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1.  Cancer Stem Cells and their Role in Metastasis 
Pharmacology & therapeutics  2013;138(2):285-293.
Cancer stem cells (CSCs), which comprise a small fraction of cancer cells, are believed to constitute the origin of most human tumors. Considerable effort has been focused on identifying CSCs in multiple tumor types and identifying genetic signatures that distinguish CSCs from normal tissue stem cells. Many studies also suggest that CSCs serve as the basis of metastases. Yet, experimental evidence that CSCs are the basis of disseminated metastases has lagged behind the conceptual construct of CSCs. Recent work, however, has demonstrated that CSCs may directly or indirectly contribute to the generation of metastasis. Moreover, CSC heterogeneity may be largely responsible for the considerable complexity and organ specificity of metastases. In this review, we discuss the role of CSCs in metastasis and their potential as therapeutic targets.
PMCID: PMC3602306  PMID: 23384596
Cancer stem cells; molecular marker; metastasis; epithelial to mesenchymal transition; circulating tumor cells; cancer therapeutic target
2.  Erythropoietin Supports the Survival of Prostate Cancer, But Not Growth and Bone Metastasis 
Journal of cellular biochemistry  2013;114(11):2471-2478.
Erythropoietin (Epo) is used in clinical settings to enhance hematopoietic function and to improve the quality of life for patients undergoing chemotherapy by reducing fatigue and the need for transfusions. However, several meta-analyses have revealed that Epo treatments are associated with an increased risk of mortality in cancer patients. In this study, we examined the role of Epo in prostate cancer (PCa) progression, using in vitro cell culture systems and in vivo bone metastatic assays. We found that Epo did not stimulate the proliferation of PCa cell lines, but did protect PCa cells from apoptosis. In animal models of PCa metastasis, no evidence was found to support the hypothesis that Epo enhances metastasis. Together, these findings suggest that Epo may be useful for treating severe anemia in PCa patients without increasing metastatic risk.
PMCID: PMC3978144  PMID: 23696192
3.  Human Very Small Embryonic-Like Cells Generate Skeletal Structures, In Vivo 
Stem Cells and Development  2012;22(4):622-630.
Human very small embryonic-like (hVSEL) cells are a resident population of multipotent stem cells in the bone marrow involved in the turnover and regeneration of tissues. The levels of VSEL cells in blood are greatly increased in response to injury, and they have been shown to repair injured tissues. Adult hVSEL cells, SSEA-4+/CD133+/CXCR4+/Lin−/CD45−, express the pluripotency markers (Oct-4 and Nanog) and may be able to differentiate into cells from all 3 germ lineages. hVSEL cells isolated from blood by apheresis following granulocyte–colony-stimulating factor mobilization were fractionated and enriched by elutriation and fluorescence activated cell sorting. Collagen sponge scaffolds containing 2,000–30,000 hVSEL cells were implanted into cranial defects generated in SCID mice. Analysis by microcomputed tomography showed that a cell population containing VSEL cells produced mineralized tissue within the cranial defects compared with controls at 3 months. Histologic studies showed significant bone formation and cellular organization within the defects compared with cellular or scaffold controls alone. Antibodies to human leukocyte antigens demonstrated that the newly generated tissues were of human origin. Moreover, human osteocalcin was identified circulating in the peripheral blood. There was evidence that some level of hVSEL cells migrated away from the defect site, using quantitative real-time polymerase chain reaction to detect for human-specific Alu sequences. This study demonstrates that hVSEL cells are able to generate human bone tissue in a mouse model of skeletal repair. These studies lay the foundation for future cell-based regenerative therapies for osseous and connective tissue disorders, including trauma and degenerative conditions, such as osteoporosis, fracture repair, and neoplastic repair.
