Murine prostate cancer inhibits both in vivo and in vitro generation of dendritic cells from bone marrow precursors

Tourkova, Irina L.; Yamabe, Kazuo; Foster, Barbara A.; Chatta, Gurkamal S.; Perez, Lori; Shurin, Michael R.

doi:10.1002/pros.10369

Cited by 19 publications

(13 citation statements)

References 32 publications

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“…However, the functional significance of these pathways in DCs that have been exposed to the tumor microenvironment has not been yet investigated. Our data demonstrate that crucial DC functions are not only regulated by RhoA, Rac1, and Cdc42 (27) but also are inhibited in tumortreated DCs (6,8,32).…”

Section: Discussionmentioning

confidence: 66%

“…Six hours later, DC were collected and used for the further analyses. Receptor-mediated endocytic activity of control-transduced (CD56), dnRac1-transduced, dnCdc42-transduced, caRac1-transduced, and caCdc42-transduced nontreated (A) and control-transduced, caRac1-transduced, and caCdc42-transduced tumor-treated DCs (B) was determined by measuring dextran 40 uptake as described in the expression of MHC and costimulatory molecules (32). Because the endocytic activity of DCs was suppressed despite their immaturity, it is reasonable to speculate that the immaturity of DCs in cancer may not be associated with the preservation of their functional activity.…”

Section: Discussionmentioning

confidence: 99%

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Small Rho GTPases Mediate Tumor-Induced Inhibition of Endocytic Activity of Dendritic Cells

Tourkova¹,

Shurin²,

Wei

et al. 2007

The Journal of Immunology

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The generation, maturation, and function of dendritic cells (DC) have been shown to be markedly compromised in the tumor microenvironment in animals and humans. However, the molecular mechanisms and intracellular pathways involved in the regulation of the DC system in cancer are not yet fully understood. Recently, we have reported on the role of the small Rho GTPase family members Cdc42, Rac1, and RhoA in regulating DC adherence, motility, and Ag presentation. To investigate involvement of small Rho GTPases in dysregulation of DC function by tumors, we next evaluated how Cdc42, Rac1, and RhoA regulated endocytic activity of DC in the tumor microenvironment. We revealed a decreased uptake of dextran 40 and polystyrene beads by DC generated in the presence of different tumor cell lines, including RM1 prostate, MC38 colon, 3LL lung, and B7E3 oral squamous cell carcinomas in vitro and by DC prepared from tumor-bearing mice ex vivo. Impaired endocytic activity of DC cocultured with tumor cells was associated with decreased levels of active Cdc42 and Rac1. Transduction of DC with the dominant negative Cdc42 and Rac1 genes also led to reduced phagocytosis and receptor-mediated endocytosis. Furthermore, transduction of DC with the constitutively active Cdc42 and Rac1 genes restored endocytic activity of DC that was inhibited by the tumors. Thus, our results suggest that tumor-induced dysregulation of endocytic activity of DC is mediated by reduced activity of several members of the small Rho GTPase family, which might serve as new targets for improving the efficacy of DC vaccines.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Small Rho GTPases Mediate Tumor-Induced Inhibition of Endocytic Activity of Dendritic Cells

Tourkova¹,

Shurin²,

Wei

et al. 2007

The Journal of Immunology

Self Cite

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“…First, when presenting tumor Ag to tumor-specific T cells, CD11c ϩ cells are in a resting state and provide deficient costimulation and possibly little or no cytokine help. Tumor-induced suppression of DCs was previously demonstrated in prostate tumor-bearing mice (33). Low levels of costimulatory molecule expression could tilt the balance toward tolerance induction through increased interaction with inhibitory molecules.…”

Section: Discussionmentioning

confidence: 90%

Tolerization of Tumor-Specific T Cells Despite Efficient Initial Priming in a Primary Murine Model of Prostate Cancer

