An international research team headed by scientists at the Cambridge Stem Cell Institute and at the Department of Physiology, Development, and Neuroscience, University of Cambridge, has shown that when tumors first emerge, interactions with healthy cells in the underlying supportive tissue determine their ability to survive, grow, and progress to advanced stages of disease. The study, carried out in mice and further validated using human tissue, may explain why some tiny, newly formed tumors disappear, while others manage to survive and eventually grow into cancer.
The researchers found that at these early stages, the tumor sends a “distress signal” to nearby fibroblasts, the supportive “first-aid” cells in the underlying tissue. This communication triggers a response that closely resembles wound healing. The fibroblasts behave as though the tissue has been damaged, producing a fibrotic scaffold around the tumor cells. This creates a supportive micro‑environment—a “pre-cancerous niche”—that shelters the tumor from being cleared and helps it persist and grow, even in the absence of underlying genetic mutations.
Maria Alcolea, PhD, at the Cambridge Stem Cell Institute, said, “Understanding the mechanisms that allow these newly-formed microscopic tumors to persist and develop into cancer opens up new possibilities for preventing the disease before it takes hold. If we can find a way to block tumor cells from communicating with surrounding tissue, we may have a new way to stop cancer in its tracks.”
Alcolea is senior and corresponding author of the team’s published paper in Nature, titled “Precancerous niche remodeling dictates nascent tumor persistence,” in which they stated, “We propose a model in which both mutations and the stromal response to genetic stress together define the likelihood of early tumors to persist and progress toward more advanced disease stages … Our findings indicate that strategies targeting tumor cells, as well as supporting neighboring cells, could open new avenues for cancer prevention and improve long-term outcomes.”
Tumors arise when our DNA accumulates errors, or mutations, causing the cells to grow faster and ignore signals that would otherwise instruct damaged cells to die before they can cause harm. However, studies over the last decade have also shown that healthy tissues accumulate these same cancer-associated mutations during aging without developing into cancer. “These observations highlight new levels of complexity in the early pathophysiology of cancer, raising the question of what other factors, beyond cancer mutations, may have a role during early carcinogenesis,” the author wrote.
To examine why this should be the case, the University of Cambridge scientists have been studying what additional factors influence tumor formation at the very early stages and what determines whether they persist and develop into cancer. Previous collaborative work by the team had shown that when a newly formed microscopic tumor first emerges in a tissue, it can be removed by other mutant cells surrounding it, which compete for space within the tissue. “… even after tumors have formed, the presence of neighboring mutant clones can continue to influence tumorigenesis,” they noted. But this does not always happen. Scientists have puzzled for some time over why some of these so-called “incipient tumors” manage to outwit the body’s defences and flourish, creating the conditions for advanced disease to develop.
To answer this question, the researchers modeled early stages of cancer in the upper part of the mouse digestive tract. They replicated key features of human disease by exposing mice to a chemical found in tobacco smoke, a known cancer risk factor. This causes mutations in the cells lining the esophagus, leading to the development of microscopic tumors, most of which disappear naturally, but some persist, as previous studies had shown.
The team tracked these nascent tumors over time, from the point when they were made up of just over a handful of altered cells (around 10 cells) through to later stages of disease. They analyzed the tumors and surrounding cells using high‑resolution confocal microscopy and a range of tools, including single‑cell RNA sequencing and genetic cell tracking, to understand what each cell was doing. In addition, the team grew three-dimensional tissue in the lab, allowing them to model the interactions between the tumor cells and surrounding tissue.
They found that the newly emerging tumors send out signals that effectively shape their microenvironment. “Analysis of nascent squamous tumors in the upper gastrointestinal tract of the mouse reveals that the stress response of early tumor cells instructs the underlying mesenchyme to form a supportive ‘precancerous niche,’ which dictates the long-term outcome of epithelial lesions,” the investigators noted. Stimulated fibroblasts beneath these emerging tumors respond to the signals by activating a wound-healing response that triggers remodeling of the extracellular matrix (ECM) and formation of a fibrotic scaffold that promotes tumor growth. “We demonstrate that, during the earliest stages of tumor development, fibroblasts react to the pre-neoplastic epithelium by promoting the formation of a fibrotic precancer niche that, in turn, feeds back on the epithelium, favoring early tumor growth and survival.”
Remarkably, the researchers found that this fibrotic scaffold alone was enough to give healthy, non-mutant cells tumor-like properties, even in the absence of cancer-causing mutations. “Functional heterotypic 3D culture assays and in vivo grafting experiments, combining carcinogen-free healthy epithelium and tumor-derived stroma, demonstrate that the precancerous niche alone is sufficient to confer tumor properties to normal epithelial cells,” they stated. This suggests that beyond genetic alterations, early tumors are shaped by how healthy cells in the underlying tissue respond, with lasting consequences for disease progression.
When the team blocked the communication between the tumor cells and the underlying tissue, they found that the pre-cancerous niche did not form efficiently, and far fewer early tumors survived. “Interfering with fibronectin fibrillogenesis in vivo impaired niche formation, prevented tumor survival, and reduced the overall tumor burden,” they explained.
Examining tissue from early-stage esophageal cancers in humans, the scientists found similar clusters of tumor cells sending stress signals, as well as the same fibrotic scaffolding seen in the mouse models, demonstrating that this mechanism is also relevant in people. Results from their human tissue studies, they reported, “… further reinforce the association between this population, mesenchymal changes, and ECM remodeling in early human esophageal tumorigenesis, revealing the potential clinical relevance of our study.” They also noted, “Whether interfering with ECM assembly represents a valid approach to prevent cancer progression in patients, and whether analogous mechanisms operate in other tumor types, requires further investigation.”
Co-lead author Greta Skrupskelyte, PhD, at the Cambridge Stem Cell Institute, commented, “A decade ago, it was assumed that it is the mutated cells themselves that determine whether or not a cancer arises. Our findings show that the way healthy tissue responds to the emergence of early tumors also plays a crucial role in whether disease develops.”
The researchers say the findings could also, in the future, help improve early diagnosis of esophageal cancer, a disease that is often caught at a late stage, when treatment options are more limited. Skrupskelyte added, “Although the clinical aspects of our work are at a very early stage, it has given us some biomarkers—red flags—that could help identify cancer much earlier. If validated, it could help us catch esophageal cancer at a much earlier stage, when it is far easier to treat.”
In their paper, the team concluded, “Overall, our data demonstrate the unprecedented capacity of the early tumor niche to perpetuate tumor survival signals beyond intrinsic changes driven by genetic alterations, enabling nascent tumors to persist in highly competitive mutant landscapes. This offers the new perspective that not only mutations, but also the environmental response to genetic stress, defines the likelihood of tumors to progress toward more advanced disease stages.”
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