Abstract
Claudin-4 (CLDN4) is a major epithelial tight junction protein overexpressed in many cancers to maintain the tumor environment. In this report, we aimed to determine the efficacy of targeting CLDN4 in colorectal cancer (CRC) using an anti-CLDN4 extracellular domain antibody, 4D3. CLDN4 was upregulated in CRC metastatic foci. CLDN4 expression in CRC cells was reduced by upregulation of TNFα, which was induced by Clostridium perfringens enterotoxin produced by gut flora. In a nude mouse liver metastasis model, inhibition of metastasis was increased by combination treatment with 5-fluorouracil (FU) and 4D3 compared to that with 5-FU alone. Moreover, combination treatment with 4D3 and anti-epithelial growth factor receptor (EGFR) antibody C225 resulted in more pronounced inhibition of in vitro sphere formation and tumor growth in nude mice compared to that observed with C225 alone. Moreover, the time interval between the administration of 4D3 and that of C225 was important for maximizing the C225-induced inhibition of EGFR phosphorylation. In a nude mouse model, sequential treatment with 4D3 and C225 with a 6-h time interval resulted in more pronounced inhibition of tumor growth than concurrent treatment. These findings suggest that the targeting of CLDN4 enhances the antitumoral effects of chemotherapeutic agents and molecular targeting antibodies when used in combination.
Highlights
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in Japan, and in the last four decades, its incidence has risen sharply [1]
One-fourth of advanced cases are associated with liver metastasis, which is a life-threatening event accounting for 30% of CRC deaths [2, 3]
Expression of CLDN4 was examined in 124 cases of CRC (Figure 1 and Table 1)
Summary
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in Japan, and in the last four decades, its incidence has risen sharply [1]. This is in part due to the increase in Western lifestyles and, in particular, high-fat and high-glucose diets. Claudins (CLDN) are the major protein components of tight junctions, which seal adjacent cells together at adherens junctions and desmosomes [4]. Tight junctions play an essential role in the establishment and maintenance of cell polarity and are involved in the regulation of other cellular functions, including proliferation and differentiation. The border formed by a tight junction maintains www.oncotarget.com the differential compositions of the apical and basolateral regions [5, 7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
