Research led by Weill Cornell Medicine has uncovered pivotal evidence suggesting that most colorectal cancers originate from the loss of intestinal stem cells prior to the onset of cancer-causing genetic mutations. This breakthrough, detailed in a study published on May 29 in Developmental Cell, challenges the longstanding theory of colorectal tumor initiation and opens new avenues for early diagnosis and intervention.
Rethinking colorectal cancer heterogeneity
“Colorectal cancer is very, very heterogeneous, which has made it difficult for many years to classify these tumors in order to inform therapy,” said Dr. Jorge Moscat, the senior author of the study. Dr. Moscat is the Homer T. Hirst III Professor of Oncology in Pathology and Vice-Chair for Cell and Cancer Pathobiology at Weill Cornell Medicine. This heterogeneity, referring to the diverse characteristics of colorectal tumor cells both across different patients and within the same tumor, complicates treatment strategies significantly.
Colorectal tumors typically emerge from two types of pre-cancerous polyps: conventional adenomas and serrated adenomas. The prevailing theory held that conventional adenomas develop from mutations in the normal stem cells located at the base of intestinal crypts, which are pit-like structures in the intestinal lining. In contrast, serrated adenomas were believed to arise from a different type of stem-like cell with fetal characteristics that mysteriously appear at the tops of the crypts. These processes were termed “bottom-up” and “top-down” tumorigenesis.
Investigating tumor initiation pathways
“We wanted to determine how those two routes really start and how they progress, so we can better understand their heterogeneity as the cancer progresses,” explained co-senior author Dr. Maria Diaz-Meco, who is also a member of the Meyer Cancer Center at Weill Cornell Medicine. This focus is particularly crucial for serrated tumors, which are often missed during initial screenings due to their flat shape but can develop into aggressive cancers over time.
Dr. Hiroto Kinoshita and Dr. Anxo Martinez-Ordoñez, postdoctoral associates at Weill Cornell Medicine, are the study's co-first authors.
The role of aPKC proteins in colorectal cancer
The researchers had previously noted that many human colorectal tumors exhibit abnormally low levels of proteins called atypical protein kinase C (aPKC). The new study delves into the consequences of inactivating aPKC genes in animal models and cultured intestinal organoids.
“We approached this project with the bottom-up and top-down theories, but we were surprised to find that both tumor types showed loss of intestinal stem cells after aPKC genes were inactivated,” Dr. Moscat said. This finding was unexpected, particularly for serrated adenomas, which were thought to originate from the top-side stem cells. However, these stem cells only appear after the normal bottom-side stem cells die, disrupting the crypt structure.
A unified model for colorectal cancer initiation
The study proposes a new unified model for colorectal cancer initiation. Damage to the intestinal crypts results in decreased aPKC protein expression, leading to the loss of normal stem cells at the crypt base. Without these stem cells, the crypt cells cannot regenerate effectively. To compensate, the crypt structure may develop either replacement regenerative stem cells at the bottom or fetal-like stem cells at the top, both of which can potentially lead to cancer.
Implications for diagnosis and treatment
“If we can better understand how aPKC protein expression is regulated, we could control and prevent tumor development, and also better understand the progression of tumors,” Dr. Diaz-Meco stated. The research team is now examining aPKC expression patterns in human tumors at various stages, aiming to develop molecular tests for earlier tumor detection, more precise tumor classification, and improved treatment strategies.
This groundbreaking study not only revises the understanding of colorectal cancer initiation but also paves the way for novel diagnostic and therapeutic approaches that could significantly improve patient outcomes.
Source: Weill Cornell Medical College