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CXCR7: A novel tumor endothelial marker in renal cell carcinoma, "Beyond the Abstract," by Kyoko Hida, DDSc, PhD, et al

BERKELEY, CA (UroToday.com) - New blood vessels are formed from preexisting capillaries during tumor development. This process, widely known as tumor angiogenesis, sustains tumor progression under pathological conditions. The molecules involved in tumor angiogenesis are potential biomarkers and targets of pharmacological intervention.[1, 2] An anti-vascular endothelial growth factor (VEGF) treatment used in patients with metastatic colon cancer validates the therapeutic value of tumor antiangiogenic intervention.[3, 4] Inhibition of VEGF-dependent angiogenesis combined with chemotherapy is clearly effective under some pathological conditions; however, its effectiveness is limited[5, 6] suggesting that the characterization of alternative molecular new targets is essential for developing novel antiangiogenic therapeutic tools. Several theoretical factors have been used for targeting tumor vasculatures as anticancer strategies. We previously reported that tumor endothelial cells (TECs) differ from normal endothelial cells (NECs) in terms of characteristics such as cell proliferation, migration, gene profile[7], and responses to growth factors[7, 8] or various chemotherapeutic drugs. Furthermore, TECs were cytogenetically abnormal.

A suitable approach for developing effective vascular targeting therapies is to identify molecular markers that are specifically expressed in TECs. Renal cell carcinoma (RCC) is one of the most common malignancies of the adult kidney, representing 2% of all malignancies and being responsible for 2% of cancer-related deaths.[9] Metastatic RCC has been associated with poor prognosis and resistance to chemotherapy. Recently, the elucidation of angiogenic mechanisms resulted in the development of new targets for antiangiogenic agents, and the introduction of these agents has significantly improved patient outcomes. For example, small-molecule inhibitors, such as sorafenib and sunitinib, have improved the prognosis of RCC cancer patients.[10, 11] However, these inhibitors also inhibit normal variants of kinases in nontumor cells, which can lead to unexpected toxicities, including cardiotoxicity or hypothyroidism.[12, 13] If a new antiangiogenic therapy targeting a molecule specific for TECs, is developed, it might be more effective and less toxic to normal blood vessels than current therapies. To develop a novel target for new antiangiogenic therapy that will specifically target TECs, we systematically compared gene expression profiles between three types of TECs (renal carcinoma EC, melanoma EC, and oral carcinoma EC) and NECs (skin-EC) by DNA microarray analysis and investigated the genes upregulated in TECs as novel TEC markers. We found that the mRNA expression level of the chemokine receptor CXCR7 was more than 20 times higher in TECs than in NEC. CXCR7 that binds the chemokines CXCL11 and CXCL12 (SDF-1) is significantly upregulated in tumor cells in several cancers such as breast, lung, cervical, prostate, pancreatic, and pituitary cancer and in sarcomas.[14, 15, 16, 17, 18, 19, 20] CXCR7 is also highly expressed in tumor blood vessels in glioma, meningioma, as well as breast and lung cancer. However, the expression of CXCR7 in RCC tumor vasculature remains unknown.[14, 18, 21, 22, 23, 24, 25]

In the present study, we investigated the expression of CXCR7 in TECs derived from human RCCs. TECs were isolated from six human RCCs and the expression of CXCR7 was analyzed in these cells. Real-time PCR revealed higher expression level of CXCR7 in cultured TECs than in cultured NECs. Furthermore, similar to mouse TECs, immunostaining revealed strong expression of CXCR7 in vivo in human tumor vessels. These findings suggest that CXCR7 is a novel TEC marker and a target for antiangiogenic therapy for RCC.

References

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Written by:

Nako Maishi,a Noritaka Ohga,a Yasuhiro Hida,c Kosuke Akiyama,a Kazuko Kitayama,a Takahiro Osawa,a Yuichiro Onodera,a Nobuo Shinohara,d Katsuya Nonomura,d Masanobu Shindoh,b and Kyoko Hidaa as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

aDepartment of Vascular Biology
bDepartment of Oral Pathology and Biology, Hokkaido University Graduate School of Dental Medicine
cDepartment of Surgical Oncology
dDepartment of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Corresponding Author:
Kyoko Hida, DDSc, PhD
Department of Vascular Biology
Hokkaido University Graduate School of Dental Medicine
N13 W7, Kita-ku, Sapporo 060-8586, Japan
E-mail:  

 

 

 

 CXCR7: A novel tumor endothelial marker in renal cell carcinoma - Abstract

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