A unique signaling pathway known as TNF- plays a significant role in changing normal epithelial cells into aggressive tumor cells. As cancer progresses, cells activate their own TNF- program, leading to invasiveness. This discovery has the potential to enhance early diagnosis and treatment for patients with skin, esophagus, bladder, or colon cancers.
How does a normal cell transition into a cancerous cell? In the central tumor model, cancer evolves gradually through an evolutionary process. Random mutations in cancer genes accumulate in individual cells, disrupting cell division and other cellular functions. This causes the cells to proliferate uncontrollably, outpacing neighboring cells, resulting in the uncontrolled multiplication of mutated cells – known as clonal expansions. This phase of clonal expansion in tissues that appear normal is a crucial initial step in the development of cancer.
Unique genetic program fuels cancer growth
A research team led by Ataman Sendoel from the Institute for Regenerative Medicine at the University of Zurich revealed that a specific signaling program acts as a key driver for clonal expansions in human epithelial tissues like the skin and the mucous membranes in the esophagus, bladder, and colon. This program also influences the cells’ propensity for tumor initiation and facilitates the invasive characteristics of epidermal stem cells. Sendoel remarks, “Our findings demonstrate that the TNF-α signaling program is a primary driver for the conversion of normal epithelial cells into malignant cancer cells during key phases of cancer development.”
Traditionally, clonal expansions were considered precursors to cancer. Mutated cell clones have the ability to overtake large areas of tissue, reshaping entire organs. Recent studies, however, have shown a more intricate picture: Clonal expansions are quite common in aging human epithelial tissues, with some instances even preventing tumor formation.
Analysis of 150 cancer genes in epithelial tissue
To understand why only certain epithelial cell clones transform into malignant tumors, researchers explored epithelial cancers such as squamous cell carcinoma, a prevalent skin tumor. They employed a single-cell CRISPR technique to map clonal expansions across the entire epithelial tissue with single-cell precision. This extensive in vivo study shed light on how cancer gene mutations affect cellular behavior. “We focused on the 150 most frequently mutated cancer genes in epithelial tumors, tracking their progression during clonal expansion and cancer formation in different cell types by profiling all active genes,” Sendoel explains.
The team identified a distinct TNF-α (tumor necrosis factor alpha) program, a signaling pathway crucial for inflammation and cellular communication. During clonal expansion in normal epithelia, TNF-α signaling from the surrounding environment, involving immune cells like macrophages, aids the proliferation of cells with accumulated cancer gene mutations. As these cells amass more driver mutations, they undergo malignant transformation, initiating tumor growth. “Interestingly, during cancer formation, some cancer cells start producing their own TNF-α, promoting invasion into surrounding tissues, a critical step in cancer development,” notes Peter Renz, lead author of the study.
Potential for early detection and treatment opportunities
By understanding the distinctions and similarities between clonal expansion in normal tissues and tumors, new strategies may emerge for early detection, prevention, and treatment of these cancer types. “Our discoveries suggest that targeting the cancer-specific aspect of TNF-α signaling could offer a promising avenue for treating patients with epithelial cancers,” Sendoel emphasizes. Moreover, the TNF-α signaling pathway levels correlate with the aggressiveness of tumors: higher activity in the cancer-specific genetic program corresponds to shorter patient survival rates. This insight could serve as a potential biomarker for predicting patient outcomes in epithelial cancers.