PMCID: PMC3564465  PMID: 23020187
4.  The Impact of Proteoglycan-4 and Parathyroid Hormone on Articular Cartilage 
Proteoglycan-4 (Prg4) protects synovial joints from arthropathic changes by mechanisms that are incompletely understood. Parathyroid hormone (PTH), known for its anabolic actions in bone, increases Prg4 expression and has been reported to inhibit articular cartilage degeneration in arthropathic joints. To investigate the effect of Prg4 and PTH on articular cartilage, 16-week-old Prg4 mutant and wildtype mice were treated with intermittent PTH (1–34) or vehicle control daily for six weeks. Analyses included histology of the knee joint, micro-CT of the distal femur, and serum biochemical analysis of type II collagen fragments (CTX-II). Compared to wildtype littermates, Prg4 mutant mice had an acellular layer of material lining the surfaces of the articular cartilage and menisci, increased articular cartilage degradation, increased serum CTX-II concentrations, decreased articular chondrocyte apoptosis, increased synovium SDF-1 expression, and irregularly contoured subchondral bone. PTH-treated Prg4 mutant mice developed a secondary deposit overlaying the acellular layer of material lining the joint surfaces, but PTH-treatment did not alter signs of articular cartilage degeneration in Prg4 mutant mice. The increased joint SDF-1 levels and irregular subchondral bone found in Prg4 mutant mice introduce novel candidate mechanisms by which Prg4 protects articular cartilage.
PMCID: PMC3502647  PMID: 22898906
Proteoglycan-4; PTH; cartilage; degeneration; SDF-1
5.  The Effects of Zoledronic Acid in the Bone and Vasculature Support of Hematopoietic Stem Cell Niches 
Journal of cellular biochemistry  2013;114(1):67-78.
Hematopoietic stem cells (HSC) are maintained in a tightly regulated bone microenvironment constituted by a rich milieu of cells. Bone cells such as osteoblasts are associated with niche maintenance as regulators of the endosteal microenvironment. Bone remodeling also plays a role in HSC mobilization although it is poorly defined. The effects of zoledronic acid (ZA), a potent bisphosphonate that inhibits bone resorption, were investigated on bone marrow cell populations focusing on HSCs, and the endosteal and vascular niches in bone. ZA treatment significantly increased bone volume and HSCs in both young and adult mice (4 week and 4 month old, respectively). ZA increased vessel numbers with no overall change in vascular volume in bones of young and had no effect on vasculature in adult mice. Since both young and adult mice had increased HSCs and bone mass with differing vasculature responses, this suggests that ZA indirectly supports HSCs via the osteoblastic niche and not the vascular niche. Additionally, gene expression in Lin- cells demonstrated increased expression of self-renewal-related genes Bmi1 and Ink4a suggesting a role of ZA in the modulation of cell commitment and differentiation toward a long-term self-renewing cell. Genes that support the osteoblastic niche, BMP2 and BMP6 were also augmented in ZA treated mice. In conclusion, ZA-induced HSC expansion occurs independent of the vascular niche via indirect modulation of the osteoblastic niche.
PMCID: PMC3593195  PMID: 22833499
6.  An HLA-DRB1-Coded Signal Transduction Ligand Facilitates Inflammatory Arthritis. A New Mechanism of Autoimmunity1 
Particular alleles of human leukocyte antigen (HLA) contribute to disease susceptibility and severity in many autoimmune conditions, but the mechanisms underlying these associations are often unknown. Here, we demonstrate that the shared epitope (SE), an HLA-DRB1-coded sequence motif that is the single most significant genetic risk factor for erosive rheumatoid arthritis (RA), acts as a signal transduction ligand that potently activates osteoclastogenesis, both in vitro and in vivo. The SE enhanced the production of several pro-osteoclastogenic factors and facilitated osteoclast (OC) differentiation in mouse and human cells in vitro. Transgenic mice expressing a human HLA-DRB1 allele that code the SE motif demonstrated markedly higher propensity for osteoclastogenesis and enhanced bone degradation capacity ex vivo. In addition, the SE enhanced the differentiation of Th17 cells expressing the receptor activator for nuclear factor-κB ligand (RANKL). When the two agents were combined, IL-17 and the SE enhanced OC differentiation synergistically. When administered in vivo to mice with collagen-induced arthritis, the SE ligand significantly increased arthritis severity, synovial tissue OC abundance and bone erosion. Thus, the SE contributes to arthritis severity by activating an OC-mediated bone-destructive pathway. These findings suggest that besides determining the target specificity of autoimmune responses, HLA molecules may influence disease outcomes by shaping the pathogenic consequences of such responses.