Anderson

Shafer‐Weaver

Greenberg

et al. 2007

The Journal of Immunology

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In this report, we studied T cell responses to a prostate cancer Ag by adoptively transferring tumor Ag-specific T cells into prostate tumor-bearing mice. Our findings demonstrate that CD8+ T cells initially encountered tumor Ag in the lymph node and underwent an abortive proliferative response. Upon isolation from the tumor, the residual tumor-specific T cells were functionally tolerant of tumor Ag as measured by their inability to degranulate and secrete IFN-γ and granzyme B. We next sought to determine whether providing an ex vivo-matured, peptide-pulsed dendritic cell (DC) vaccine could overcome the tolerizing mechanisms of tumor-bearing transgenic adenocarcinoma of the mouse prostate model mice. We demonstrate that tumor Ag-specific T cells were protected from tolerance following provision of the DC vaccine. Concurrently, there was a reduction in prostate tumor size. However, even when activated DCs initially present tumor Ag, T cells persisting within the tolerogenic tumor environment gradually lost Ag reactivity. These results suggest that even though a productive antitumor response can be initiated by a DC vaccine, the tolerizing environment created by the tumor still exerts suppressive effects on the T cells. Furthermore, our results demonstrate that when trying to elicit an effective antitumor immune response, two obstacles must be considered: to maintain tumor Ag responsiveness, T cells must be efficiently primed to overcome tumor Ag presented in a tolerizing manner and protected from the suppressive mechanisms of the tumor microenvironment.

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“…Herein, we describe the use of a cell line derived from the MPR model, the RM1 cell line, as a potentially effective model for investigating prostate cancer:bone stromal interactions in immune competent mice. To our knowledge, the introduction of RM1 cells into bone has been limited to studies investigating prostate cancer regulation of dendritic cell formation [15,16].…”

Section: Discussionmentioning

confidence: 99%

Intraosseous injection of RM1 murine prostate cancer cells promotes rapid osteolysis and periosteal bone deposition

McCabe

Madajka

Vasanji

et al. 2008

Clin Exp Metastasis

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The molecular mechanisms associated with prostate cancer (PCa) progression within bone remain a topic of intense investigation. With the availability of transgenic mouse strains, a model of PCa for use in immune competent/transgenic mice would be highly beneficial. This study was designed to explore the utility of RM1 mouse PCa cells in investigations of tumor:bone interactions. The efficacies of several implantation techniques were examined for reliably producing intra-bone RM1 tumor growth and bone lesion formation in immune competent mice. Longitudinal monitoring of bone remodeling and lesion phenotypes was conducted by microcomputed tomography (μCT) and histological analyses. Our results indicate that direct intrabone injections of RM1 cells are necessary for tumor growth within bone and direct implantation promotes the rapid development of osteolytic bone lesions with periosteal bone deposition post-cortical breach. In vitro, RM1 cells promote the proliferation of osteoblast (MC3T3-E1) and osteoclast (Raw264.7) progenitors in a dose dependent manner. Conditioned culture media from RM1 cells appears to promote earlier expression of genes/ proteins associated with osteoblastic differentiation. While clearly stimulating osteoclast function in vivo, RM1 cells had little effect on differentiation and tartate resistant acid phosphatase (TRAP) expression by Raw264.7 cells. These data, coupled with in vivo μCT images, indicate the ability of RM1 cells to induce mixed, yet predominentally osteolytic, responses in bone and illustrate the potential of RM1 cells as a model of investigating prostate tumor:stroma interactions in immune competent/transgenic mice on a C57BL/6 background.

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Murine prostate cancer inhibits both in vivo and in vitro generation of dendritic cells from bone marrow precursors

Abstract: The generation and function of DC are significantly suppressed in the CaP microenvironment in both in vivo and in vitro murine models.

Cited by 19 publications

References 32 publications

Small Rho GTPases Mediate Tumor-Induced Inhibition of Endocytic Activity of Dendritic Cells

Small Rho GTPases Mediate Tumor-Induced Inhibition of Endocytic Activity of Dendritic Cells

Tolerization of Tumor-Specific T Cells Despite Efficient Initial Priming in a Primary Murine Model of Prostate Cancer

Intraosseous injection of RM1 murine prostate cancer cells promotes rapid osteolysis and periosteal bone deposition

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