Tumor microvasculature with endothelial fenestrations in <i><scp>VHL</scp></i> null clear cell renal cell carcinomas as a potent target of anti‐angiogenic therapy

Yamasaki, Toshinari; Kamba, Tomomi; Kanno, Toru; Inoue, Takahiro; Shibasaki, Noboru; Arakaki, Ryuichiro; Yamada, Tomomi; Kondo, Keiichi; Nishiyama, Hiroyuki; Ogawa, Osamu; Nakamura, Eijiro

doi:10.1111/j.1349-7006.2012.02412.x

Cited by 13 publications

(25 citation statements)

References 40 publications

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“…The results of the present and previous studies indicate that there are substantial differences in the regulation of MCP-1 expression between VHL -/ -RCC cell lines, such as 786-O, and VHL + / + cells, such as CaKi-1 (16,17,19), and this may have an impact on the progression and treatment of RCC. Our previous study showed that, in CaKi-1 cells, NFAT5 activity is increased (22) and MCP-1 expression largely depends on this increased NFAT5 activity, as supported by the results of the present study.…”

Section: Discussionsupporting

confidence: 51%

“…In patients exhibiting RCC, enhanced MCP-1 expression in tumor cells, and infiltration of the tumors with tumor-associated macrophages and tumor-infiltrating lymphocytes has been observed (14,15). In xenograft models of RCC, enhanced MCP-1 expression is associated with microvessel density and tumor size (16,17).…”

Section: Introductionmentioning

confidence: 99%

“…In prostate carcinoma cells, in addition to paracrine signaling to recruit inflammatory or endothelial cells, autocrine MCP-1 signaling to promote cell proliferation and invasiveness has also been observed (18). Deletion of VHL stimulates MCP-1 expression, possibly via VEGF signaling (16,17,19); however, the mechanism of regulation of MCP-1 expression in VHL + / + RCC is largely unknown. Therefore, the present study examined the regulation and function of MCP-1 in the VHL + / + RCC cell line, CaKi-1, and the VHL -/ -RCC cell line, 786-O.…”

Section: Introductionmentioning

confidence: 99%

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Autocrine MCP-1/CCR2 signaling stimulates proliferation and migration of renal carcinoma cells

Küper¹,

Beck²,

Neuhofer

2016

Oncology Letters

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The chemokine monocyte chemoattractant protein-1 [MCP-1; also known as chemokine (C-C motif) ligand 2] is an important mediator of monocyte recruitment during inflammatory processes. Pathologically high expression levels of MCP-1 by tumor cells have been observed in a variety of cancer types. In the majority of cases, high MCP-1 expression is associated with a poor prognosis, as infiltration of the tumor with inflammatory monocytes promotes tumor progression and metastasis. MCP-1 is also expressed in renal cell carcinoma (RCC). In the present study, the function and the regulation of MCP-1 was investigated in two RCC cell lines, CaKi-1 and 786-O. In both cell lines, expression of MCP-1 was significantly enhanced compared with non-cancerous control cells. As expected, secretion of MCP-1 into the medium facilitated the recruitment of peripheral blood monocytes via the chemokine (C-C motif) receptor type 2 (CCR2). As expression of CCR2 was also detected in 786-O and CaKi-1 cells, the effect of autocrine MCP-1/CCR2 signaling was evaluated in these cells. In proliferation assays, administration of an MCP-1 neutralizing antibody or of a CCR2 antagonist to CaKi-1 and 786-O cells significantly decreased cell growth; supplementation of the growth medium with recombinant human MCP-1 had no additional effect on proliferation. The migration ability of RCC cells was impaired by MCP-1 neutralization or pharmacological CCR2 inhibition, while it was stimulated by the addition of recombinant human MCP-1, compared with untreated control cells. Finally, substantial differences in the regulation of MCP-1 expression were observed between RCC cell lines. In CaKi-1 cells, expression of MCP-1 appears to be largely mediated by the transcription factor nuclear factor of activated T cells 5, while in 786-O cells, deletion of the tumor suppressor gene Von-Hippel-Lindau appeared to be responsible for MCP-1 upregulation, as suggested by previous studies. Taken together, the results of the current study indicate that expression of MCP-1 in RCC cells promotes tumor progression and metastasis not only by paracrine, but also by autocrine, MCP-1/CCR2 signaling events, enhancing cell proliferation and migration ability. Therefore, the present findings suggest the MCP-1/CCR2 axis is a potential target for future therapeutic strategies in the treatment of metastatic RCC.