PMCID: PMC3529776  PMID: 23180817
7.  Molecular Signature and In Vivo Behavior of Bone Marrow Endosteal and Subendosteal Stromal Cell Populations and their Relevance to Hematopoiesis 
Experimental cell research  2012;318(19):2427-2437.
In the bone marrow cavity, hematopoietic stem cells (HSC) have been shown to reside in the endosteal and subendosteal perivascular niches, which play specific roles on HSC maintenance. Although cells with long-term ability to reconstitute full hematopoietic system can be isolated from both niches, several data support a heterogenous distribution regarding the cycling behavior of HSC. Whether this distinct behavior depends upon the role played by the stromal populations which distinctly create these two niches is a question that remains open. In the present report, we used our previously described in vivo assay to demonstrate that endosteal and subendosteal stromal populations are very distinct regarding skeletal lineage differentiation potential. This was further supported by a microarray-based analysis, which also demonstrated that these two stromal populations play distinct, albeit complementary, roles in HSC niche. Both stromal populations were preferentially isolated from the trabecular region and behave distinctly in vitro, as previously reported. Even though these two niches are organized in a very close range, in vivo assays and molecular analyses allowed us to identify endosteal stroma (F-OST) cells as fully committed osteoblasts and subendosteal stroma (F-RET) cells as uncommitted mesenchymal cells mainly represented by perivascular reticular cells expressing high levels of chemokine ligand, CXCL12. Interestingly, a number of cytokines and growth factors including interleukin-6 (IL-6), IL-7, IL-15, Hepatocyte growth factor (HGF) and stem cell factor (SCF) matrix metalloproteases (MMPs) were also found to be differentially expressed by F-OST and F-RET cells. Further microarray analyses indicated important mechanisms used by the two stromal compartments in order to create and coordinate the “quiescent” and “proliferative” niches in which hematopoietic stem cells and progenitors reside.
PMCID: PMC3445703  PMID: 22841688
bone marrow; trabecular bone; microenvironment; osteoblast; niche
8.  Erythropoietin Modulates the Structure of Bone Morphogenetic Protein 2–Engineered Cranial Bone 
Tissue Engineering. Part A  2012;18(19-20):2095-2105.
The ideally engineered bone should have similar structural and functional properties to the native tissue. Although structural integrity is critical for functional bone regeneration, we know less about modulating the structural properties of the engineered bone elicited by bone morphogenetic protein (BMP) than efficacy and safety. Erythropoietin (Epo), a primary erythropoietic hormone, has been used to augment blood transfusion in orthopedic surgery. However, the effects of Epo on bone regeneration are not well known. Here, we determined the role of Epo in BMP2-induced bone regeneration using a cranial defect model. Epo administration improved the quality of BMP2-induced bone and more closely resembled natural cranial bone with a higher bone volume (BV) fraction and lower marrow fraction when compared with BMP2 treatment alone. Epo increased red blood cells (RBCs) in peripheral blood and also increased hematopoietic and mesenchymal stem cell (MSC) populations in bone marrow. Consistent with our previous work, Epo increased osteoclastogenesis both in vitro and in vivo. Results from a metatarsal organ culture assay suggested that Epo-promoted osteoclastogenesis contributed to angiogenesis because angiogenesis was blunted when osteoclastogenesis was blocked by alendronate (ALN) or osteoprotegerin (OPG). Earlier calcification of BMP2-induced temporary chondroid tissue was observed in the Epo+BMP group compared to BMP2 alone. We conclude that Epo significantly enhanced the outcomes of BMP2-induced cranial bone regeneration in part through its actions on osteoclastogenesis and angiogenesis.
PMCID: PMC3463277  PMID: 22703029
9.  Getting Blood from Bone: An Emerging Understanding of the Role That Osteoblasts Play In Regulating Hematopoietic Stem Cells Within Their Niche 
Experimental hematology  2012;40(9):685-694.
