A Nod Scid mouse model to study human prostate cancer

Bastide, C.; Bagnis, Claude; Mannoni, P; Hassoun, Jacques; Bladou, Franck

doi:10.1038/sj.pcan.4500606

Cited by 51 publications

(46 citation statements)

References 19 publications

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“…44 In the current study, we used the PC3 prostate cancer cell line, which in most systems produces bone tumors that are predominantly osteolytic. 33,45,46 We consider the PC3 bone model to mimic osteolytic processes that are present in all clinical bone metastases; an obvious limitation of this model, however, is that it does not include an element of osteoblastic activity.…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase Activity and Osteoclasts in Experimental Prostate Cancer Bone Metastasis Tissue

Dong

Bonfil

Chinni

et al. 2005

The American Journal of Pathology

100

102

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Previously, we and others showed that broad spectrum pharmaceutical inhibition of matrix metalloproteinase (MMP) activity reduces intraosseous tumor burden and bone degradation in animal models of bone metastasis. Herein, we used specific assays to measure net enzymatic activities of individual MMPs during colonization of bone by prostate cancer cells. PC3 cells were injected into the marrow of human fetal femurs previously implanted in SCID mice. Net MMP-9 activity in bone tissues peaked 2 weeks after injection, coinciding with a wave of osteoclast recruitment. In contrast, MMP-2 and MT1-MMP activity did not change. In vitro, co-culture of PC3 cells with bone tissue led to activation of pro-MMP-9 and increases in secreted net MMP-9 activity. Activation of pro-MMP-9 was prevented by metalloprotease inhibitors but not by inhibitors of other classes of proteases. Ribozyme suppression of MMP-9 expression in PC3 cells did not affect pro-MMP-9 activation or net MMP-9 activity and did not affect the phenotype of bone tumors. siRNA targeting of MMP-9 expression in preosteoclasts in vitro demonstrated that tumorinduced preosteoclast motility was dependent on MMP-9 expression. These data suggest that osteoclastderived MMP-9 may represent a potential therapeutic target in bone metastasis and provide a rationale for the development of MMP-9-specific inhibitors. Prostate cancer is the most common cancer and second leading cause of cancer death in American males.1 The overwhelming majority of prostate cancer deaths occurs in patients with metastases, and up to 90% of prostate cancer metastases occurs at skeletal sites. 2 Patients with bone metastasis frequently suffer from pain, pathological fractures, spinal cord compression, hypercalcemia, and bone marrow suppression.3,4 Although prostate cancer metastases typically appear osteosclerotic on radiographical imaging studies, multiple lines of evidence demonstrate clearly that both bone degradation and bone formation are present within the metastatic deposits. Importantly, there is now evidence that therapies that specifically target skeletal metastases, as opposed to general metastases, may extend survival in patients with prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase Activity and Osteoclasts in Experimental Prostate Cancer Bone Metastasis Tissue

Dong

Bonfil

Chinni

et al. 2005

The American Journal of Pathology

100

102

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“…Apart from genetic models, human prostate cancer cell lines (such as LNCaP, PC-3, and DU-145) have been used in subcutaneous, renal, and orthotopic xenograft models. The latter ones are in so far limited, as orthotopic implantations of human tumor cells into the mouse prostate might bear the risk of an artificial route of metastasis delivery (5), although previous subcutaneous xenograft models rarely showed spontaneous metastatic spread (6). Other xenograft approaches should rather be designated as "dissemination models" as they use intravenous injections of tumor cells (7) or "metastasis microenvironment models" as they implant prostate cancer cells directly into the mouse bone marrow as the site of metastasis (8), both of which do not reflect the entire metastatic cascade.…”

Section: Introductionmentioning

confidence: 99%

Human Prostate Cancer in a Clinically Relevant Xenograft Mouse Model: Identification of β(1,6)-Branched Oligosaccharides as a Marker of Tumor Progression

