In a discovery that upends conventional wisdom, researchers have found that low-oxygen zones inside colon tumors can paradoxically accelerate cancer growth—by weaponizing support cells.
Key Points at a Glance
- Oxygen-poor areas within colon tumors transform helpful fibroblasts into tumor-promoting cells
- These inflammatory fibroblasts release Wnt5a and epiregulin, fueling tumor growth
- Wnt5a prevents blood vessel formation, locking tissue in a cancer-friendly hypoxic state
- Findings confirmed in both mouse models and human samples
- Study opens path to therapies targeting Wnt5a-producing fibroblasts in colon cancer
For decades, scientists assumed that starving tumors of oxygen—a state known as hypoxia—would suffocate their growth. But new research led by a team from Osaka University reveals the opposite can happen, especially in colon cancer. Oxygen-deprived zones within tumors may instead *nurture* cancer by corrupting normal tissue cells into allies of malignancy.
Published in *Nature Communications*, the study shows how low-oxygen environments reprogram structural support cells called fibroblasts into a harmful, inflammatory form. These transformed fibroblasts release molecules that feed tumors and sabotage the body’s natural defenses. It’s a revelation that could rewrite strategies for both cancer therapy and the treatment of inflammatory diseases.
“We uncovered a surprising mechanism by which hypoxia may promote tumor growth, and it involves the formation of cells called inflammatory fibroblasts,” said Akikazu Harada, the study’s lead author.
Ordinarily, fibroblasts provide mechanical support to tissue. But when colon tumors deprive their environment of oxygen, fibroblasts near these hypoxic pockets change. They begin secreting a molecule called epiregulin, which encourages cancer cell proliferation. Even more critically, they also produce Wnt5a, a protein that blocks blood vessel formation near its release site. This means that the oxygen-poor state isn’t just a side effect—it’s preserved and even enhanced by the very cells that tumors manipulate.
This feedback loop effectively traps areas of tissue in a stable, hypoxic condition, which paradoxically benefits tumor growth. “It’s like the cancer is building its own survival zone,” explains Harada.
To verify the phenomenon in humans, the researchers analyzed samples from patients with colon cancer, healthy colons, and inflammatory bowel disease (IBD). The presence of Wnt5a-secreting fibroblasts and their transformation from a healthy to an inflammatory state was a common thread—showing remarkable similarity between the mouse models and human samples.
According to senior author Akira Kikuchi, these findings place fibroblasts squarely into the spotlight as the third therapeutic target in cancer, joining immune cells and the cancer cells themselves. “By targeting Wnt5a-producing fibroblasts, we could weaken a hidden support system that tumors rely on to grow,” he said.
This insight is especially important in Japan, where colon cancer is the most common form of the disease. But the implications go beyond oncology. Chronic inflammatory diseases like IBD also exhibit fibroblast transformation and tissue remodeling. The same Wnt5a pathway may be involved, hinting at a shared mechanism behind inflammation and cancer progression.
Illustrations from the study show how “good” fibroblasts in healthy tissue gradually turn “bad” when exposed to localized hypoxia. These cells stop aiding the body and begin releasing biochemical cues that attract, support, and shelter cancer cells. The result is a kind of molecular Stockholm syndrome—where support cells not only tolerate the tumor’s presence, but help it flourish.
This paradigm shift could explain why anti-angiogenesis therapies—those that aim to cut off a tumor’s oxygen supply—have produced inconsistent clinical results. “Sometimes, these treatments backfire by inadvertently increasing the population of Wnt5a-secreting fibroblasts,” notes Kikuchi.
As the field of cancer therapeutics shifts toward precision medicine, these results underscore the importance of understanding the tumor microenvironment. Future drugs that selectively block Wnt5a or prevent fibroblast transformation could enhance current treatments or offer standalone therapies for hard-to-treat colon cancers.
In the battle against cancer, it turns out oxygen deprivation may not be a weakness, but a weapon. Understanding how tumors exploit their microenvironment could unlock a new class of treatments that targets not the invader itself, but the ground it stands on.
Source: Osaka University