Blood and bone are dynamic tissues that are continuously renewed through out life. Early observations based upon the proximity of bone and hematopoietic progenitor populations in marrow suggested that interactions between skeletal and hematopoietic elements are likely to be crucial in the development and function of each system. As a result of these morphologic observations, several groups have demonstrated that the osteoblasts play an important role in hematopoiesis by serving as a specific local microenvironment, or “niche”, for hematopoietic stem cells (HSC). Significant new developments in this area of active investigation have emerged since our last examination of this area in 2005. Here we discuss these new insights into the function and morphology of the HSC niche with a particular focus on cells of the osteoblastic lineage.
PMCID: PMC3419274  PMID: 22640993
10.  TBK1 Regulates Prostate Cancer Dormancy through mTOR Inhibition12 
Neoplasia (New York, N.Y.)  2013;15(9):1064-1074.
The mechanisms that regulate hematopoietic stem cell (HSC) dormancy and self-renewal are well established and are largely dependent on signals emanating from the HSC niche. Recently, we found that prostate cancer (PCa) cells target the HSC niche in mouse bone marrow (BM) during metastasis. Little is known, however, as to how the HSC niche may regulate dormancy in cancer cells. In this study, we investigated the effects of TANK binding kinase 1 (TBK1) on PCa dormancy in the BM niche. We found that binding with niche osteoblasts induces the expression of TBK1 in PCa cells PC3 and C4-2B. Interestingly, TBK1 interacts with mammalian target of rapamycin (mTOR) and inhibits its function. Rapamycin, an mTOR inhibitor, induces cell cycle arrest of PCa cells and enhances chemotherapeutic resistance of PCa cells. As a result, the knockdown of TBK1 decreases PCa stem-like cells and drug resistance in vitro and in vivo. Taken together, these results strongly indicate that TBK1 plays an important role in the dormancy and drug resistance of PCa.
PMCID: PMC3769885  PMID: 24027431
11.  Recruitment of Mesenchymal Stem Cells Into Prostate Tumors Promotes Metastasis 
Nature communications  2013;4:1795.
Tumors recruit mesenchymal stem cells (MSCs) to facilitate healing, which induces their conversion into cancer-associated fibroblasts that facilitate metastasis. However, this process is poorly understood on the molecular level. Here we show that the CXCR6 ligand CXCL16 facilitates MSC or Very Small Embryonic-Like (VSEL) cells recruitment into prostate tumors. CXCR6 signaling stimulates the conversion of MSCs into cancer-associated fibroblasts, which secrete stromal-derived factor-1, also known as CXCL12. CXCL12 expressed by cancer-associated fibroblasts then binds to CXCR4 on tumor cells and induces an epithelial to mesenchymal transition, which ultimately promotes metastasis to secondary tumor sites. Our results provide the molecular basis for MSC recruitment into tumors and how this process leads to tumor metastasis.
PMCID: PMC3649763  PMID: 23653207
12.  Cancer Stem Cells and the Bone Marrow Microenvironment 
BoneKEy reports  2012;2012(1):48.
“Cancer” is a disease that can spread to the other organs over time. The prognosis of cancer patients with metastasis is generally poor. Accordingly, there is an urgent need to establish a greater understanding of metastatic processes. It is highly likely that cancer stem cells (CSCs) are the key cells that mediate metastases, even while the cellular origin of CSCs remains unknown. Growing evidence has also revealed that the microenvironment has profound effects on the regulation of CSCs. Recently, it has been shown that bone metastatic cancer cells target the microenvironment or ‘niche’ which houses hematopoietic stem cells (HSCs). The major function of the HSC niche is to maintain ‘stemness’ of HSCs. These findings suggest that by targeting the HSC niche metastatic cells parasitize the very foundation of hematopoiesis to maintain their stemness. These observations suggest that there will be a need to target the HSC niche to provide effective therapies to eradicate metastatic CSCs.
PMCID: PMC3671623  PMID: 23745167
Cancer stem cells; Bone marrow niche; Disseminated tumor cells; and Tumor heterogeneity
13.  Hypoxia stabilizes GAS6/AXl signaling in metastatic prostate cancer 
Molecular Cancer Research  2012;10(6):703-712.
