Connective Tissue Growth Factor Acts as a Therapeutic Agent and Predictor for Peritoneal Carcinomatosis of Colorectal Cancer

Abstract

Purpose: Here, we aimed to investigate the role of connective tissue growth factor (CTGF) in peritoneal carcinomatosis (PC) associated with colorectal cancer (CRC) and to characterize the underlying mechanism of CTGF mediating adhesion.Experimental Design: A cohort of 136 CRC patient specimens was analyzed in this study. CRC cell lines were used for in vitro adhesion assay and in vivo peritoneal dissemination experiment. Recombinant CTGF protein treatment, transfection of CTGF expression plasmids, and knockdown of CTGF expression in CRC cells were utilized to evaluate the integrin a5, which served as a target of CTGF in inhibiting peritoneal seeding.Results: The analysis of CRC tissues revealed an inverse correlation between CTGF expression and prevalence of PC. Lower CTGF level in CRC patients was associated with higher peritoneal recurrence rate after surgery. Inducing CTGF expression in cancer cells resulted in decreased incidence of PC and increased rate of mice survival. The mice received intraperitoneal injection of recombinant CTGF protein simultaneously with cancer cells or following tumor formation; in both cases, peritoneal tumor dissemination was found to be effectively inhibited in the mouse model. Functional assay revealed that CTGF significantly decreased the CRC cell adhesion ability, and integrin a5 was confirmed by reverse transcriptase PCR and functional blocking assay as a downstream effector in the CTGF-mediated inhibition of CRC cell adhesion.Conclusions: CTGF acts as a molecular predictor of PC and could be a potential therapeutic target for the chemoprevention and treatment of PC in CRC patients.

Connective tissue growth factor inhibits gastric cancer peritoneal metastasis by blocking integrin α3β1-dependent adhesion

“…This is the first study indicating that CTGF is an antiadhesion protein in peritoneal metastasis for gastric cancer, and we suggest a therapeutic use for recombinant CTGF in the late stage of this disease. Previous studies in abdominal cancers, such as colorectal cancer, have demonstrated a negative correlation between CTGF expression and cancer progression (survival as well as metastasis) [18,19]. These results are consistent with our findings that CTGF expression is negatively correlated with gastric cancer, which is also an abdominal-origin cancer.…”

“…Our in vivo results indicate that recombinant CTGF treatment is an effective prevention strategy for peritoneal dissemination as well as an independent prognostic marker for gastric cancer patients. Although previous studies have shown that blocking CTGF using antibodies has shown some promising results in inhibiting pancreatic tumor growth and metastasis in nude mice [28], it was found that the CTGF recombinant protein had a significantly therapeutic effect in advanced colorectal cancer [19]. However, previous studies have reported that CTGF may contribute positively to gastric cancer progression and attenuate adhesion of gastric cancer cells to cultured human peritoneal mesothelial cells [29][30][31].…”

“…To determine the in vitro adhesive ability of wild-type gastric cancer cell lines as well as CTGF overexpressed and knockdown cells, Matrigel (BD bioscience, USA) was coated onto 96-well cell culture plates, and an in vitro adhesion assay was carried out as described by Lin et al [19].…”

“…CTGF has also been reported to be a key regulator of colorectal cancer invasion and metastasis. Moreover, it appears to be a good prognostic factor [18], and recombinant CTGF was suggested to be a potential therapeutic agent in colorectal cancer therapy [19]. However, the underlying mechanisms and functions of CTGF in gastric cancer have not yet been clarified.…”

Enhanced antitumor effects by docetaxel/LL37-loaded thermosensitive hydrogel nanoparticles in peritoneal carcinomatosis of colorectal cancer

“…32 Chemotherapy is widely used in the clinic and has proved to be effective. Coencapsulation of multiple drugs into nanocapsules may play prominent roles in the treatment of cancers to achieve higher antitumor efficacy and minimize the emergence of resistance.…”