha v beta 3 integrins by SDF-1/CXC12 increases the aggressiveness of prostate cancer cells.

BACKGROUND: Stromal cell-derived factor-1 (SDF-1 or CXCL12) and CXCR4 are key elements in the metastasis of prostate cancer cells to bone--but the mechanisms as to how it localizes to the marrow remains unclear. METHODS: Prostate cancer cell lines were stimulated with SDF-1 and evaluated for alterations in the expression of adhesion molecules using microarrays, FACs, and Western blotting to identify alpha(v)beta(3) receptors. Cell-cell adhesion and invasion assays were used to verify that activation of the receptor is responsive to SDF-1. RESULTS: We demonstrate that SDF-1 transiently regulates the number and affinity of alpha(v)beta(3) receptors by prostate cancer cells to enhance their metastatic behavior by increasing adhesiveness and invasiveness. SDF-1 transiently increased the expression of beta(3) receptor subunit and increased its phosphorylation in metastatic but not nonmetastatic cells. CONCLUSIONS: The transition from a locally invasive phenotype to a metastatic phenotype may be primed by the elevated expression of alpha(v)beta(3) receptors. Activation and increased expression of alpha(v)beta(3) within SDF-1-rich organs may participate in metastatic localization.

Bone Neoplasms↗
PubMed2007

A glycolytic mechanism regulating an angiogenic switch in prostate cancer.

The generation of an "angiogenic switch" is essential for tumor growth, yet its regulation is poorly understood. In this investigation, we explored the linkage between metastasis and angiogenesis through CXCL12/CXCR4 signaling. We found that CXCR4 regulates the expression and secretion of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1). Overexpression of PGK1 reduced the secretion of vascular endothelial growth factor and interleukin-8 and increased the generation of angiostatin. At metastatic sites, however, high levels of CXCL12 signaling through CXCR4 reduced PGK1 expression, releasing the angiogenic response for metastastic growth. These data suggest that PGK1 is a critical downstream target of the chemokine axis and an important regulator of an "angiogenic switch" that is essential for tumor and metastatic growth.

Angiostatins↗
PubMed2006

The pivotal role of CXCL12 (SDF-1)/CXCR4 axis in bone metastasis.

Tumor cells are known to adapt to and utilize existing physiological mechanisms to promote survival and metastasis. The role of the microenvironment in the establishment of a metastatic lesion has become increasingly important as several factors secreted by stromal cells regulate metastatic pattern in a variety of tumor types. Tumor cells interact with osteoblasts, osteoclasts and bone matrix to form a vicious cycle that is essential for successful metastases. Here we review the current concepts regarding the role of an important chemokine/chemokine receptor (SDF-1 or CXCL12/CXCR4) pathway in tumor development and metastasis. CXCL12 secretion by stromal cells is known to attract cancer cells via stimulation of the CXCR4 receptor that is up regulated by tumor cells. CXCL12/CXCR4 activation regulates the pattern of metastatic spread with organs expressing high levels of CXCL12 developing secondary tumors (i.e., the bone marrow compartment). CXCL12 has a wide range of effects in regards to tumor development but the primary role of CXCL12 appears to be the mobilization of hematopoietic stem cells and the establishment of the cancer stem-like cell niche where high levels of CXCL12 recruit a highly tumorigenic population of tumor cells and promotes cell survival, proliferation, angiogenesis, and metastasis.

Animals↗
PubMed2006

Ablation of proliferating marrow with 5-fluorouracil allows partial purification of mesenchymal stem cells.

