Up-regulation of the interferon gamma (IFN-gamma)-inducible chemokines IFN-inducible T-cell alpha chemoattractant and monokine induced by IFN-gamma and of their receptor CXC receptor 3 in human renal cell carcinoma.
BACKGROUND
The antiangiogenic CXC chemokines interferon gamma (IFN-gamma)-inducible T-cell alpha chemoattractant (I-TAC) and monokine induced by IFN-gamma (Mig) are known as members of IFN-gamma-inducible antiangiogenic CXC chemokines. However, the expression of these chemokines in highly angiogenic tumors remains poorly understood. The authors examined expression of I-TAC, Mig, and their receptor, CXCR3, in tissue samples from patients with renal cell carcinoma (RCC).


METHODS
Twenty-one samples of untreated RCC and corresponding normal renal tissues were obtained from surgical specimens. The expression levels of I-TAC, Mig, and CXCR3 were investigated using reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, real-time RT-PCR analysis, and Western blot analysis. Immunohistochemistry was carried out to clarify the localization of both chemokines and of CXCR3.


RESULTS
RT-PCR analysis showed strong expression levels of I-TAC, Mig, and CXCR3 in RCC tissues and very weak or undetectable expression in normal kidney tissues. Real-time RT-PCR analysis showed that expression levels of I-TAC, Mig, and CXCR3 in RCC tissues were 14.9 times greater, 30.3 times greater, and 9.9 times greater compared with the levels in the corresponding normal kidney tissues, respectively (P < 0.01). Western blot analysis showed up-regulation of I-TAC, Mig, and CXCR3 at the protein level. Immunofluorescence double stainings revealed that I-TAC coincided with pericytes and vascular smooth muscle cells (VSMCs) in tumor angiogenic vessels. Mig was detected in tumor endothelial cells (TECs) and in infiltrating leukocytes. In the corresponding normal kidney tissues, neither VSMCs nor endothelial cells showed positive stainings for these chemokines. CXCR3 was expressed in both tumor cells and infiltrating leukocytes.


CONCLUSIONS
The results revealed special feature of vascular mural cells and TECs in RCC. The up-regulated I-TAC and Mig, produced by tumor vessels, may interact with CXCR3 expressed in tumor cells, with possible pathophysiologic significance in RCC progression.
Suyama
Takahito
T
Department of Molecular Pathology, Chiba University Graduate School of Medicine, Chiba, Japan.
Furuya
Mitsuko
M
Nishiyama
Mariko
M
Kasuya
Yoshitoshi
Y
Kimura
Sadao
S
Ichikawa
Tomohiko
T
Ueda
Takeshi
T
Nikaido
Takashi
T
Ito
Haruo
H
Ishikura
Hiroshi
H
D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000032:analysis; D001707:Biopsy, Needle; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology*; D054371:Chemokine CXCL11; D019743:Chemokines, CXC / Q000032:analysis / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000032:analysis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000032:analysis / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008969:Molecular Sequence Data; D011336:Probability; D011379:Prognosis; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000032:analysis / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D029701:Saccharomyces cerevisiae Proteins; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D046509:Tissue Culture Techniques; D015854:Up-Regulation
D014408:Biomarkers, Tumor; C515202:CXCL11 protein, human; C515187:CXCR3 protein, human; D054371:Chemokine CXCL11; D019743:Chemokines, CXC; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; C085976:MIG1 protein, S cerevisiae; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins