Changes in extracellular matrix (ECM) and ECM-associated proteins in the metastatic progression of prostate cancer

Prostate cancer (PCa) is no exception to the multi-step process of metastasis. As PCa progresses, changes occur within the microenvironments of both the malignant cells and their targeted site of metastasis, enabling the necessary responses that result in successful translocation. The majority of patients with progressing prostate cancers develop skeletal metastases. Despite advancing efforts in early detection and management, there remains no effective, long-term cure for metastatic PCa. Therefore, the elucidation of the mechanism of PCa metastasis and preferential establishment of lesions in bone is an intensive area of investigation that promises to generate new targets for therapeutic intervention. This review will survey what is currently know concerning PCa interaction with the extracellular matrix (ECM) and the roles of factors within the tumor and ECM microenvironments that contribute to metastasis. These will be discussed within the context of changes in expression and functional heterodimerization patterns of integrins, changes in ECM expression and reorganization by proteases facilitating invasion. In this context we also provide a brief summary of how growth factors (GFs), cytokines and regulatory signaling pathways favor PCa metastasis to bone

A Novel Massage Therapy Technique for Management of Chronic Cervical Pain: A Case Series

Background: Neck pain is a generalized condition resulting from a complex etiology with presentation of a wide variety of symptoms. Neck pain is most often accompanied by decreased range of motion (ROM), muscle and joint stiffness, and limitations in functional capabilities. This condition may result in significant personal and societal burden. Purpose: We evaluated the effectiveness of a novel massage therapy intervention by following the treatment regimen and outcomes of two patients experiencing chronic neck pain. Participants: Two patients (46 and 53 years old) experienced chronic (>5 years) neck pain. Both patients reported pain, limited ROM, and muscle and joint stiffness. Additionally, the first patient reported a lack of sleep, and both patients stated their pain interfered with their quality of life and activities of daily living. Intervention: Patients received the Integrative Muscular Movement Technique (IMMT) intervention approximately twice a week for a total of eight treatments, each approximately 20 minutes in duration. Results: Both patients experienced a reduction in pain and an increase in cervical ROM in flexion, extension, rotation, and sidebending. The first patient also reported an increased ability to sleep. Both patients reported an increased ability to perform activities of daily living, including work-related responsibilities. Conclusions: For the two patients included in this report, therapist observations and patient reports indicate that inclusion of the IMMT treatment in a treatment regimen for chronic neck pain may lead to decreased pain and increased cervical ROM. These positive effects of the IMMT intervention may have a role in enhancing functional outcomes of these patients

Expression and activation of Α v Β 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 Α v Β 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 Α v Β 3 receptors by prostate cancer cells to enhance their metastatic behavior by increasing adhesiveness and invasiveness. SDF-1 transiently increased the expression of Β 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 Α v Β 3 receptors. Activation and increased expression of Α v Β 3 within SDF-1-rich organs may participate in metastatic localization. Prostate 67:61–73, 2007. © 2006 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55878/1/20500_ftp.pd

Decreased galectin-3 expression in prostate cancer

BACKGROUND Galectin-3 is a carbohydrate-binding protein whose level of expression has been shown to be correlated with metastatic potential in a number of different tumor types. The purpose of this investigation was to examine galectin-3 expression in several tumorigenic and nontumorigenic prostate cell lines and prostate tissue samples. METHODS The expression of galectin-3 in cell lines and tissue samples was evaluated by tissue immunohistochemistry and Western blot analysis. RESULTS Human cell lines PC-3M, PC-3, DU-145, PrEC-1, and MCF10A demonstrated the presence of galectin-3. Galectin-3 was not detected in TSU-pr1 and LNCaP by Western blot analysis. We furthered our studies by examining a series of human prostate tissue samples for expression of galectin-3. Overall, approximately 60–70% of the normal tissue examined demonstrated heterogenous expression of galectin-3. In stage II tumors, however, there was a dramatic decrease in galectin-3 expression in both PIN and tumor sections, with only 10.5% (2/19) of these samples expressing this protein. Stage III tumors also demonstrated a decreased expression of galectin-3, although this downregulation was not as dramatic, with 35% of PIN samples and 52% of tumor tissue expressing galectin-3 ( P < 0.01). CONCLUSIONS These data demonstrate that galectin-3 is downregulated in prostate cancer. The altered downregulation pattern of galectin-3 observed between tumor stages suggests different roles for galectin-3 in the progression of prostate cancer. Prostate 44:118–123, 2000. © 2000 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34754/1/4_ftp.pd