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Section: Discussionsupporting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Autocrine MCP-1/CCR2 signaling stimulates proliferation and migration of renal carcinoma cells

Küper¹,

Beck²,

Neuhofer

2016

Oncology Letters

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“…We previously reported CCL2 mRNA and protein expression in ccRCC cell lines as determined by qRT‐PCR and ELISA . CCL2 expression was higher in VHL −/− pRC3 cells than wt‐VHL‐expressing WT8 cells.…”

Section: Resultsmentioning

confidence: 99%

CCL2 as a potential therapeutic target for clear cell renal cell carcinoma

et al. 2016

Self Cite

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We previously reported that the pVHL‐atypical PKC‐JunB pathway contributed to promotion of cell invasiveness and angiogenesis in clear cell renal cell carcinoma (ccRCC), and we detected chemokine (C‐C motif) ligand‐2 (CCL2) as one of downstream effectors of JunB. CCL2 plays a critical role in tumorigenesis in other types of cancer, but its role in ccRCC remains unclear. In this study, we investigated the roles and therapeutic potential of CCL2 in ccRCC. Immunohistochemical analysis of CCL2 expression for ccRCC specimens showed that upregulation of CCL2 expression correlated with clinical stage, overall survival, and macrophage infiltration. For functional analysis of CCL2 in ccRCC cells, we generated subclones of WT8 cells that overexpressed CCL2 and subclones 786‐O cells in which CCL2 expression was knocked down. Although CCL2 expression did not affect cell proliferation in vitro, CCL2 overexpression enhanced and CCL2 knockdown suppressed tumor growth, angiogenesis, and macrophage infiltration in vivo. We then depleted macrophages from tumor xenografts by administration of clodronate liposomes to confirm the role of macrophages in ccRCC. Depletion of macrophages suppressed tumor growth and angiogenesis. To examine the effect of inhibiting CCL2 activity in ccRCC, we administered CCL2 neutralizing antibody to primary RCC xenografts established from patient surgical specimens. Inhibition of CCL2 activity resulted in significant suppression of tumor growth, angiogenesis, and macrophage infiltration. These results suggest that CCL2 is involved in angiogenesis and macrophage infiltration in ccRCC, and that CCL2 could be a potential therapeutic target for ccRCC.

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“…32 Treatment with anti-VEGF inhibitors has been investigated during the in vivo treatment of VHL-null renal cell carcinoma 123 and of VHLassociated retinal hemangioblastomas. 41 A recent study showed that variable expression of VEGF-A, VHL, and VEGF-C along with other genes may predict the efficacy of bevacizumab.…”

Section: Hemangioblastomasmentioning

confidence: 99%

The genetic basis of intradural spinal tumors and its impact on clinical treatment

Karsy

Guan

Sivakumar

et al. 2015

FOC

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Genetic alterations in the cells of intradural spinal tumors can have a significant impact on the treatment options, counseling, and prognosis for patients. Although surgery is the primary therapy for most intradural tumors, radiochemothera-peutic modalities and targeted interventions play an ever-evolving role in treating aggressive cancers and in addressing cancer recurrence in long-term survivors. Recent studies have helped delineate specific genetic and molecular differences between intradural spinal tumors and their intracranial counterparts and have also identified significant variation in therapeutic effects on these tumors. This review discusses the genetic and molecular alterations in the most common intradural spinal tumors in both adult and pediatrie patients, including nerve sheath tumors (that is, neurofibroma and schwannoma), meningioma, ependymoma, astrocytoma (that is, low-grade glioma, anaplastic astrocytoma, and glioblastoma), hemangioblastoma, and medulloblastoma. It also examines the genetics of metastatic tumors to the spinal cord, arising either from the CNS or from systemic sources. Importantly, the impact of this knowledge on therapeutic options and its application to clinical practice are discussed.

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Tumor microvasculature with endothelial fenestrations in VHL null clear cell renal cell carcinomas as a potent target of anti‐angiogenic therapy

Cited by 13 publications

References 40 publications

Autocrine MCP-1/CCR2 signaling stimulates proliferation and migration of renal carcinoma cells

Autocrine MCP-1/CCR2 signaling stimulates proliferation and migration of renal carcinoma cells

CCL2 as a potential therapeutic target for clear cell renal cell carcinoma

The genetic basis of intradural spinal tumors and its impact on clinical treatment

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