The receptor tyrosine kinase Axl is over-expressed in a variety of cancers and is known to play a role in proliferation and invasion. Previous data from our lab indicates that Axl and its ligand GAS6 may play a role in establishing metastatic dormancy in the bone marrow microenvironment. In the current study, we found that Axl is highly expressed in metastatic prostate cancer (PCa) cell lines PC3 and DU145 and has negligible levels of expression in a non-metastatic cancer cell line LNCaP. Knockdown of Axl in PC3 and DU145 cells resulted in decreased expression of several mesenchymal markers including Snail, Slug, and N-cadherin, and enhanced expression of the epithelial marker E-cadherin, suggesting that Axl is involved in the epithelial to mesenchymal transition in PCa cells. The Axl-knockdown PC3 and DU145 cells also displayed decreased in vitro migration and invasion. Interestingly, when PC3 and DU145 cells were treated with GAS6, Axl protein levels were down-regulated. Moreover, CoCl2, a hypoxia mimicking agent, prevented GAS6 mediated down-regulation of Axl in these cell lines. Immunochemical staining of human PCa tissue microarrays demonstrated that Axl, GAS6 and Hif1-α (indicator of hypoxia) were all co-expressed in PCa and in bone metastases, compared to normal tissues. Together, our studies indicate that Axl plays a crucial role in PCa metastasis, and that GAS6 regulates the expression of Axl. Importantly, in a hypoxic tumor microenvironment Axl expression maintained leading to enhanced signaling.
PMCID: PMC3378814  PMID: 22516347
Bone Metastasis; prostate cancer; EMT; Hypoxia; tumor microenvironment; GAS6; Axl
14.  GAS6 Receptor Status Is Associated with Dormancy and Bone Metastatic Tumor Formation 
PLoS ONE  2013;8(4):e61873.
Disseminated tumor cells (DTCs) are believed to lie dormant in the marrow before they can be activated to form metastases. How DTCs become dormant in the marrow and how dormant DTCs escape dormancy remains unclear. Recent work has shown that prostate cancer (PCa) cell lines express the growth-arrest specific 6 (GAS6) receptors Axl, Tyro3, and Mer, and become growth arrested in response to GAS6. We therefore hypothesized that GAS6 signaling regulates the proliferative activity of DTCs in the marrow. To explore this possibility, in vivo studies were performed where it was observed that when Tyro3 expression levels exceed Axl expression, the PCa cells exhibit rapid growth. When when Axl levels predominate, PCa cells remain largely quiescent. These findings suggest that a balance between the expression of Axl and Tyro3 is associated with a molecular switch between a dormant and a proliferative phenotype in PCa metastases.
PMCID: PMC3634826  PMID: 23637920
15.  Where is Leadership Training Being Taught in U.S. Dental Schools 
Journal of dental education  2012;76(6):713-720.
Leadership is vital in all professions and organizations. Our purpose was to determine where in dental schools leadership is taught, and to what degree it is emphasized so that we could establish a base line from which to generate recommendations for best practices. Therefore we surveyed all US Deans of Academic Affairs in Dental Schools to determine where in the curriculum leadership is taught and emphasized. Our results showed that leadership training is delivered in many different parts of the curriculum, and at various levels. Generally, respondents indicated that leadership education is delivered either in the setting of practice management, community outreach or in public health settings. In some cases, specific training programs are dedicated specifically to leadership development. Thus several models for leadership development were identified showing design and flexibility to address regional and national needs. In the future it would be of value to assess the effectiveness of the different models and whether single or multiple pathways for leadership training are most beneficial.