Prostate Carcinoma Skeletal Metastases: Cross-talk between Tumor and Bone

The majority of men with progressive prostate cancer develop metastases with the skeleton being the most prevalent metastatic site. Unlike many other tumors that metastasize to bone and form osteolytic lesions, prostate carcinomas form osteoblastic lesions. However, histological evaluation of these lesions reveals the presence of underlying osteoclastic activity. These lesions are painful, resulting in diminished quality of life of the patient. There is emerging evidence that prostate carcinomas establish and thrive in the skeleton due to cross-talk between the bone microenvironment and tumor cells. Bone provides chemotactic factors, adhesion factors, and growth factors that allow the prostate carcinoma cells to target and proliferate in the skeleton. The prostate carcinoma cells reciprocate through production of osteoblastic and osteolytic factors that modulate bone remodeling. The prostate carcinoma-induced osteolysis promotes release of the many growth factors within the bone extracellular matrix thus further enhancing the progression of the metastases. This review focuses on the interaction between the bone and the prostate carcinoma cells that allow for development and progression of prostate carcinoma skeletal metastases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44522/1/10555_2004_Article_402865.pd

The regulation of prostate cancer cell adhesion to human bone marrow endothelial cell monolayers by androgen dihydrotestosterone and cytokines

A previous study from our laboratory suggested that prostate cancer metastasis to bone may be mediated, in part, by preferential adhesion to human bone marrow endothelial (HBME) cells. Tumor cell adhesion to endothelial cells may be modulated by the effect of cytokines on cell adhesion molecules (CAMs). Tumor necrosis factor-alpha (TNF-α) regulates VCAM expression on the endothelium and this effect is enhanced by dihydrotestosterone (DHT). Transforming growth factor-beta (TGF-β) stimulates the expression of α 2 β 1 integrin on PC-3 cells. The current study investigated the effects of the above cytokines and DHT (singularly and in various combinations) upon HBME and prostate cancer cell expression of VCAM, α 2 integrin subunit, and β 1 integrin subunit by flow cytometry. We also monitored the effects of the above treatments on PC-3 cell adhesion to HBME monolayers. The data demonstrate that none of the treatments significantly altered the expression of selected CAMs on HBME cell and neoplastic prostate cell lines. The treatment of HBME monolayers with various combinations of cytokines and DHT prior to performing adhesion assays with PC-3 demonstrates that treatments containing TGF-β reduced PC-3 cell adhesion to HBME monolayers by 32% or greater ( P <0.05). The reduction in PC-3 cell adhesion to TGF-β-treated HBME monolayers was dose dependent. Interestingly, LNCaP cells but not PC-3 cells treated with TGF-β had a reduced ability to adhere to untreated HBME monolayers. These results suggest that TGF-β may reduce tumor cell adhesion to bone marrow microvascular endothelium, in vivo . The biological significance of this observation is discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42583/1/10585_2004_Article_383338.pd

Soluble perlecan domain i enhances vascular endothelial growth factor-165 activity and receptor phosphorylation in human bone marrow endothelial cells

<p>Abstract</p> <p>Background</p> <p>Immobilized recombinant perlecan domain I (PlnDI) binds and modulates the activity of heparin-binding growth factors, <it>in vitro</it>. However, activities for PlnDI, in solution, have not been reported. In this study, we assessed the ability of soluble forms to modulate vascular endothelial growth factor-165 (VEGF₁₆₅) enhanced capillary tube-like formation, and VEGF receptor-2 phosphorylation of human bone marrow endothelial cells, <it>in vitro</it>.</p> <p>Results</p> <p>In solution, PlnDI binds VEGF₁₆₅in a heparan sulfate and pH dependent manner. Capillary tube-like formation is enhanced by exogenous PlnDI; however, PlnDI/VEGF₁₆₅mixtures combine to enhance formation beyond that stimulated by either PlnDI or VEGF₁₆₅alone. PlnDI also stimulates VEGF receptor-2 phosphorylation, and mixtures of PlnDI/VEGF₁₆₅reduce the time required for peak VEGF receptor-2 phosphorylation (Tyr-951), and increase Akt phosphorylation. PlnDI binds both immobilized neuropilin-1 and VEGF receptor-2, but has a greater affinity for neuropilin-1. PlnDI binding to neuropilin-1, but not to VEGF receptor-2 is dependent upon the heparan sulfate chains adorning PlnDI. Interestingly, the presence of VEGF₁₆₅but not VEGF₁₂₁significantly enhances PlnDI binding to Neuropilin-1 and VEGF receptor-2.</p> <p>Conclusions</p> <p>Our observations suggest soluble forms of PlnDI are biologically active. Moreover, PlnDI heparan sulfate chains alone or together with VEGF₁₆₅can enhance VEGFR-2 signaling and angiogenic events, <it>in vitro</it>. We propose PlnDI liberated during basement membrane or extracellular matrix turnover may have similar activities, <it>in vivo</it>.</p

Trichomonas Transmembrane Cyclases Result from Massive Gene Duplication and Concomitant Development of Pseudogenes

Trichomonas vaginalis is the only medically important protist (single-cell eukaryote) that is sexually transmitted. The ∼160-Mb Trichomonas genome contains more predicted protein-encoding genes (∼60,000) than the human genome. To begin to understand why there are so many copies of some genes, we chose here to study a large family of genes encoding unique transmembrane cyclases. Our most important results include the following. More than 100 transmembrane cyclase genes do not result from chromosomal duplications, because for the most part only the coding regions of the genes, rather than flanking sequences, are duplicated. Almost half of the transmembrane cyclase genes are pseudogenes, and these pseudogenes are polymorphic among laboratory strains of Trichomonas. Messenger RNAs for numerous transmembrane cyclases are expressed simultaneously, and representative cyclase domains have adenylyl cyclase activity. In summary, the large family of Trichomonas genes encoding transmembrane adenylyl cyclases results from massive gene duplication and concomitant development of pseudogenes

Epidemiological Evidence for Work Load as a Risk Factor for Osteoarthritis of the Hip: A Systematic Review

Osteoarthritis of the hip (OA) is a common degenerative disorder of the joint cartilage that presents a major public health problem worldwide. While intrinsic risk factors (e.g, body mass and morphology) have been identified, external risk factors are not well understood. In this systematic review, the evidence for workload as a risk factor for hip OA is summarized and used to derive recommendations for prevention and further research.Epidemiological studies on workload or occupation and osteoarthritis of the hip were identified through database and bibliography searches. Using pre-defined quality criteria, 30 studies were selected for critical evaluation; six of these provided quantitative exposure data.Study results were too heterogeneous to develop pooled risk estimates by specific work activities. The weight of evidence favors a graded association between long-term exposure to heavy lifting and risk of hip OA. Long-term exposure to standing at work might also increase the risk of hip OA.It is not possible to estimate a quantitative dose-response relationship between workload and hip OA using existing data, but there is enough evidence available to identify job-related heavy lifting and standing as hazards, and thus to begin developing recommendations for preventing hip OA by limiting the amount and duration of these activities. Future research to identify specific risk factors for work-related hip OA should focus on implementing rigorous study methods with quantitative exposure measures and objective diagnostic criteria