Floreasca Emmergency Clinical Hospital REZUMAT Aceasta lucrare este o trecere in revista a datelor din literatura privind bazele moleculare cu referire la expresia anormala a proteinelor matricei osoase, osteocalcina si sialoproteina, de catre celulele epiteliale ale prostatei maligne. Aceste date au relevat faptul ca activitatile de promoter ale osteocalcinei umane si sialoproteinei in linia celulara metastatic cancer define, provenind din cancerul de prostata, metastatic cancer define —independenta LNCaP, CB, au fost marcant crescute de la 7 la 12 ori intr-o maniera dependenta de concentratie de catre mediul conditionat colectat din cancerul de prostata si celulele strome b.
Analiza osteocalcinei si regiunile promoter identificate ale sialoproteinei, elemente responsive AMP ciclic cAMP - CRE arata ca determinanti critici pentru expresia genelor osteocalcinei si sialoproteinei osoase in celulele canceroase ale prostatei.
Concluzii: Expresia osteocalcinei si sialoproteinei osoase este coordonata si reglata prin intermediul semnalizarii cAMP dependent PKA care poate defini bazele moleculare ale osteomimetismului, manifestat de catre celulele canceroase ale prostatei. Cuvinte-cheie: osteocalcina, sialoproteina, metastatic cancer define de prostata, matrice osoasa ABSTRACT This paper is a review of literature data on molecular basis regarding the abnormal expression of noncollagenous bone gastric cancer keytruda approval proteins Osteocalcin and sialoprotein by malignant prostate epithelial cells.
These data revealed that a human osteocalcin and bone sialoprotein promoter activities in an androgen-independent prostate cancer cell line of LNCaP lineage, CB, were markedly enhanced 7- to fold in a concentration-dependent manner by conditioned medium collected from prostate cancer and bone stromal cells.
Conclusion: Osteocalcin and bone sialoprotein expression is coordinated and regulated through cAMPdependent PKA signaling, which may define the molecular basis of the osteomimicry exhibited by prostate cancer cells. Keywords: osteocalcin, sialoprotein, prostate cancer, bone matrix, metastasis Introduction Despite the prevalence of prostate cancer metastasis to the skeleton, the molecular mechanisms of bone tropism are poorly understood. Previous studies suggest that prostate cancer cell adhesion, extravasation, migration, and interaction with bone cells are critical determinants that govern prostate cancer bone colonization .
Reports using clinical prostate cancer metastasis specimens  and experimental cell and animal models  found the bone-specific proteins osteocalcin and bone sialoprotein to be expressed in a heterogeneous manner by human prostate cancer specimens.
The authors have proposed metastatic cancer define prostate cancer cells acquire osteomimetic or bonelike properties to improve their adhesion, proliferation, and survival metastatic cancer define bone .
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This communication delineates the molecular mechanisms underlying the induction of human osteocalcin and bone sialoprotein promoter activities and their endogenous gene expression in the bone microenvironment by factors secreted from prostate cancer and bone stromal cells. Because of the potential importance of osteomimicry in enhancing cancer cell adhesion, invasion, metastatic cancer define metastasis, the authors have designed studies to define how the expression of bone-specific proteins in prostate cancer cells is regulated.
The authors chose to study osteocalcin and bone sialoprotein because of the prevalence of expression of metastatic cancer define genes by prostate cancer cell lines  and in clinical prostate cancer specimens.
Metastatic cancer define data showed that osteocalcin and bone sialoprotein expression is stimulated in a selective manner in human prostate cancer but not in bone stromal cell lines. The selective nature of soluble factors serving as paracrine mediators in stimulating osteocalcin and bone sialoprotein expression in prostate cancer cell lines agrees with their immunohistochemical staining patterns metastatic cancer define are generally heterogeneous .
The authors also observed that conditioned medium stimulated human osteocalcin and bone sialoprotein promoter activities in a dose-dependent manner and that these increased promoter reporter activities corresponded with the enhancement of the steady-state levels of endogenous osteocalcin and bone sialoprotein mRNA expressed metastatic cancer define LNCaP and CB cells. These results support the idea that osteocalcin and bone sialoprotein, once induced in prostate cancer cells, could facilitate the formation of hydroxyapatite complexes, leading to altered biological functions of prostate cancer cells i.
This is supported by the lack of increased osteocalcin expression in these o que e bom para oxiurus cancer and osteosarcoma cell lines after exposure to ARCaP conditioned medium. Further, nuclear extracts from prostate cancer and bone cells that failed to respond to PKA pathway activators showed a lack of CRE binding and supershift activity.
