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Researchers have disproved the prevailing theory about the onset of colorectal tumors
Last reviewed: 02.07.2025
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A 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 an existing theory about how colorectal cancer begins and offer new ways to diagnose the disease before it occurs.
“Colorectal cancer is very, very heterogeneous, which has made it difficult for many years to classify these tumors for treatment,” said senior study author Dr. Jorge Moscat, the Homer T. Hurst III Professor of Oncology in Pathology and vice chair of cell and tumor biology in the Department of Pathology and Laboratory Medicine at Weill Cornell Medical College. This heterogeneity, the varying characteristics of tumor cells from one patient to another and within the same tumor, makes treatment particularly challenging.
Colorectal tumors can arise from two types of precancerous polyps: conventional adenomas and serrated adenomas. Conventional adenomas were once thought to develop from mutations in normal stem cells found at the bottom of crypts, pit-like structures in the lining of the intestine. Serrated adenomas, on the other hand, are associated with a different type of stem cell with fetal characteristics that mysteriously appear at the tops of crypts. Scientists described these supposedly different tumorigenesis processes 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. Hurst Professor of Oncology in Pathology 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 serrated tumors, which are sometimes overlooked by doctors because of their initially flat shape and which can become aggressive cancers later.
The study's co-primary authors are Dr. Hiroto Kinoshita and Dr. Anjo Martinez-Ordonez, postdoctoral fellows in the Department of Pathology and Laboratory Medicine at Weill Cornell Medical College.
Uncovering the Causes of Colorectal Cancer
Researchers have previously found that many colorectal tumors in humans of both types have abnormally low levels of proteins called atypical protein kinase C (aPKC). The 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 after inactivation of aPKC genes,” said Dr. Moscat, who is also a member of the Sandra and Edward Meyer Cancer Center 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 entire crypt structure into disarray. “So normal cancers grow from the bottom up, and serrated cancers also grow from the bottom up,” Dr. Moscat said.
The findings suggest a new unified model for the onset of colorectal cancer, where damage to the intestinal crypts causes a decrease in aPKC protein expression, leading to the loss of normal stem cells at the bottom of the crypt. Without these stem cells, the crypts cannot regenerate. To survive, the structure can either generate a replacement population of regenerative stem cells at the bottom or more fetal-like stem cells at the tip. These replacement cells can then lead to cancer.
"If we can better understand how aPKC protein expression is regulated, we might be able to control and prevent tumor development, as well as better understand tumor progression," said Dr. Maria Diaz-Meco.
The team is now studying aPKC expression patterns in human tumours at different stages with the hope of developing molecular tests that could be used for early tumour detection, categorisation of tumours in patients and development of better treatments.