The ability to identify and maintain mesenchymal stem cells in vitro is a prerequisite for the ex vivo expansion of cells capable of effecting mesenchymal tissue regeneration. The aim of this investigation was to develop an assay to enrich and ultimately purify mesenchymal stem cells. To enrich the population of mesenchymal stem cell-like cells, rats or mice were administered 5-fluorouracil (5-FU) in vivo. Limiting dilution analysis demonstrated that 5-FU-treated bone marrow had the potential to form colony-forming units-fibroblastic (CFU-F) at a 10-fold or sixfold enrichment compared to normal bone marrow in rats or mice, respectively. In vivo and in vitro differentiation assays supported the enrichment and purification effects. In vitro, bone marrow cultures from 5-FU-treated bone marrow demonstrated lineage-specific gene expression in lineage-specific medium conditions in contrast to the multilineage gene expression of control bone marrow cultures. In vivo implantation of 5-FU-treated cells that were not expanded in culture generated ossicles containing an intact bone cortex and mature hematopoietic components, whereas non-5-FU-treated bone marrow only formed fibrous tissues. Our results demonstrate that enrichment of a quiescent cell population in the bone marrow by in vivo treatment of 5-FU spares those undifferentiated mesenchymal stem cells and influences the differentiation of bone marrow stromal cells in vitro and in vivo. This prospective identification of a population of mesenchymal cells from the marrow that maintain their multilineage potential should lead to more focused studies on the characterization of a true mesenchymal stem cell.

Animals↗
PubMed2005

Cells of the osteoclast lineage as mediators of the anabolic actions of parathyroid hormone in bone.

PTH is an anabolic agent used to treat osteoporosis, but its mechanisms of action are unclear. This study elucidated target cells and mechanisms for anabolic actions of PTH in mice during bone growth. Mice with c-fos ablation are osteopetrotic and lack an anabolic response to PTH. In this study, there were no alterations in PTH-regulated osteoblast differentiation or proliferation in vitro in cells from c-fos -/- mice compared with +/+; hence, the impact of osteoclastic cells was further investigated. A novel transplant model was used to rescue the osteopetrotic defect of c-fos ablation. Vertebral bodies (vossicles) from c-fos -/- and +/+ mice were implanted into athymic hosts, and the c-fos -/- osteoclast defect was rescued. PTH treatment to vossicle-bearing mice increased 5-bromo-2'-deoxyuridine (BrdU) positivity in the bone marrow and increased bone area regardless of the vossicle genotype. To inhibit recruitment of osteoclast precursors to wild-type vossicles, stromal derived factor-1 signaling was blocked, which blunted the PTH anabolic response. Treating mice with osteoprotegerin to inhibit osteoclast differentiation also blocked the anabolic action of PTH. In contrast, using c-src mutant mice with a late osteoclast differentiation defect did not hinder the anabolic action, suggesting key target cells reside in the intermediately differentiated osteoclast population in the bone marrow. These results indicate that c-fos in osteoblasts is not critical for PTH action but that cells of the osteoclast lineage are intermediate targets for the anabolic action of PTH.

Anabolic Agents↗
PubMed2005

Diverse signaling pathways through the SDF-1/CXCR4 chemokine axis in prostate cancer cell lines leads to altered patterns of cytokine secretion and angiogenesis.

The establishment of metastatic bone lesions in prostate cancer (CaP) is a process partially dependent on angiogenesis. Previously we demonstrated that the stromal-derived factor-1 (SDF-1 or CXCL12)/CXCR4 chemokine axis is critical for CaP cell metastasis. In this investigation, cell lines were established in which CXCR4 expression was knocked down using siRNA technology. When CaP cells were co-transplanted with human vascular endothelial cells into SCID mice, significantly fewer human blood vessels were observed paralleling the reductions in CXCR4 levels. Likewise, the invasive behaviors of the CaP cells were inhibited in vitro. From these functional observations we explored angiogenic and signaling mechanisms generated following SDF-1 binding to CXCR4. Differential activation of the MEK/ERK and PI3K/AKT pathways that result in differential secretion IL-6, IL-8, TIMP-2 and VEGF were seen contingent on the cell type examined; VEGF and TIMP-2 expression in PC3 cells are dependent on AKT activation and ERK activation in LNCaP and LNCaP C4-2B cells leads to IL-6 or IL-8 secretion. At the same time, expression of angiostatin levels were inversely related to CXCR4 levels, and inhibited by SDF-1 stimulation. These data link the SDF-1/CXCR4 pathway to changes in angiogenic cytokines by different signaling mechanisms and, suggest that the delicate equilibrium between proangiogenic and antiangiogenic factors may be achieved by different signal transduction pathways to regulate the angiogenic phenotype of prostate cancers. Taken together, our results provide new information regarding expression of functional CXCR4 receptor-an essential role and potential mechanism of angiogenesis upon SDF-1 stimulation.

