Abstract
The key role of the Wnt/β-catenin signaling in colorectal cancer (CRC) insurgence and progression is now recognized and several therapeutic strategies targeting this pathway are currently in developing. Wnt/β-catenin signaling not only dominates the early stages of sporadic colorectal cancer (SCC), but could also represent the connection between inflammatory bowel diseases (IBD) and increased risk of developing SCC. The knowledge on the sequential molecular events of Wnt-signaling cascade in IBD and during colorectal carcinogenesis, might provide new diagnostic/prognostic markers and could be helpful for optimizing the treatment protocols, thus improving the efficacy of Wnt-targeting therapies. We performed a comparative evaluation of the expression of some crucial molecules participating to Wnt signaling in an animal model of chemically-induced CRC and in human tissues obtained from patients suffering from IBD or at sequential stages of SCC. Specifically, we analyzed upstream events of Wnt signaling including β-catenin nuclear translocation and loss of E-cadherin and APC functions, and downstream events including c-Myc and Cyclin-D1 expression. We demonstrated that these crucial components of the Wnt/β-catenin pathway, when evaluated by immunohistochemistry using a multiparametric approach that includes the analyses of both expression and localization, could be potent markers for diagnosis, prevention and therapy in IBD and SCC, also possessing a predictive value for responsiveness to Wnt-targeting therapies. Furthermore, we showed that the animal model of chemically-induced CRC mimics the molecular events of Wnt signaling during IBD and SCC development in humans and may therefore be suitable for testing chemopreventive or therapeutic drugs targeting this pathway.
Highlights
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the developed countries [1], where it has a leading position in malignant cancerassociated morbidity and mortality
We preliminary assessed whether our experimental model of DMH-induced colon carcinogenesis in BDIX rats mimicked the histopatological lesion of inflammatory bowel diseases (IBD), dysplasia and sporadic colorectal cancer recovered in humans, and defined the timing of the sequential steps during cancer insurgence and progression in rats
Starting from the 16th week, rat tissue showed histological features of dysplastic colorectal epithelium, with hyperchromatic, crowded and elongated nuclei confined to the basal half of the epithelial cells, and sparse goblet mucinous cells, to the low grade dysplasia (LD) recovered in human tissues (Figure 1, step2)
Summary
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the developed countries [1], where it has a leading position in malignant cancerassociated morbidity and mortality. Even if the addition of new chemotherapeutic agents such as Irinotecan and Oxaliplatin to standard 5-Fluorouracilbased chemotherapy improved the survival of patients with metastatic CRC to about 20 months [7,8,9,10], the CRCderived metastatic disease, and peritoneal carcinomatosis, is basically considered by oncologists a terminal condition for which systemic chemotherapy results almost inefficient. The lack of effective and well-tolerated treatments for advanced CRC highlights the need for innovative approaches for diagnosis, prognosis and therapy for colorectal cancer. Chemoprevention is an attractive emerging option to reduce CRC mortality and researches aiming to develop natural or synthetic chemopreventive agents are giving promising results [11]
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