Adenoviral Gene Transfer of Stromal Cell–Derived Factor-1 to Murine Tumors Induces the Accumulation of Dendritic Cells and Suppresses Tumor Growth

Fushimi, Toshiaki; O’Connor, Timothy P.; Crystal, Ronald G.

doi:10.1158/0008-5472.can-05-1493

Cited by 31 publications

(25 citation statements)

References 53 publications

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“…Chemokine-mediated inhibition of tumorigenesis has been attributed to trafficking of immune cells to the tumor (9,35,36). Our work supports a cancer progression model in which locally produced CXCL12 limits the migration potential by either desensitizing cells to endocrine ligand or by exceeding the optimal level for chemotaxis, resulting in the absence of actin polymerization and cell migration characteristic of dimeric CXCL12 (13)(14)(15).…”

Section: Discussionsupporting

confidence: 71%

Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways

Drury

Ziarek²,

Gravel

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

189

236

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Chemokines and chemokine receptors are extensively and broadly involved in cancer metastasis. Previously, we demonstrated that epigenetic silencing of the chemokine CXCL12 sensitizes breast and colon cancer cells to endocrine signaling and metastasis to distant tissues. Yet, the precise mechanism whereby CXCL12 production by tumor cells regulates dissemination remains unclear. Here, we show that administration of CXCL12 extended survival of tumorbearing mice by potently limiting metastasis of colorectal carcinoma or murine melanoma. Because secreted CXCL12 is a mixture of monomeric and dimeric species in equilibrium, oligomeric variants that either promote (monomer) or halt (dimer) chemotaxis were used to dissect the mechanisms interrupting carcinoma metastasis. Monomeric CXCL12 mobilized intracellular calcium, inhibited cAMP signaling, recruited β-arrestin-2, and stimulated filamentous-actin accumulation and cell migration. Dimeric CXCL12 activated G-protein-dependent calcium flux, adenylyl cyclase inhibition, and the rapid activation of ERK1/2, but only weakly, if at all, recruited arrestin, stimulated actin polymerization, or promoted chemotaxis. NMR analyses illustrated that CXCL12 monomers made specific contacts with CXCR4 that were lost following dimerization. Our results establish the potential for inhibiting CXCR4-mediated metastasis by administration of CXCL12. Chemokine-mediated migration and β-arrestin responses did not dictate the antitumor effect of CXCL12. We conclude that cellular migration is tightly regulated by selective CXCR4 signaling evoked by unique interactions with distinct ligand quaternary structures.malignancy | functional selectivity | cellular idling | cancer therapeutics | chemokine oligomer C hemokines are chemoattractant cytokines that bind G-protein-coupled receptors and are mediators for many physiological processes including cell trafficking, angiogenesis, and embryogenesis (1-3). Chemokine receptor signaling is linked with cancer metastasis as well as infiltration of tumor-associated immune cells, neoangiogenesis, and proliferation (4, 5). Chemokines as primary mediators of metastasis were first identified by Muller and colleagues who implicated the chemokine receptor CXCR4 in tumor cell trafficking (6-8). At least 23 different cancers have been shown to express elevated levels of CXCR4, sensitizing these cancers to CXCL12 gradients in distant tissues (9). CXCL12 is constitutively expressed in the bone marrow, lungs, and liver, which are common tissues of metastatic growth. Efforts to block metastatic dissemination have mainly used small molecule antagonists of CXCR4 (10) to limit cancer malignancy (11, 12). However, this avenue has proven difficult to move into the clinic (5, 12), suggesting alternative strategies to interfere with CXCR4-guided metastatic homing (for example, by the use of agonists rather than antagonists) are required. Our previous data indicate that epigenetic silencing of the Cxcl12 promoter enhances metastasis of colonic and mammary carcinoma, implicating...