Lange

Ullrich

Müller

et al. 2012

Clinical Cancer Research

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Purpose: To establish xenograft mouse models of metastatic and nonmetastatic human prostate cancer and to apply these models to the search for aberrant glycosylation patterns associated with tumor progression in vivo and in patients.Experimental Design: Prostate cancer cells (LNCaP, PC-3, LuCaP 23.1, and DU-145) were xenografted subcutaneously into immunodeficient pfpÀ/À mice. Tumor growth and metastasis formation were quantified and as altered glycosylation patterns have been associated with metastasis formation in several other malignancies, prostate cancer cells were profiled by a quantitative real-time PCR (qRT-PCR) glycosylation array and compared with normal human prostate cells. The activity of upregulated glycosyltransferases was analyzed by their sugar residues end products using lectin histochemistry on primary tumors and metastases in the animal experiments and on 2,085 clinical samples.Results: PC-3 cells produced the largest number of spontaneous lung metastases, followed by LNCaP and LuCaP 23.1, whereas DU-145 was nonmetastatic. qRT-PCR revealed an upregulation of b1,6-Nacetylglucosaminyltransferase-5b (Mgat5b) in all prostate cancer cell lines. Mgat5b products [b(1,6)-branched oligosaccharides] were predominantly detectable in metastatic xenografts as shown by increased binding of Phaseolus vulgaris leukoagglutinin (PHA-L). The percentage of prostate cancer patients who were PHA-L positive was 86.5. PHA-L intensity correlated with serum prostate-specific antigen and a cytoplasmic staining negatively affected disease-free survival.Conclusion: We show a novel xenograft mouse model for human prostate cancer respecting the complete metastatic cascade. Specific glycosylation patterns reveal Mgat5b products as relevant markers of both metastatic competence in mice and disease-free survival in patients. This is the first description of Mgat5b in prostate cancer indicating a significant biologic importance of b(1,6)-branched oligosaccharides for prostate cancer progression.

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“…Inactivating mutations in human IL-2Rgc cause T 2 B + SCID, characterized by decreased numbers of T cells and a diminished immune response (13). Mice lacking IL-2rgc display a T 2 B 2 form of SCID (14), with reduced B and T cells (15), and have proved to be an invaluable model for a range of studies, especially relating to immunity and cancer (16)(17)(18)(19)(20)(21). The zebrafish is now established as an important alternate model for the study of vertebrate development and disease, with particular relevance to hematopoiesis and immunity (22,23).…”

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confidence: 99%

Conserved IL-2Rγc Signaling Mediates Lymphopoiesis in Zebrafish

Sertori

Liongue

Basheer

et al. 2016

The Journal of Immunology

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The IL-2 receptor γ common (IL-2Rγc) chain is the shared subunit of the receptors for the IL-2 family of cytokines, which mediate signaling through JAK3 and various downstream pathways to regulate lymphopoiesis. Inactivating mutations in human IL-2Rγc result in SCID, a primary immunodeficiency characterized by greatly reduced numbers of lymphocytes. This study used bioinformatics, expression analysis, gene ablation, and specific pharmacologic inhibitors to investigate the function of two putative zebrafish IL-2Rγc paralogs, il-2rγc.a and il-2rγc.b, and downstream signaling components during early lymphopoiesis. Expression of il-2rγc.a commenced at 16 h post fertilization (hpf) and rose steadily from 4–6 d postfertilization (dpf) in the developing thymus, with il-2rγc.a expression also confirmed in adult T and B lymphocytes. Transcripts of il-2rγc.b were first observed from 8 hpf, but waned from 16 hpf before reaching maximal expression at 6 dpf, but this was not evident in the thymus. Knockdown of il-2rγc.a, but not il-2rγc.b, substantially reduced embryonic lymphopoiesis without affecting other aspects of hematopoiesis. Specific targeting of zebrafish Jak3 exerted a similar effect on lymphopoiesis, whereas ablation of zebrafish Stat5.1 and pharmacologic inhibition of PI3K and MEK also produced significant but smaller effects. Ablation of il-2rγc.a was further demonstrated to lead to an absence of mature T cells, but not B cells in juvenile fish. These results indicate that conserved IL-2Rγc signaling via JAK3 plays a key role during early zebrafish lymphopoiesis, which can be potentially targeted to generate a zebrafish model of human SCID.

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A Nod Scid mouse model to study human prostate cancer

Cited by 51 publications

References 19 publications

Matrix Metalloproteinase Activity and Osteoclasts in Experimental Prostate Cancer Bone Metastasis Tissue

Matrix Metalloproteinase Activity and Osteoclasts in Experimental Prostate Cancer Bone Metastasis Tissue

Human Prostate Cancer in a Clinically Relevant Xenograft Mouse Model: Identification of β(1,6)-Branched Oligosaccharides as a Marker of Tumor Progression

Conserved IL-2Rγc Signaling Mediates Lymphopoiesis in Zebrafish

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