Researchers have disproved the prevailing theory about the onset of colon tumors

The study, led by researchers at Weill Cornell Medical College, provides new evidence that most colorectal cancers begin with the loss of intestinal stem cells before the genetic changes that cause cancer occur. The findings, published May 29 in the journal Developmental Cell, challenge existing theories about the onset of colorectal cancer and suggest new ways to diagnose the disease before it occurs.

“Colorectal cancer is very, very heterogeneous, which for many years has made it difficult to classify these tumors to target therapy,” said senior study author Dr. Jorge Moscat, the Homer T. Hurst III Professor of Oncology in Pathology and vice chair of cellular and oncopathobiology in the Department of Pathology and Laboratory Medicine at Weill Cornell Medical College. This heterogeneity, the varied characteristics of tumor cells between patients and also within the same tumor, makes treatment particularly challenging.

Colorectal tumors can arise from two types of precancerous polyps: conventional adenomas and serrated adenomas. It was previously thought that conventional adenomas develop from mutations in normal stem cells located at the bottom of the crypts, pit-like structures in the intestinal mucosa. Serrated adenomas, on the other hand, are associated with a different type of stem cell with fetal characteristics that appears mysteriously at the tips of the crypts. Scientists have described these supposedly different processes of tumor formation as “bottom-up” and “top-down.”

"We wanted to determine exactly how these two pathways begin and progress to better understand their heterogeneity as cancer progresses," said study co-lead author Dr. Maria Diaz-Meco, the Homer T Professor of Oncology in Pathology. Hurst in the Department of Pathology and Laboratory Medicine at Weill Cornell Medical College and a member of the Meyer Cancer Center at Weill Cornell Medical College. This is especially important for jagged tumors, which doctors sometimes miss because of their initially flat shape and which can become aggressive cancers later.

Co-first authors of the study are Dr. Hiroto Kinoshita and Dr. Anjo Martinez-Ordoñez, postdoctoral fellows in the Department of Pathology and Laboratory Medicine at Weill Cornell Medical College.

Uncovering the causes of colorectal cancer

Researchers previously found that many colorectal tumors in both types of people have abnormally low levels of proteins called atypical protein kinase C (aPKC). A new study examined what happens when aPKC genes are inactivated in animal models and cultured intestinal organoids.

“We approached this project with bottom-up and top-down theories, but were surprised to find that both tumor types showed loss of intestinal stem cells following inactivation of aPKC genes,” said Dr. Moscat, who is also a member of the Sandra and Edward Meyer at Weill Cornell Medical College.

The characteristic apical stem cells in serrated adenomas arise only after the normal stem cells at the bottom of the crypts die, throwing the structure of the entire crypt into disarray. "So regular cancer develops from the bottom up, and serrated cancer also develops from the bottom up," Dr. Moscat said.

The findings suggest a new unified model for the onset of colorectal cancer, where damage to intestinal crypts causes a decrease in aPKC protein expression, leading to loss of normal stem cells at the bottom of the crypt. Without these stem cells, the crypts cannot regenerate. To survive, the structure can give rise to either a replacement population of regenerative stem cells at the bottom or more fetal-like stem cells at the top. These replacement cells can then lead to cancer.

“If we can better understand how aPKC protein expression is regulated, we could control and prevent tumor development and better understand tumor progression,” said Dr. Maria Diaz-Meco.

The team is now studying aPKC expression patterns in human tumors at different stages with the hope of developing molecular tests that can be used for early detection of tumors, classifying tumors in patients and developing better treatments.