PMCID: PMC3616398  PMID: 22659699
16.  Prostate Cancer and Parasitism of the Bone Hematopoietic Stem Cell Niche 
A subpopulation of men that appear cured of prostate cancer (PCa) develop bone metastases many years after prostatectomy. This observation indicates that PCa cells were present outside of the prostate at the time of prostatectomy and remained dormant. Several lines of evidence indicate that there are disseminated tumor cells (DTCs) in the bone marrow at the time of prostatectomy. DTCs parasitize the bone microenvironment, where they derive support and impact the microenvironment itself. These DTCs appear to be a heterogeneous population of PCa cells; however, some of them appear to have some aspects of a cancer stem cell (CSC) phenotype as they can develop into clinically detectable metastases. The concept of CSC is controversial; however, several markers of CSC have been identified for PCa, which may represent cells of either basal or luminal origin. These DTCs have now been shown to compete for the hematopoietic stem cell niche in bone, where they may be placed in a dormant state. Interaction with a variety of host factors, including cytokine and cells, may impact the metastatic development and progression, including the dormant state. For example, myeloid cells have been shown to impact both the premetastatic niche and established tumors. Understanding the concepts of how PCa successfully parasitizes the bone microenvironment is paramount toward identifying therapeutic candidates to prevent or diminish PCa bone metastases.
PMCID: PMC3615416  PMID: 22856431
cancer stem cell; monocytes; prostate cancer; hematopoietic stem cell; microenvironment
17.  Annexin II/annexin II receptor axis regulates adhesion, migration, homing, and growth of prostate cancer 
Journal of cellular biochemistry  2008;105(2):370-380.
One of the most life-threatening complications of prostate cancer is skeletal metastasis. In order to develop treatment for metastasis, it is important to understand its molecular mechanisms. Our work in this field has drawn parallels between hematopoietic stem cell and prostate cancer homing to the marrow. Our recent work demonstrated that annexin II expressed by osteoblasts and endothelial cells plays a critical role in niche selection. In this study, we demonstrate that annexin II and its receptor play a crucial role in establishing metastasis of prostate cancer. Prostate cancer cell lines migrate toward annexin II and the adhesion of prostate cancer to osteoblasts and endothelial cells was inhibited by annexin II. By blocking annexin II or its receptor in animal models, short-term and long-term localization of prostate cancers are limited. Annexin II may also facilitate the growth of prostate cancer in vitro and in vivo by the MAPK pathway. These data strongly suggest annexin II and its receptor axis plays a central role in prostate cancer metastasis, and that prostate cancer utilize the hematopoietic stem cell homing mechanisms to gain access to the niche.
PMCID: PMC3614912  PMID: 18636554
Annexin II; Annexin II receptor; prostate cancer; metastasis; niche
18.  Cancer stem cells and the bone marrow microenvironment 
BoneKEy reports  2012;1:48.
'Cancer' is a disease that can spread to the other organs over time. The prognosis of cancer patients with metastasis is generally poor. Accordingly, there is an urgent need to establish a greater understanding of metastatic processes. It is highly likely that cancer stem cells (CSCs) are the key cells that mediate metastases, even while the cellular origin of CSCs remains unknown. Growing evidence has also revealed that the microenvironment has profound effects on the regulation of CSCs. Recently, it has been shown that bone metastatic cancer cells target the microenvironment or 'niche', which houses hematopoietic stem cells (HSCs). The major function of the HSC niche is to maintain 'stemness' of HSCs. These findings suggest that by targeting the HSC niche, metastatic cells parasitize the very foundation of hematopoiesis to maintain their stemness. These observations suggest that there will be a need to target the HSC niche to provide effective therapies to eradicate metastatic CSCs.
PMCID: PMC3671623  PMID: 23745167
19.  The Prostate Cancer Bone Marrow Niche: More than Just “Fertile Soil” 
Asian journal of andrology  2012;14(3):423-427.
The hematopoietic stem cell (HSC) niche in the bone marrow has been studied extensively over the past few decades, yet the bone marrow microenvironment that supports the growth of metastatic prostate cancer (PCa) has only been recently considered to be a specialized “niche” as well. New evidence supports the fact that disseminated tumor cells (DTCs) of PCa actually target the HSC niche, displace the occupant HSCs, and take up residence in the pre-existing niche space. This review describes some of the evidence and mechanisms by which DTCs act as molecular parasites of the HSC niche. Furthermore, the interactions between DTCs, HSCs, and the niche may provide new targets for niche-directed therapy, as well as insight into the perplexing clinical manifestations of metastatic PCa disease.
