AIM: To examine the expression of connective tissue growth factor (CTGF), also known as CCN2, in gastric carcinoma (GC), and the correlation between the expression of CTGF, clinicopathologic features and clinical outcomes of patients with GC.

METHODS: One hundred and twenty-two GC patients were included in the present study. All patients were followed up for at least 5 years. Proteins of CTGF were detected using the Powervision two-step immunostaining method.

RESULTS: Of the specimens from 122 GC patients analyzed for CTGF expression, 58 (58/122, 47.5%) had a high CTGF expression in cytoplasm of gastric carcinoma cells and 64 (64/122, 52.5%) had a low CTGF expression. Patients with a high CTGF expression showed a higher incidence of lymph node metastasis than those with a low CTGF expression (P = 0.032). Patients with a high CTGF expression had significantly lower 5-year survival rate than those with a low CTGF expression (27.6% vs 46.9%, P = 0.0178), especially those staging I + II + III (35.7% vs 65.2%, P = 0.0027).

CONCLUSION: GC patients with an elevated CTGF expression have more lymph node metastases and a shorter survival time. CTGF seems to be an independent prognostic factor for the successful differentiation of high-risk GC patients staging I + II + III. Over-expression of CTGF in human GC cells results in an increased aggressive ability.

Gastric cancer (GC), one of the most common malignant diseases, is the second leading cause for cancer-related death both in China and in the world (700 000 deaths annually)[12].

TNM staging system is used worldwide to predict the prognosis and direct therapeutic decisions of patients with GC[3]. The 5-year survival rate of GC patients at stages I and IV is close to 90% and less than 30%, respectively[4]. GC exhibits markedly heterogenous in histologic feature and biologic behavior, especially at advanced stages. It was reported that the biological behavior and prognosis of GC can be significantly different among GC patients at the same stage[5]. Some studies showed that some biomarkers could provide additional information for predicting the biological behavior and prognosis of GC. More specific and effective markers and therapies should be identified and developed for improving the survival of GC patients.

Connective tissue growth factor (CTGF), also known as CCN2, is a member of the CCN family, including cysteine-rich protein 61 (Cyr61), also known as CCN1, and nephroblastoma-overexpressed gene (Nov), also known as CCN3, as well as Wisp-1/elm1 (CCN4), Wisp-2/rCop1 (CCN5) and Wisp-3 (CCN6)[67]. The primary translational products of CCN family members are 343-381 residues, which generate proteins of Mr 35 000-40 000 with homologies ranging from 60% to 90%. All members of the CCN gene family possess a secretory signal peptide at the NH₂ terminus, indicating that they are secreted proteins. CTGF can bind to integrins on cell surface[6], and is a potent stimulator of endothelial cell adhesion, proliferation, migration and angiogenesis in vivo[9–11]. CTGF is believed to be a multifunctional signaling modulator involved in a wide variety of biologic or pathologic processes, such as angiogenesis, osteogenesis, fibrosis in kidneys and skin, and tumor development[6–812–15]. It was reported that CTGF plays an important role in the progression of several types of cancer[16]. Elevated CTGF levels have been detected in a number of cancers including pancreatic cancer[1617], breast cancer[1819], prostate cancer[20], esophageal adenocarcinoma[21], glioma[22] and melanoma[23]. However, little information on the association between expression of CTGF and GC prognosis is available.

In this study, we examined the expression of CTGF in gastric carcinoma in order to analyze its correlation with histologic type, clinicopathologic feature, and clinical outcome of gastric carcinoma patients.

In the present study, we detected CTGF expression in GC patients. High CTGF expression was closely related with lymph node metastasis, grade of differentiation, and Lauren type. Univariate and multivariate analyses revealed that high CTGF expression was a powerful independent predictor for the poor survival of GC patients, especially for those at stage I + II + III. The overall 5-year survival rate of GC patients with a higher CTGF expression and a lower CTGF expression was 27.6% and 46.9%, respectively (P = 0.0178). The 5-year survival rate of GC patients with a higher CTGF expression and a lower CTGF expression at stage I + II + III was 35.7% and 65.2%, respectively (P = 0.0027), indicating that over-expression of CTGF could promote the aggressive behavior of GC.

CTGF is a novel, potent angiogenic factor[910], which was first identified as a mitogen, detected in conditioned medium from human umbilical vein endothelial cells[26]. Integrin is an important receptor for CCN proteins, and receptor activation may produce a variety of effects. CTGF protein can bind directly to integrins αvβ3 and αIIbβ3[1011]. Shimo et al[9] and Babic et al[10] reported that CTGF mediates endothelial cell adhesion and migration through binding to integrin αvβ3, prolong endothelial cell survival, and induce angiogenesis in vivo. Yang et al[20] reported that CTGF is a downstream mediator of TGF-β1 action in cancer-associated reactive stroma, and one of the key promoters of angiogenesis in tumor-reactive stromal microenvironment, and plays an important role in prostate carcinogenesis. Breast cancer stage is positively associated with tumor size, lymph node metastasis status and over-expression of CTGF[19]. In our study, high CTGF expression was related with lymph node metastasis, depending on the ability of CTGF to induce angiogenesis.

CTGF is believed to be a multifunctional signaling modulator involved in a wide variety of biologic or pathologic processes. CTGF proteins exhibit diverse cellular functions, such as regulation of cell division, proliferation, mitogenesis, differentiation, survival, adhesion and migration, apoptosis, motility, and ion transport. CTGF plays a role in the development and progression of cancer. Recently, Dornhöfer et al[16] showed that CTGF promotes anchorage-independent pancreatic cancer cell growth. Furthermore, anti-CTGF treatment inhibits anchorage-independent growth in vitro, primary tumor growth in vivo and macroscopic lymph node metastases[16]. In contrast to the above results, CTGF is a new autocrine survival and differentiation factor for human rhabdomyosarcoma cells[27]. It was reported that over-expression of CTGF suppresses the growth of oral squamous carcinoma cells transplanted into mice[28]. Furthermore, apoptosis of MCF-7 cells induced by TGF-β appears to be mediated by CTGF, suggesting that CTGF may play an important role in human breast cancer cell growth[29]. Elevated level of CTGF is significantly correlated with a good prognosis of colorectal cancer[30] and lung adenocarcinoma[25], suggesting that the role of CTGF in different types of cancer may vary considerably, depending on the tissue involved. The question of how cell or tissue context determines the action of CTGF protein is interesting and deserves further investigation.

The present study showed that high CTGF expression was a powerful independent predictor for the poor overall survival of GC patients, especially for those at stage I + II + III. Multi-mechanisms are involved in aggressive behaviors of tumors at stage IV. The 5-year survival rate was only about 10% of GC patients at stage IV. Additional biomarkers might be helpful in predicting the prognosis of GC patients and more specific and effective therapies should be developed to improve the survival of GC patients at stage I + II + III. However, the value of additional biomarkers for predicting the prognosis of GC patients at stage IV is poor.

In conclusion, GC patients with an elevated CTGF expression have more lymph node metastases and a shorter survival time. CTGF seems to be an independent prognostic factor that allows successful differentiation of high-risk GC patients at stage I + II + III. Over-expression of CTGF in human GC cells results in an increased aggressive ability of cancer.