Angiostatins↗
PubMed2004

Blood and bone: two tissues whose fates are intertwined to create the hematopoietic stem-cell niche.

The mechanisms of bone and blood formation have traditionally been viewed as distinct, unrelated processes, but compelling evidence suggests that they are intertwined. Based on observations that hematopoietic precursors reside close to endosteal surfaces, it was hypothesized that osteoblasts play a central role in hematopoiesis, and it has been shown that osteoblasts produce many factors essential for the survival, renewal, and maturation of hematopoietic stem cells (HSCs). Preceding these observations are studies demonstrating that the disruption or perturbation of normal osteoblastic function has a profound and central role in defining the operational structure of the HSC niche. These observations provide a glimpse of the dimensions and ramifications of HSC-osteoblast interactions. Although more research is required to secure a broader grasp of the molecular mechanisms that govern blood and bone biology, the central role for osteoblasts in hematopoietic stem cell regulation is reviewed herein from the perspectives of (1) historical context; (2) the role of the osteoblast in supporting stem cell survival, proliferation, and maintenance; (3) the participation, if any, of osteoblasts in the creation of a stem cell niche; (4) the molecules that mediate HSC-osteoblast interactions; (5) the role of osteoblasts in stem cell transplantation; and (6) possible future directions for investigation.

Animals↗
PubMed2004

Skeletal localization and neutralization of the SDF-1(CXCL12)/CXCR4 axis blocks prostate cancer metastasis and growth in osseous sites in vivo.

UNLABELLED: To delineate the role of SDF-1 and CXCR4 in metastatic prostate cancer (CaP), positive correlations were established between SDF-1 levels and tumor metastasis. Neutralization of CXCR4 limited the number and the growth of intraosseous metastasis in vivo. Together, these in vivo metastasis data provide critical support that SDF-1/CXCR4 plays a role in skeletal metastasis. INTRODUCTION: Previously we determined that the stromal-derived factor-1 (SDF-1)/CXCR4 chemokine axis is activated in prostate cancer (CaP) metastasis to bone. To delineate the role of SDF-1/CXCR4 in CaP, we evaluated SDF-1 levels in a variety of tissues and whether neutralization of SDF-1 prevented metastasis and/or intraosseous growth of CaPs. MATERIALS AND METHODS: SDF-1 levels were established in various mouse tissues by ELISA, immunohistochemistry, and in situ hybridization. To assess the role of SDF-1/CXCR4 in metastasis, bone metastases were established by administering CaP cells into the left cardiac ventricle of nude animals in the presence or absence of neutralizing CXCR4 antibody. The effect of SDF-1 on intraosseous growth of CaP cells was determined using intratibial injections and anti-CXCR4 antibodies and peptides. RESULTS: There was a positive correlation between the levels of SDF-1 and tissues in which metastatic CaP lesions were observed. SDF-1 levels were highest in the pelvis, tibia, femur, liver, and adrenal/kidneys compared with the lungs, tongue, and eye, suggesting a selective effect. SDF-1 staining was generally low or undetectable in the center of the marrow and in the diaphysis. SDF-1 mRNA was localized to the metaphysis of the long bones nearest to the growth plate where intense expression was observed near the endosteal surfaces covered by osteoblastic and lining cells. Antibody to CXCR4 significantly reduced the total metastatic load compared with IgG control-treated animals. Direct intratibial injection of tumor cells followed by neutralizing CXCR4 antibody or a specific peptide that blocks CXCR4 also decreased the size of the tumors compared with controls. CONCLUSIONS: These data provide critical support for a role of SDF-1/CXCR4 in skeletal metastasis. Importantly, these data show that SDF-1/CXCR4 participate in localizing tumors to the bone marrow for prostate cancer.

Amino Acids↗
PubMed2004

Inhibition of breast cancer metastasis by selective synthetic polypeptide against CXCR4.