PMCID: PMC3602965  PMID: 22367179
Dormancy; Hematopoietic Stem Cell; Osteoblasts; Prostate Cancer; Metastasis; Niche
20.  Structure and function of the solid tumor niche 
Although the hematopoietic stem cell (HSC) niche has been an active area of study, the concept of the bone marrow microenvironment (BMM) harboring a niche for solid metastatic tumor cells has only recently been considered. The HSC niche and microenvironment that is thought to constitute the solid tumor niche share many of the same structural and functional components, suggesting the possibility that the HSC and tumor niche are one in the same. The osteoblast is a critical component for each of these niches, and is important for regulating cellular processes such homing and migration, growth and survival, and quiescence and dormancy. Current understanding of the HSC niche may provide more insight to better defining the solid tumor niche. As role of the niche in regulating these processes is better understood, new insights to the role of the BMM in metastatic disease may be gained, and provide more potential targets for therapy.
PMCID: PMC3594847  PMID: 22202039
niche; bone marrow microenvironment; hematopoietic stem cell; metastasis; disseminated tumor cell
21.  Hematopoietic stem cell niche is a potential therapeutic target for bone metastatic tumors 
Despite significant improvement in therapy, the prognosis of cancer with bone metastasis is generally poor. Therefore, there is a great need for new therapeutic approaches for metastatic disease. It has been appreciated that tumor cells metastasize to bone using similar mechanisms of hematopoietic stem cell (HSC) homing to bone marrow (e.g. CXCL12/CXCR4). It was recently found that prostate cancer (PCa) cells target the bone marrow microenvironment for HSCs, or HSC niche, during metastasis. Importantly, these disseminated PCa cells can be mobilized out of the niche using HSC mobilizing agents. These findings suggest that bone marrow HSC niche is a potential therapeutic target for metastatic disease. Therefore, the hypothesis worth considering is that agents that can disrupt the interactions between tumor cells and the HSC niche may prove efficacious when used in conjunction with standard chemotherapeutic agents. Although further understanding of the tumor-niche interactions is needed, the concept of targeting the niche in conjunction with chemotherapy could open up new windows to eradicate incurable metastatic diseases.
PMCID: PMC3593121  PMID: 21676926
22.  Disseminated Prostate Cancer Cells Can Instruct Hematopoietic Stem and Progenitor Cells to Regulate Bone Phenotype 
Molecular Cancer Research  2012;10(3):282-292.
Prostate cancer (PCa) metastases and hematopoietic stem cells (HSCs) frequently home to the bone marrow where they compete to occupy the same HSC niche. We have also shown that under conditions of hematopoietic stress, HSCs secrete the bone morphogenetic proteins (BMPs)-2 and BMP-6 that drives osteoblastic differentiation from mesenchymal precursors. Because it is not known, we examined if metastatic PCa cells can alter regulation of normal bone formation by HSCs and hematopoietic progenitor cells (HPCs). HSC/HPCs isolated from mice bearing non-metastatic and metastatic tumor cells were isolated and their ability to influence osteoblastic and osteoclastic differentiation was evaluated. When the animals were inoculated with the LNCaP C4-2B cell line which produces mixed osteoblastic and osteolytic lesions in bone, HPCs but not HSCs were able to induced stromal cells to differentiate down an osteoblastic phenotype. Part of the mechanism responsible for this activity was the production of BMP-2. On the other hand, when the animals were implanted with PC3 cells that exhibits predominantly osteolytic lesions in bone, HSCs derived from these animals were capable of directly differentiating into tartrate-resistant acid phosphatase (TRAP) positive osteoclasts through an interleukin-6 (IL-6) mediated pathway. These studies for the first time identify HSC/HPCs as novel targets for future therapy involved in the bone abnormalities of PCa.
PMCID: PMC3307952  PMID: 22241219
Hematopoietic stem cells; osteoblast; osteoclast; differentiation; disseminated tumor cells
23.  Erythropoietin Mediated Bone Formation Is Regulated by mTOR Signaling 
Journal of cellular biochemistry  2012;113(1):220-228.
