The prognostic significance of chemokine receptor CXCR3 expression in colorectal carcinoma

doi:10.1016/j.biopha.2011.12.003

Biomedicine & Pharmacotherapy

Volume 66, Issue 5, July 2012, Pages 373-377

https://doi.org/10.1016/j.biopha.2011.12.003 Get rights and content

Abstract

The expression of chemokine receptor CXCR3 has been associated with tumor dissemination and poor prognosis in breast cancer patients. However, it is still unclear whether CXCR3 can be used as an independent molecular marker for predicting the prognosis of colonrectal carcinoma (CRC) patients. In this study, we found that the relative level of CXCR3 mRNA expression in primary colorectal cancer tissues was significantly higher than that in corresponding non-tumor colon tissues. CXCR3 protein expression was also detected in 98 of 112 primary CRC patients. Thus, CXCR3 might play a vital role in the progression of colorectal cancer. By analyzing the correlation between clinicopathological factors of patients and expression of CXCR3 protein, we showed that high level of CXCR3 protein expression was significantly associated with tumor differentiation, tumor size, lymph node metastasis, distant metastasis, and Dukes’ classification, but not with other factors of CRC patients including gender, age, tumor location and tumor invasion. Furthermore, patients with high CXCR3 expression showed poorer overall survival than those with low CXCR3 expression. Univariate and multivariate analysis indicated that the status of CXCR3 protein expression might be an independent prognostic marker for CRC patients. Therefore, CXCR3 is an indicator of a poor prognosis and a promising target for cancer therapy in colorectal cancer.

Introduction

Colonrectal carcinoma (CRC) is a common digestive malignancy, which is the third most abundant type of cancer and a major cause of cancer mortality in the world [1]. Although the 5-year-survival rates for patients with early stage and local CRC are nearly 90%, once local recurrence and distant metastasis occur, the survival is significantly decreased and 5-year-survival may be 19% [1]. The low survival rate of advanced cancer patients is due to colorectal cancer metastasis to the liver, lung and lymph nodes [2].

Despite the advances made in diagnosis and therapy, largely by an improved surgery and an increasing number of available chemotherapy drags, the prognosis of advanced CRC patients still remains poor [3].

Therefore, studies of finding the prognostic markers and new therapeutic targets of advanced colorectal cancers are still a clinical problem to be solved.

In recent years, an increasing number of studies are focusing on the role of chemokines and chemokine receptors in tumorigenesis and progression. It has been shown that chemokines and chemokine receptors are involved in promoting tumor cell proliferation, angiogenesis and migration [4]. There are currently four subgroups within the chemokine family: CXC, CC, CX₃C and C chemokine ligands. However, less is known about the role of the CXCR3 receptor, which binds the ligands CXCL9, CXCL10 and CXCL11. Researches have shown that CXCR3 is expressed in melanoma, colon, and breast carcinoma, which facilitates tumor metastasis to lymph nodes [5], [6], [7]. Surprisingly, antagonism of CXCR3 inhibits pulmonary metastasis of breast cancer [8] and colorectal cancer [9] in murine tumor models. Although Kawada et al. [6] have indicated that patients with CXCR3-positive cancer showed significantly poorer prognosis than those without CXCR3, less is known about the relationship of CXCR3 expression to clinical characteristics of CRC patients and whether CXCR3 can be used as an independent molecular marker for predicting the prognosis of CRC patients.

This study demonstrates that high level of CXCR3 protein expression was significantly associated with clinical characteristics of CRC patients, including tumor differentiation, tumor size, lymph node metastasis, distant metastasis, and Dukes’ classification. We further indicate that CXCR3 overexpression was an independent prognostic factor in CRC patients and is a potential therapeutic target.

Section snippets

Patients and tissue samples

In our study, there were 112 patients with colorectal cancer who underwent surgery at the department of Surgery, The Sixth People's Hospital affiliated to Shanghai Jiao Tong University between 2000 and 2005. All patients were definitively identified as having colorectal cancer based on their clinicopathological findings. None of these patients had received preoperative chemotherapy and/or radiotherapy. Clinicopathological factors of patients are shown in Table 1. The Dukes’ classification was

CXCR3 expression in colorectal carcinoma

Firstly, quantitative real-time RT-PCR was performed to detect the CXCR3 mRNA expression in 20 cases of CRC and corresponding adjacent colon tissues. We found that 15 of the 20 patients (75%) showed a higher expression level of CXCR3 mRNA in CRC than in non-cancerous tissue. As indicated in Fig. 1, our results showed that the average expression level of CXCR3 mRNA in CRC tissues (0.83 ± 0.20) was significantly higher than that in corresponding non-tumor colon tissues (0.18 ± 0.12; P < 0.05).

Discussion and conclusion

Chemokines and chemokine receptors are now well known to be involved in different steps of tumorigenesis, including angiogenesis, tumor growth, invasion and metastasis [4], [10]. Schimanski et al. [11] have demonstrated that strong expression of CXCR4 by colorectal cancer cells was significantly associated with lymphatic and distant dissemination in CRC patients. And the prognostic significance of CXCR4 expression in CRC patients was also reported by others [12], [13]. Similar to CXCR4, CXCR3

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

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¹: These authors contributed equally to this work.

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Original articleThe prognostic significance of chemokine receptor CXCR3 expression in colorectal carcinoma

Abstract

Introduction

Section snippets

Patients and tissue samples

CXCR3 expression in colorectal carcinoma

Discussion and conclusion

Disclosure of interest

Crit Rev Oncol Hematol

Cancer Lett

Cancer Lett

Trends Cardiovasc Med

Cancer statistics, 2008

CA Cancer J Clin

Dissemination and growth of cancer cells in metastatic sites

Nat Rev Cancer

Pivotal role of CXCR3 in melanoma cell metastasis to lymph nodes

Cancer Res

Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes

Oncogene

CXCR3 expression is associated with poor survival in breast cancer and promotes metastasis in a murine model

Mol Cancer Ther

Antagonism of CXCR3 inhibits lung metastasis in a murine model of metastatic breast cancer

Cancer Res

Original article
The prognostic significance of chemokine receptor CXCR3 expression in colorectal carcinoma