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In sharp contrast, however, an increased complex formation between cis-element CRE and trans-acting factor CREB and an expected supershift of this complex were observed in the responsive CB cells on the addition of anti-CREB antibody tion is likely to account for increased human osteocalcin promoter activity and enhanced endogenous osteocalcin mRNA expression in human prostate cancer cells in response to factor s from the tumor cell microenvironment.
A similar mechanism regulating human bone sialoprotein promoter activity and mRNA expression was also observed in LNCaP and CB cells after exposure to ARCaP conditioned medium, a result supported by additional studies using interfering pharmacologic agents that either metastatic cancer define db cAMP and forskolin or repressed H cAMP accumulation in target cells.
Our results show for the first time that conditioned medium harvested from prostate cancer and bone stromal cells stimulated osteocalcin and bone sialoprotein expression primarily through a cAMP-dependent PKA signaling pathway in LNCaP and CB human prostate cancer cells. This stimulation by conditioned medium lends further support to the observation papilloma vestibular adalah osteocalcin and metastatic cancer define metastatic cancer define are prevalently expressed by clinically localized and bone and lymph node metastatic human prostate cancer tissue specimens and can be the molecular basis of osteomimicry during disease progression.
Several growth factors fibroblast growth factor-2 or basic fibroblast growth factor, insulin-like growth factor-I, and transforming growth factor-h and hormones glucocorticoids, estrogens,parathyroid hormone, and parathyroid hormone—related peptide have been shown to regulate osteocalcin and bone sialoprotein expression in rodent, chick, or human cell lines.
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Boudreaux and Towler showed the metastatic cancer define metastatic cancer define osteocalcin promoter activity by a growth metastatic cancer define, fibroblast growth factor-2,in MC3T3-E1 cells. Boguslawski et al. A similar activation of bone sialoprotein promoter activity was documented for fibroblast growth factor-2  parathyroid hormone,and metastatic cancer define E2 in which bone sialoprotein transcription was stimulated through a PKA-dependent pathway, although a protein kinase C—mediated pathway may play a minor role.
The present study differs from previous metastatic cancer define in two important aspects. First, none of the earlier observations showed conclusively at the molecular level that the involvement of CRE elements within osteocalcin and bone sialoprotein promoters, as defined in the present study, conferred soluble factor—induced osteocalcin and bone sialoprotein expression by cancer or normal cells.
Our results emphasized the roles of CRE ciselements in osteomimicry by prostate cancer cells. Second, none of the previously reported factors tested in our assay system activated human osteocalcin and bone sialoprotein promoter activities in CB cells data not shown.
These important distinctions suggest the following possibilities. Because osteocalcin and bone sialoprotein expression in LNCaP, C, and CB cells are responsive to soluble factors and osteocalcin and bone sialoprotein are prevalently expressed in both primary and metastatic human prostate cancer tissues, we suggest that LNCaP and its derivative cell lines are superior models for the study of human prostate cancer progression. This conclusion is also supported by a large body of literature devoted to the study of the molecular mechanisms of androgen receptor and androgen-independent metastatic .
To further understand differences in responsiveness among prostate cancer and bone stromal cells to soluble factors in conditioned medium, it must isolate and characterize the responsible factors and evaluate cell surface or intracellular receptors coupling to cell signaling systems in prostate cancer and bone cells. In summary, authors data using human prostate cancer cell lines show dramatic cell background—dependent differences in responsiveness to ARCaP conditioned medium and the involvement of the cAMP-PKA signaling cascade metastatic cancer define the induction of osteocalcin and bone sialoprotein gene expression in LNCaP and CB cells.
These results could have significant implications for understanding metastatic cancer define and targeting it therapeutically in human prostate cancer. References 1.
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Differential expression of osteopontin and bone sialoprotein in bone metastasis of breast and prostate carcinoma. Clin Exp Metastasis ;— Regulation of human osteocalcin promoter in hormone-independent human prostate cancer cells.
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Prostate ;—61 5. Prostate ;—21 6. Expression of metastatic cancer define in prostate cancer before and after hormonal therapy. Anticancer Res ;—11 7.
Invasive prostate cancer cells secret soluble protein factors that upregulate osteocalcin OC promoter activity: implication to stroma desmoplastic response and cancer metastasis. J Urol ;—4; abstract 8.
Synergistic induction of osteocalcin gene expression: identification of a bipartite element conferring fibroblast growth factor 2 and cyclic Is human papillomavirus contagious responsiveness in the rat osteocalcin promoter. Activation of osteocalcin transcription involves interaction of protein kinase A- and protein kinase C-dependent pathways.
Identification of FGF2-response element in the rat bone sialoprotein gene promoter.
Connect Tissue Res ;44 Suppl —8. Notch signaling and ERK activation are important for the osteomimetic properties of prostate cancer bone metastatic cell lines.
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