Researchers at the University of Zurich (UZH) have identified a distinct signaling pathway, TNF-α, as a critical driver in the transformation of epithelial cells into aggressive tumor cells. During cancer progression, cells activate their own TNF-α program, becoming invasive. This discovery could enhance early detection and treatment of cancers in the skin, esophagus, bladder, or colon.
Evolutionary Process of Cancer
Cancer develops through an evolutionary process where randomly distributed mutations accumulate in single cells. This accumulation disrupts cell division and other cellular properties, leading to uncontrolled cell multiplication and clonal expansions in superficially normal tissues. This clonal expansion is the first of two key phases in tumorigenesis.
TNF-α Signaling Program
An international research team, led by Ataman Sendoel from the Institute for Regenerative Medicine (IREM) at UZH, found that the TNF-α signaling program acts as a primary driver for clonal expansions in human epithelia, including the skin and mucous membranes. This program contributes to the predisposition for tumor initiation and mediates invasive properties of epidermal stem cells.
Clonal Expansions and Cancer
Traditionally, clonal expansions were seen as precursors to cancer, with mutated cell clones potentially remodeling entire organs. However, recent research shows that clonal expansions are frequent in aging human epithelia and are not always harmful. Sometimes, they can even help prevent tumors.
Single-Cell CRISPR Technique
To understand why only certain epithelial cell clones transform into malignant tumors, researchers studied epithelial cancers like squamous cell carcinoma using a single-cell CRISPR technique. This allowed them to document clonal expansions in epithelial tissue with single-cell precision, focusing on the 150 most frequently mutated cancer genes.
Role of TNF-α in Tumor Formation
The team identified the TNF-α program as crucial in inflammation and cellular communication. During clonal expansion, TNF-α signaling from the surrounding environment, involving immune cells, helps proliferate cells with cancer gene mutations. Once these cells accumulate too many mutations, they begin malignant transformation and tumor formation.
Implications for Detection and Treatment
The study suggests that targeting the cancer-specific arm of TNF-α signaling could offer new therapeutic avenues for epithelial cancers. The activity level of this signaling correlates with tumor aggressiveness and patient survival rates, providing a potential biomarker for assessing prognosis.
Summary Key Pathway: TNF-α drives transformation of epithelial cells into tumor cells. -Cancer Development:** Involves an evolutionary process with clonal expansions. TNF-α Program: Acts as a driver in epithelial cancers. Clonal Expansions: Frequent in aging epithelia, not always harmful. Single-Cell CRISPR: Used to study cancer gene mutations. Tumor Formation: TNF-α promotes invasive properties and tumor growth. Detection and Treatment :Targeting TNF-α signaling offers new therapeutic possibilities.
