A study led by Weill Cornell Medicine has found new evidence that the majority of colorectal cancers start with the loss of intestinal stem cells, even before cancer-causing genetic changes occur. The findings, which were published on May 29 in Developmental Cell, challenge the current theory for how colorectal tumors begin and suggest new approaches for detecting the disease at an earlier stage.The initiation of colorectal tumors is being researched to find new ways to diagnose the disease before it becomes established. According to Dr. Jorge Moscat, a professor at Weill Cornell Medicine, colorectal cancer is highly heterogeneous, making it challenging to classify tumors for effective therapy. This heterogeneity refers to the varying characteristics of colorectal tumor cells in different patients and even within the same tumor.It is particularly difficult to treat colorectal cancer. Colorectal tumors can develop from two types of pre-cancerous polyps: conventional adenomas and serrated adenomas. Conventional adenomas were believed to be caused by mutations in normal stem cells found at the bottom of intestinal crypts. Serrated adenomas, however, are linked to a different type of stem-like cell with fetal characteristics that mysteriously appear at the tops of the crypts. Scientists have referred to these seemingly different tumor-forming processes as “bottom-up” and “top-down.”The co-senior author, Dr. Maria Diaz-Meco, expressed the importance of understanding the initial stages and progression of two tumor routes in order to comprehend their differences as cancer develops. This research is particularly crucial for serrated tumors, which can be challenging to detect due to their initial flat shape and can later become aggressive cancers. Dr. Hiroto Kinoshita and Dr. Anxo Martinez-Ordoñez are the co-first authors of the study.The Department of Pathology and Laboratory Medicine at Weill Cornell Medicine conducted a study on colorectal cancer. The researchers discovered that both human colorectal tumors and those of animal origin have lower levels of atypical protein kinase C (aPKC). They then investigated the effects of inactivating aPKC genes in animal models and cultured intestinal organoids. Surprisingly, both types of tumors showed loss of intestinal function.Dr. Moscat, a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, explained that the inactivation of aPKC genes resulted in changes to the stem cells. The typical top-side stem cells found in serrated adenomas only develop after the normal stem cells at the bottom of the crypt die, causing disruption to the entire crypt structure. This indicates that both conventional and serrated cancers initiate from the bottom-up. These findings propose a new comprehensive model for the start of colorectal cancer, where damage to the intestinal crypts leads to a decrease in aPKC protein expression, followed by loss of t.The regular stem cells located at the base of the crypt are essential for the regeneration of crypt cells. In the absence of these stem cells, the crypt is unable to renew itself. To survive, the structure has the capability to produce either a new population of regenerative stem cells at the base, or more immature fetal-like stem cells at the top. These replacement cells have the potential to contribute to the development of cancer.
Dr. Diaz-Meco stated, “If we can gain a better understanding of how the expression of the aPKC protein is controlled, we could potentially manage and prevent the development of tumors, and also gain a better understanding of tumor progression.” The team is currently examining the patterns of aPKC expression in human tumors at various stages, in the hopes of creating molecular tests that could help with this.The technology has the potential to improve detection and classification of tumors, leading to better treatments for patients. The study conducted by Hiroto Kinoshita and colleagues demonstrates the impact of epithelial aPKC deficiency on stem cell loss and metaplasia in the initiation of colorectal cancer. The findings have significant implications for early detection and treatment of tumors. This research is a step forward in the development of more effective cancer therapies.