Metastasis shares many similarities with leukocyte trafficking. Among those chemokine receptors thought to be involved in hemopoietic cell homing, stromal cell-derived factor-1 and its receptor CXC chemokine receptor-4 (CXCR4) have received considerable attention. Like hemopoietic cell homing, levels of stromal cell-derived factor-1 are high at sites of breast cancer metastasis including lymph node, lung, liver, and the marrow. Moreover, CXCR4 expression is low in normal breast tissues and high in malignant tumors, suggesting that a blockade of CXCR4 might limit tumor metastasis. We therefore investigated the role of a synthetic antagonist 14-mer peptide (TN14003) in inhibiting metastasis in an animal model. Not only was TN14003 effective in limiting metastasis of breast cancer by inhibiting migration, but it may also prove useful as a diagnostic tool to identify CXCR4 receptor-positive tumor cells in culture and tumors in paraffin-embedded clinical samples.

Adult↗
PubMed2004

Vascular endothelial growth factor contributes to the prostate cancer-induced osteoblast differentiation mediated by bone morphogenetic protein.

Human prostate cancer has a high predisposition to metastasize to bone, resulting in the formation of osteoblastic metastases. The mechanism through which prostate cancer cells promote osteoblastic lesions is undefined. Vascular endothelial growth factor (VEGF) has been implicated as a mediator of osteoblast activity. In the present study, we examined if prostate cancer cells promote osteoblastic activity through VEGF. We found that LNCaP and C4-2B prostate cancer cell lines and primary tumor and metastatic prostate cancer tissues from patients expressed VEGF. Bone morphogenetic proteins (BMPs), which are normally present in the bone environment, induced VEGF protein and mRNA expression in C4-2B cells. Furthermore, BMP-7 activated the VEGF promoter. Noggin, a BMP inhibitor, diminished VEGF protein expression and promoter activity in C4-2B cells. Conditioned media (CM) from C4-2B cells induced pro-osteoblastic activity (increased alkaline phosphatase, osteocalcin, and mineralization) in osteoblast cells. Both noggin alone and anti-VEGF antibody alone diminished C4-2B CM-induced pro-osteoblastic activity. Transfection of C4-2B cells with VEGF partially rescued the C4-2B CM-induced pro-osteoblastic activity from noggin inhibition. These observations indicate that BMPs promote osteosclerosis through VEGF in prostate cancer metastases. These results suggest a novel function for VEGF in skeletal metastases. Specifically, VEGF promotes osteoblastic lesion formation at prostate cancer bone metastatic sites.

Bone Morphogenetic Proteins↗
PubMed2003

Expression of CXCR4 and CXCL12 (SDF-1) in human prostate cancers (PCa) in vivo.

Human prostate cancers (PCa) express great variability in their ability to metastasize to bone. The identification of molecules associated with aggressive phenotypes will help to define PCa subsets and will ultimately lead to better treatment strategies. The chemokine stromal-derived factor-1 (SDF-1 or CXCL12) and its receptor CXCR4 are now known to modulate the migration and survival of an increasing array of normal and malignant cell types including breast, pancreatic cancers, glioblastomas, and others. The present investigation extends our previous investigations by determining the expression of CXCR4 and CXCL12 in humans using high-density tissue microarrays constructed from clinical samples obtained from a cohort of over 600 patients. These data demonstrate that CXCR4 protein expression is significantly elevated in localized and metastastic cancers. At the RNA level, human PCa tumors also express CXCR4 and message, but overall, they were not significantly different suggesting post-transcriptional regulation of the receptor plays a major role in regulating protein expression. Similar observations were made for CXCL12 message, but in this case more CXCL12 message was expressed by metastastic lesions as compared to normal tissues. PCa cell lines also express CXCL12 mRNA, and regulate mRNA expression in response to CXCL12 and secrete biologically active protein. Furthermore, neutralizing antibody to CXCL12 decreased the proliferation of bone homing LNCaP C4-2B and PC3 metastastic tumor cells. These investigations provide important new information pertaining to the molecular basis of how tumors may 'home' to bone, and the mechanisms that may account for their growth in selected end organs.

Adult↗
PubMed2003

Stromal factors involved in prostate carcinoma metastasis to bone.

