Cancer Is Not Caused by Mutations

The role of the tumor microenvironment (TME) matters more

“We find ourselves at the present time in the era of molecular biology, and we are perhaps unduly influenced by the genetic code as the dominant principle in biology. Perhaps, in a decade or two from now, the dominant principle may shift to another plane, which in turn will influence our speculations about tumor causation.”

— Biochemist Isaac Berenblum, 1974

For decades, the prevailing view in medical science has been that cancer is primarily caused by the accumulation of genetic mutations over time. This perspective has fueled the development of gene-targeted therapies and reinforced the notion that cancer is an almost inevitable consequence of aging.

However, this paradigm doesn’t hold water under closer investigation, as many hunter-gatherer groups around the world show little evidence of cancer. The absence of cancer in these populations isn’t due to shortened lifespans either—analyses have found a common lifespan of up to 78 years among hunter-gatherers (once the bottleneck of high infant mortality is bypassed), suggesting that lifestyle and environment play pivotal roles in health outcomes.

Additionally, the existence of the “Blue Zones”—regions of the world where centenarians exhibit low rates of chronic diseases like cardiovascular disease, diabetes, and cancer—also contradicts the idea that cancer is an inescapable fate given the passage of enough time. While the exact factors contributing to the purported longevity of Blue Zone populations are still under investigation, common themes include plant-based diets, regular physical activity, strong social connections, and low levels of chronic stress.

It’s the Environment, Stupid

Contrary to conventional wisdom, emerging research emphasizes that the accumulation of genetic mutations is not sufficient to cause cancer. The tumor microenvironment (TME)—the surrounding cells, signaling molecules, blood vessels, and extracellular matrix—significantly influences whether mutated cells progress to form tumors. In other words, the same mutation that is adaptive for cancer in altered tissue is not advantageous to cancer in healthy, homeostatic cells.

James DeGregori at the University of Colorado School of Medicine provides the following analogy: When tackling drug dealing in the inner city, arresting all the drug dealers is unlikely to work since the root causes remain unaddressed. On the other hand, improving socioeconomic conditions by creating better jobs, schools, and infrastructure will yield lasting results, as citizens won’t have to resort to crime as a means of survival. Addressing the environment that led to the problem in the first place will provide a more stable solution.

Similarly, instead of simply targeting the cancer and selecting for resistance, altering the microenvironment to disfavor cancer proliferation may provide a more viable long-term strategy. Highlighting the importance of the microenvironment in regulating development, homeostasis, and cancer, biologist Mina Bissell writes,

The sequence of our genes are like the keys on the piano; it is the context that makes the music.

A Tale of Two Tissues

An intriguing observation in oncology is the disparity in cancer frequencies at different anatomical sites. For example, colorectal cancer is very common while small intestinal cancer is rare despite the fact that the small intestine is five times longer (30 feet versus 6 feet for the colon) and characterized by nearly identical rates of mutation as the colon. The discrepancy may be due to strikingly different microenvironments with the colon serving as host to more diverse and numerous microbiota.

Photo of human colorectal cancer cells by National Cancer Institute

Even within the colon, different sections exhibit differential risk patterns. Colorectal cancer almost exclusively occurs in the distal colon where factors such as bile acid concentration, bacterial metabolism, and inflammation may contribute to a pro-carcinogenic environment. Insufficient intake of sufficient dietary resistant starch may prevent production of a short-chain fatty acid called butyrate, which lowers colonic pH, prevents pathogen invasion, and appears to preclude cancer formation.

To further illustrate the importance of the tissue microenvironment, Bissell expounds,

Indeed, how else would one explain the tissue specificity of heritable cancers, for example, BRCA1 and breast cancer, where, despite mutations in all of more than 10 trillion cells, the tumors are not only tissue specific but also formed from just one or a few cells of those tissues?

Turn On, Turn Off

Alongside uncontrolled cell growth/proliferation, cancer is often associated with abnormal changes in DNA methylation. Almost all types of human tumors are characterized by two distinct phenomena: global loss of methylation, which may activate oncogenes, genes that promote tumor formation, as well as increased methylation near tumor suppressor genes.

In other words, genes that promote tumor formation are turned on while genes that suppress tumor formation are turned off. Cigarette smoke has been shown to cause changes in the activity of enzymes, leading to the activation of genes that help cancer spread and the deactivation of genes that normally protect against cancer. In short, genes themselves are not driving tumor formation. Rather, inappropriate gene expression increases the risk of tumor development.

Hidden in Plain Sight

Emerging research has demonstrated the role of the tissue microenvironment in influencing cancer susceptibility. Bissell and Hines observed that many people harbor “occult” tumors without showing any signs of overt disease, suggesting that while the initiation of tumorigenesis may be relatively common, progression to malignant disease requires additional environmental or contextual factors.

The first evidence hinting at the ubiquitous nature of tumors came in 1935 from Arnold Rich when he observed frequent “small carcinomata” in autopsied prostate tissues from men who had died of unrelated causes. Over the decades, countless autopsy studies have found a high prevalence of such "occult" tumors in the prostate, breast, thyroid, and lungs of individuals who died from unrelated causes, leading to concerns of overdiagnosis.

Taken together, these findings reveal that indolent and occult tumors are much more common than previously realized and not adequate for the progression to overt cancer in the absence of an altered tumor-promoting microenvironment. As Bissell and Hines summarize,

Once a tumor, not always a cancer.

A New Paradigm for Cancer Care

Contemporary research is reshaping the longstanding view of cancer as an inevitable consequence of aging due to genetic mutations. The tumor microenvironment plays a pivotal role in cancer development, influencing whether mutated cells progress to form clinically significant tumors.

By expanding our focus from tumors to environmental and contextual factors, we may improve cancer prevention strategies and develop more effective, sustainable treatments. Strategies that focus on modifying the microenvironment—such as immunomodulatory interventions, microbiome modulation, and metabolic therapies—may enhance the effectiveness of existing treatments and reduce the risk of resistance.