Abstract
The chemokine receptor CXCR4 is overexpressed and functional in colorectal cancer. To investigate the role of CXCR4 antagonism in potentiating colon cancer standard therapy, the new peptide CXCR4 antagonist Peptide R (Pep R) was employed. Human colon cancer HCT116 xenograft-bearing mice were treated with chemotherapeutic agents (CT) 5-Fluorouracil (5FU) and oxaliplatin (OX) or 5FU and radio chemotherapy (RT-CT) in the presence of Pep R. After two weeks, CT plus Pep R reduced by 4-fold the relative tumor volume (RTV) as compared to 2- and 1.6-fold reductions induced, respectively, by CT and Pep R. In vitro Pep R addition to CT/RT-CT impaired HCT116 cell growth and further reduced HCT116 and HT29 clonal capability. Thus, the hypothesis that Pep R could target the epithelial mesenchyme transition (EMT) process was evaluated. While CT decreased ECAD and increased ZEB-1 and CD90 expression, the addition of Pep R restored the pretreatment expression. In HCT116 and HT29 cells, CT/RT-CT induced a population of CD133+CXCR4+ cells, supposedly a stem-resistant cancer cell population, while Pep R reduced it. Taken together, the results showed that targeting CXCR4 ameliorates the effect of treatment in colon cancer through inhibition of cell growth and reversal of EMT treatment-induced markers, supporting further clinical studies.
Highlights
Colorectal cancer (CRC) is among the most frequently diagnosed malignancies in western countries [1]
Nude mice were subcutaneously (SC) injected with HCT116 cells and, when the tumor was well-established, the animals were treated with either 5-Fluorouracil (5FU) + Oxaliplatin (OX) (CT), Peptide R (Pep R), or both (5FU-OX + Pep R) (Figure S1A)
The addition of Pep R to chemotherapeutic agents (CT) significantly improved the efficacy of chemotherapy, reducing relative tumor volume (RTV) 4-fold (4.67 ± 1.17)
Summary
Colorectal cancer (CRC) is among the most frequently diagnosed malignancies in western countries [1]. Diagnostics and screening, up to 30% of patients present with synchronous metastases [2], and 40–50% will eventually develop metastases after primary therapies for localized disease within 3 years from diagnosis [3]. Colonization of distant organs depends on acute changes in cellular attributes such as adhesion and migratory potential [4]. These features characterize the epithelial-to-mesenchyme transition (EMT) program in which epithelial cells gradually lose their morphological features (polarity, membrane adhesion, cell-to-cell contacts) to acquire spindle morphology [5]. Low E-Cadherin (CDH1/ECAD) and high N-Cadherin significantly correlated with local infiltration, tumor stage and vascular invasion [6]. Low E-Cadherin (CDH1/ECAD) and high N-Cadherin significantly correlated with local infiltration, tumor stage and vascular invasion [6]. miR-125b regulates Wnt/β-catenin signaling and triggers EMT, conferring
Sign-in/Register to view highlights & summary 
Published Version (
Free)
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 call