The role of erythropoietin (Epo) and Epo/Epo receptor (EpoR) signaling pathways for production of red blood cells are well established. However, little is known about Epo/EpoR signaling in non-hematopoietic cells. Recently, we demonstrated that Epo activates JAK/STAT signaling in hematopoietic stem cells (HSCs), leading to the production of bone morphogenetic protein 2 (BMP2) and bone formation and that Epo also directly activate mesenchymal cells to form osteoblasts in vitro. In this study, we investigated the effects of mTOR signaling on Epo-mediated osteoblastogenesis and osteoclastogenesis. We found that mTOR inhibition by rapamycin blocks Epo-dependent and -independent osteoblastic phenotypes in human bone marrow stromal cells (hBMSCs) and ST2 cells, respectively. Furthermore, we found that rapamycin inhibits Epo-dependent and -independent osteoclastogenesis in mouse bone marrow mononuclear cells and Raw264.7 cells. Finally, we demonstrated that Epo increases NFATc1 expression and decreases cathepsin K expression in an mTOR-independent manner, resulting in an increase of osteoclast numbers and a decrease in resorption activity. Taken together, these results strongly indicate that mTOR signaling plays an important role in Epo-mediated bone homeostasis.
PMCID: PMC3237787  PMID: 21898543
osteoblasts; HSCs; osteoclasts; erythropoietin; mTOR; rapamycin
24.  Hematopoietic Stem Cells Regulate Mesenchymal Stromal Cell Induction into Osteoblasts Thereby Participating in The Formation of the Stem Cell Niche 
Stem cells (Dayton, Ohio)  2008;26(8):2042-2051.
Cross-talk between hematopoietic stem cells (HSCs) and the cells comprising the niche is critical for maintaining stem cell activities. Yet little evidence supports the concept that HSCs regulate development of the niche. Here the ability of HSCs to directly regulate endosteal development was examined. Marrow was isolated 48h after ‘stressing’ mice with a single acute bleed or from control non-stressed animals. ‘Stressed’ and ‘non-stressed’ HSCs were co-cultured with bone marrow stromal cells to map mesenchymal fate. The data suggest that HSCs are able to guide mesenchymal differentiation towards the osteoblastic lineage under basal conditions. HSCs isolated from animals subjected to an acute stress were significantly better at inducing osteoblastic differentiation in vitro and in vivo than from control animals. Importantly, HSC-derived BMP-2 and BMP-6 were responsible for these activities. Furthermore, significant differences in the ability of HSCs to generate a BMP response following stress were noted in aged and in osteoporotic animals. Together these data suggest a coupling between HSC functions and bone turnover as in aging and in osteoporosis. For the first time, these results demonstrate that HSCs do not rest passively in their niche. Instead, they directly participate in bone formation and niche activities.
PMCID: PMC3513687  PMID: 18499897
HSCs; Niche; Osteoblasts; MSCs; Endosteal
25.  Mechanisms of cancer cell metastasis to the bone: a multistep process 
Future Oncology (London, England)  2011;7(11):1285-1297.
For metastasis to occur, tumor cells must first detach from their tissue of origin. This requires altering both the tissue of origin and the cancer cell. Once detached, cancer cells in circulation must also acquire survival mechanisms. Although many may successfully disseminate, variation exists in the efficiency with which circulating tumor cells home to and invade the bone marrow as metastastic seeds. Disseminated tumor cells that do successfully invade the marrow are secured by cell–cell and cell–extracellular matrix adhesion. However, establishing a foothold in the marrow is not sufficient for disseminated tumor cells to create metastases. A significant latent phase must be overcome by either rescuing cellular proliferation or attenuating micrometastatic mass dormancy programs. Finally, growing metastases fuel osteolysis, osteoblastogenesis and T-cell differentiation, creating a variety of tumor phenotypes. Each step in the metastatic cascade is rich in biological targets and mechanistic pathways.
PMCID: PMC3258525  PMID: 22044203
anoikis; autophagy; circulating tumor cells; disseminated tumor cells; dormancy; metastasis; osteoblastogenesis; osteolysis; survival

Results 1-25 (50)