BACKGROUND: Prostate carcinoma (PC) frequently metastasizes to bone, where it causes significant morbidity and mortality. Stromal elements in the primary and metastatic target organs are important mediators of tumor cell intravasation, chemoattraction, adhesion to target organ microvascular endothelium, extravasation, and growth at the metastatic site. METHODS: The role of stromal factors in bone metastasis was determined with a cyclic DNA microarray comparison of a bone-derived cell PC cell line with a soft tissue-derived cell PC cell line and by evaluating the effects of selected stromal components on PC cell chemotaxis, cell adhesion to human bone marrow endothelium (HBME), and PC cell growth. RESULTS: The authors demonstrate that PC cells express protease-activated receptor 1 (PAR1; thrombin receptor), and its expression is up-regulated in PC compared with normal prostate tissue. In addition, this overexpression was very pronounced in bone-derived PC cell lines (VCaP and PC-3) compared with soft tissue PC cell lines (DUCaP, DU145, and LNCaP). The authors report that bone stromal factors, including stromal cell-derived factor 1 (SDF-1) and collagen Type I peptides, are chemoattractants for PC cells, and they demonstrate that some of these factors (e.g., extracellular matrix components, transforming growth factor beta, bone morphogenic proteins [BMPs], and SDF-1) significantly alter PC-HBME interaction in vitro. Finally, stromal factors, such as BMPs, can regulate the proliferation of PC cells in vitro. CONCLUSIONS: Soluble and insoluble elements of the stroma are involved in multiple steps of PC metastasis to bone. The authors hypothesize that PAR1 may play a central role in prostate tumorigenesis.

Bone Morphogenetic Proteins↗
PubMed2002

G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4.

Granulocyte colony-stimulating factor (G-CSF) induced hematopoietic stem cell mobilization is widely used for clinical transplantation; however, the mechanism is poorly understood. We report here that G-CSF induced a reduction of the chemokine stromal cell derived factor 1 (SDF-1) and an increase in its receptor CXCR4 in the bone marrow (BM), whereas their protein expression in the blood was less affected. The gradual decrease of BM SDF-1, due mostly to its degradation by neutrophil elastase, correlated with stem cell mobilization. Elastase inhibition reduced both activities. Human and murine stem cell mobilization was inhibited by neutralizing CXCR4 or SDF-1 antibodies, demonstrating SDF-1 CXCR4 signaling in cell egress. We suggest that manipulation of SDF-1 CXCR4 interactions may be a means with which to control the navigation of progenitors between the BM and blood to improve the outcome of clinical stem cell transplantation.

Animals↗
PubMed2002

Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone.

Neoplasms have a striking tendency to metastasize or "home" to bone. Hematopoietic cells also home to bone during embryonic development, where evidence points to the chemokine stromal cell-derived factor-1 (SDF-1 or CXCL12; expressed by osteoblasts and endothelial cells) and its receptor (CXCR4) as key elements in these processes. We hypothesized that metastatic prostate carcinomas also use the SDF-1/CXCR4 pathway to localize to the bone. To test this, levels of CXCR4 expression were determined for several human prostate cancer cell lines by reverse transcription-PCR and Western blotting. Positive results were obtained for cell lines derived from malignancies that had spread to bone and marrow. Prostate cancer cells were also observed migrating across bone marrow endothelial cell monolayers in response to SDF-1. In in vitro adhesion assays, pretreatment of the prostate cancer cells with SDF-1 significantly increased their adhesion to osteosarcomas and endothelial cell lines in a dose-dependent manner. Invasion of the cancer cell lines through basement membranes was also supported by SDF-1 and inhibited by antibody to CXCR4. Collectively, these results suggest that prostate cancers and perhaps other neoplasms may use the SDF-1/CXCR4 pathway to spread to bone.

Bone Neoplasms↗
PubMedDate not supplied

Detection and isolation of circulating tumor cells in urologic cancers: a review.

The American Cancer Society has estimated that in 2003, there will be approximately 239,600 new cases of urologic cancer diagnosed and 54,600 urologic cancer-related deaths in the United States. To date, the majority of research and therapy design have focused on the microenvironment of the primary tumor site, as well as the microenvironment of the metastatic or secondary (target) tumor site. Little attention has been placed on the interactions of the circulating tumor cells and the microenvironment of the circulation (i.e., the third microenvironment). The purpose of this review is to present the methods for the detection and isolation of circulating tumor cells and to discuss the importance of circulating tumor cells in the biology and treatment of urologic cancers.

Cell Survival↗