Mer Tyrosine Kinase Regulates Disseminated Prostate Cancer Cellular Dormancy.

Many prostate cancer (PCa) recurrences are thought to be due to reactivation of disseminated tumor cells (DTCs). We previously found a role of the TAM family of receptor tyrosine kinases TYRO3, AXL, and MERTK in PCa dormancy regulation. However, the mechanism and contributions of the individual TAM receptors is largely unknown.

The marrow niche controls the cancer stem cell phenotype of disseminated prostate cancer.

Dissemination of cancer stem cells (CSCs) serves as the basis of metastasis. Recently, we demonstrated that circulating prostate cancer targets the hematopoietic stem cell (HSCs) 'niche' in marrow during dissemination. Once in the niche, disseminated tumor cells (DTCs) may remain dormant for extended periods.

Bone marrow as a metastatic niche for disseminated tumor cells from solid tumors.

Bone marrow is a heterogeneous organ containing diverse cell types, and it is a preferred metastatic site for several solid tumors such as breast and prostate cancer. Recently, it has been shown that bone metastatic cancer cells interact with the bone marrow microenvironment to survive and grow, and thus this microenvironment is referred to as the 'metastatic niche'. Once cancer cells spread to distant organs such as bone, the prognosis for the patient is generally poor.

Tissue engineering a surrogate niche for metastatic cancer cells.

In breast and prostate cancer patients, the bone marrow is a preferred site of metastasis. We hypothesized that we could use tissue-engineering strategies to lure metastasizing cancer cells to tissue-engineered bone marrow. First, we generated highly porous 3D silk scaffolds that were biocompatible and amenable to bone morphogenetic protein 2 functionalization.

Annexin 2-CXCL12 interactions regulate metastatic cell targeting and growth in the bone marrow.

Unlabelled: Annexin 2 (ANXA2) plays a critical role in hematopoietic stem cell (HSC) localization to the marrow niche. In part, ANXA2 supports HSCs by serving as an anchor for stromal-derived factor-1 (CXCL12/SDF-1). Recently, it was demonstrated that prostate cancer cells, like HSCs, use ANXA2 to establish metastases in marrow.

Molecular pathways: niches in metastatic dormancy.

Despite the best available treatments for primary tumors, cancer can return, even after a long disease-free interval. During this period, cancer cells are believed to lie dormant in either primary sites, metastatic sites, or independent sites like bone marrow, effectively escaping adjuvant cytotoxic treatments. To date, little is known about how these cells transition to dormancy, or how they are reactivated if cancer recurs.

A novel method for monitoring tumor proliferation in vivo using fluorescent dye DiD.

Monitoring single cell proliferation in vivo is difficult, but optimizing this technique is essential in order to expand our knowledge of the regulation of tumor proliferation. In this study, we used a lipophilic fluorescent dye, DiD, that rapidly and stably integrates into the phospholipid cell membrane. We cultured DiD-stained prostate cancer cell lines for 10 days and isolated cells by flow cytometry based on expression levels of DiD.

Erythropoietin supports the survival of prostate cancer, but not growth and bone metastasis.

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.

Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis.

Tumours recruit mesenchymal stem cells 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 CXCL16, a ligand for CXCR6, facilitates mesenchymal stem cell or very small embryonic-like cells recruitment into prostate tumours.

GAS6 receptor status is associated with dormancy and bone metastatic tumor formation.

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.

The effects of zoledronic acid in the bone and vasculature support of hematopoietic stem cell niches.

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.

Prevalence of prostate cancer metastases after intravenous inoculation provides clues into the molecular basis of dormancy in the bone marrow microenvironment.

Bone is the preferred metastasis site of advanced prostate cancer (PCa). Using an in vivo murine model of human PCa cell metastasis to bone, we noted that the majority of animals that develop skeletal metastasis have either spinal lesions or lesions in the bones of the hindlimb. Much less frequently, lesions develop in the bones of the forelimb.

Cyclophosphamide creates a receptive microenvironment for prostate cancer skeletal metastasis.

A number of cancers predominantly metastasize to bone, due to its complex microenvironment and multiple types of constitutive cells. Prostate cancer especially has been shown to localize preferentially to bones with higher marrow cellularity. Using an experimental prostate cancer metastasis model, we investigated the effects of cyclophosphamide, a bone marrow-suppressive chemotherapeutic drug, on the development and growth of metastatic tumors in bone.

Hypoxia stabilizes GAS6/Axl signaling in metastatic prostate cancer.

The receptor tyrosine kinase Axl is overexpressed in a variety of cancers and is known to play a role in proliferation and invasion. Previous data from our laboratory indicate that Axl and its ligand growth arrest-specific 6 (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 cell lines PC3 and DU145 and has negligible levels of expression in a nonmetastatic cancer cell line LNCaP.