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Section: Discussionsupporting

confidence: 71%

Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways

Drury

Ziarek²,

Gravel

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

189

236

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“…Its disruption in CCR7Ϫ/Ϫ animals indeed is sufficient to strongly impair DC migration to secondary lymphoid organs upon activation [38,39]. Other chemokines and chemokine receptors including CXCL12 and its ligand CXCR4 [40] are, however, involved in the fine regulation of this event, influencing the eventual en route acquisition of full immunostimulatory ability by migrating DC [38,39].…”

Section: Discussionmentioning

confidence: 99%

The secretion of HMGB1 is required for the migration of maturing dendritic cells

Dumitriu¹,

Bianchi

Bacci³

et al. 2006

Journal of Leukocyte Biology

215

183

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Chemokines regulate the migration and the maturation of dendritic cells (DC) licensed by microbial constituents. We have recently found that the function of DC, including their ability to activate naïve, allogeneic CD4+ T cells, requires the autocrine/paracrine release of the nuclear protein high mobility group box 1 (HMGB1). We show here that human myeloid DC, which rapidly secrete upon maturation induction their own HMGB1, remodel their actin-based cytoskeleton, up-regulate the CCR7 and the CXCR4 chemokine receptors, and acquire the ability to migrate in response to chemokine receptor ligands. The events are apparently causally related: DC challenged with LPS in the presence of HMGB1-specific antibodies fail to up-regulate the expression of the CCR7 and CXCR4 receptors and to rearrange actin-rich structures. Moreover, DC matured in the presence of anti-HMGB1 antibodies fail to migrate in response to the CCR7 ligand CCL19 and to the CXCR4 ligand CXCL12. The blockade of receptor for advanced glycation end products (RAGE), the best-characterized membrane receptor for HMGB1, impinges as well on the up-regulation of chemokine receptors and on responsiveness to CCL19 and CXCL12. Our data suggest that the autocrine/paracrine release of HMGB1 and the integrity of the HMGB1/RAGE pathway are required for the migratory function of DC.

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“…When overexpressed, CXCL14 inhibits angiogenesis and hence tumor growth (69, 72) (Figure 3). Further, normal and lower levels of CXCL14 would increase the chances of dendritic cells penetrating the tumor, leading to detection of the tumor by the immune system (69, 71–73). Thus, CXCL14 has anti-tumor activities via impairing angiogenesis and enhancing the detection of tumor by the immune system.…”

Section: The 26s Proteasome Complex In Different Cellular Events and mentioning

confidence: 99%

The 26S proteasome complex: An attractive target for cancer therapy

Frankland-Searby

Bhaumik

2012

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

130

145

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The 26S proteasome complex engages in an ATP-dependent proteolytic degradation of a variety of oncoproteins, transcription factors, cell cycle specific cyclins, cyclin-dependent kinase inhibitors, ornithine decarboxylase, and other key regulatory cellular proteins. Thus, the proteasome regulates either directly or indirectly many important cellular processes. Altered regulation of these cellular events is linked to the development of cancer. Therefore, the proteasome has become an attractive target for the treatment of numerous cancers. Several proteasome inhibitors that target the proteolytic active sites of the 26S proteasome complex have been developed and tested for anti-tumor activities. These proteasome inhibitors have displayed impressive anti-tumor functions by inducing apoptosis in different tumor types. Further, the proteasome inhibitors have been shown to induce cell cycle arrest, and inhibit angiogenesis, cell-cell adhesion, cell migration, immune and inflammatory responses, and DNA repair response. A number of proteasome inhibitors are now in clinical trials to treat multiple myeloma and solid tumors. Many other proteasome inhibitors with different efficiencies are being developed and tested for anti-tumor activities. Several proteasome inhibitors currently in clinical trials have shown significantly improved anti-tumor activities when combined with other drugs such as histone deacetylase (HDAC) inhibitors, Akt (protein kinase B) inhibitors, DNA damaging agents, Hsp90 (heat shock protein 90) inhibitors, and lenalidomide. The proteasome inhibitor bortezomib is now in the clinic to treat multiple myeloma and mantle cell lymphoma. Here, we discuss the 26S proteasome complex in carcinogenesis and different proteasome inhibitors with their potential therapeutic applications in treatment of numerous cancers.

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Adenoviral Gene Transfer of Stromal Cell–Derived Factor-1 to Murine Tumors Induces the Accumulation of Dendritic Cells and Suppresses Tumor Growth

Abstract: The human CXC chemokine, stromal cell-derived factor 1

Cited by 31 publications

References 53 publications

Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways

Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways

The secretion of HMGB1 is required for the migration of maturing dendritic cells

The 26S proteasome complex: An attractive target for cancer therapy

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