Proteoglycan 4, a novel immunomodulatory factor, regulates parathyroid hormone actions on hematopoietic cells.

Proteoglycan 4 (PRG4), a critical protective factor in articular joints, is implicated in hematopoietic progenitor cell expansion and megakaryopoiesis. PRG4 loss-of-function mutations result in camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome, which is characterized primarily by precocious joint failure. PRG4 was identified as a novel parathyroid hormone (PTH) responsiveness gene in osteoblastic cells in bone, and was investigated as a potential mediator of PTH actions on hematopoiesis.

Parathyroid hormone mediates hematopoietic cell expansion through interleukin-6.

Parathyroid hormone (PTH) stimulates hematopoietic cells through mechanisms of action that remain elusive. Interleukin-6 (IL-6) is upregulated by PTH and stimulates hematopoiesis. The purpose of this investigation was to identify actions of PTH and IL-6 in hematopoietic cell expansion.

Technology support in nursing education: clickers in the classroom.

Research has shown that the present generation of students has a preference for digital literacy, experiential learning, interactivity, and immediacy; therefore, greater use of technology is being brought into university courses to aid in student involvement. Student Response Systems, called clickers, were incorporated as a teaching methodology to enhance student interaction and learning in a didactic pediatric nursing course. This course was taught over Interactive Television (ITV) with students at a distant site as well as face to face, creating the challenge of whole-class engagement.

Tumor expressed PTHrP facilitates prostate cancer-induced osteoblastic lesions.

Expression of parathyroid hormone-related protein (PTHrP) correlates with prostate cancer skeletal progression; however, the impact of prostate cancer-derived PTHrP on the microenvironment and osteoblastic lesions in skeletal metastasis has not been completely elucidated. In this study, PTHrP overexpressing prostate cancer clones were stably established by transfection of full length rat PTHrP cDNA. Expression and secretion of PTHrP were verified by western blotting and IRMA assay.

JunB as a downstream mediator of PTHrP actions in cementoblasts.

Unlabelled: The role of AP-1 family members in the action of PTHrP was examined in cementoblasts. PTHrP increased mRNA and protein levels of all Fos members, but only one Jun member (JunB) was increased. Overexpression of JunB in cementoblasts mimicked actions of PTHrP to support osteoclastogenesis and inhibit cementoblast differentiation, suggesting that the actions of PTHrP on mesenchymal cells operate through JunB.

Bisphosphonate modulates cementoblast behavior in vitro.

Background: Cementum formation is deemed to be instrumental for the successful regeneration of periodontal tissues, and thus events and modifiers of cementum formation and mineralization need to be determined. This study aimed to determine whether the bisphosphonate 1-hydroxyethylidene-1,1-bisphosphonate (HEBP) altered the behavior of immortalized cementoblasts (osteocalcin-cementoblasts [OCCM]).

Methods: OCCM from transgenic mice were exposed to HEBP at concentrations ranging from 0.

Dexamethasone and basic-fibroblast growth factor regulate markers of mineralization in cementoblasts in vitro.

Background: The aim of this study was to determine the effects of basic-fibroblast growth factor (b-FGF) and/or dexamethasone (Dex) on cementoblasts in vitro.

Methods: Murine cementoblasts were treated as follows: 1) 5% FBS (fetal bovine serum) + ascorbic acid (AA, 50 microg/ml, control); 2) 5% FBS + Dex (10(7)M) + AA; 3) 5% FBS + b-FGF (50 ng/ml)+AA; or 4) 5% FBS + Dex (10(7) M) + b-FGF (50 ng/ml)+AA and then evaluated by Northern analysis for changes in specific genes and by von Kossa stain for changes in mineral nodule formation.

Results: Mitotic activity: b-FGF stimulated DNA synthesis significantly versus negative control.

PTHrP signaling targets cyclin D1 and induces osteoblastic cell growth arrest.

Unlabelled: PTHrP control of the MC3T3-E1 cell cycle machinery showed that, during differentiation, PTHrP induced G1 growth arrest. Cyclin D1 was a critical mediator as a downstream effector of cAMP, PKC, and MAPK signaling, and the process was PKA-independent. The involvement of JunB has been found critical for PTHrP effects.

The role of parathyroid hormone-related protein in the regulation of osteoclastogenesis by cementoblasts.

Background: Parathyroid hormone-related protein (PTHrP) promotes osteoclastogenesis by inhibiting expression of osteoprotegerin (OPG), a decoy receptor for the receptor activator of nuclear factor kappa B (RANK), and by enhancing production of RANK ligand (RANKL) by osteoblasts. However, little is known regarding the role of PTHrP in regulating cementoblast-mediated osteoclastogenesis.

Methods: This study determined the impact of PTHrP on osteoclastogenesis using: 1) OCCM-30 (immortalized murine cementoblasts), 2) RAW 264.