The Hidden Danger Increasing Cancer Metastasis Risk: The Role of Oxygen Deprivation and New Opportunities

The spread of cancer cells throughout the body, known as metastasis, is a complex process that can have serious consequences for many patients with cancer. Hypoxia, or low oxygen levels in tissue, can trigger this process by placing cells within a tumor under stress and increasing the risk of metastasis.

Hypoxia is defined as insufficient oxygen levels in tissues, and some cancer cells can adapt to survive in these low-oxygen conditions. This leads to changes in gene expression within the cells, activating mechanisms that allow them to survive under stress.

Understanding the role of hypoxia in metastasis is critical for controlling cancer and developing treatment strategies. This article draws on a new study published on September 28, 2024, in Nature Communications to examine in detail how hypoxia affects metastasis and how this could open a door to new treatment opportunities.

However, hypoxia is a consequence of cancer, not a cause. Trying to fill the cancerous environment with oxygen—for example, through alternative methods such as ozone therapies—therefore targets only a consequence of cancer rather than its cause and does not provide an effective solution. This article focuses on the basic biological mechanisms through which cancer creates a hypoxic microenvironment and innovative approaches that could target these mechanisms.

How Cells Surviving in Hypoxic Conditions Affect Cancer Spread

Research in patients with breast cancer has shown that hypoxia is associated with the risk of metastasis and death. However, explaining this directly is difficult because cancer cells undergo reoxygenation when they enter the bloodstream. A research team led by Dr. Daniele Gilkes at Johns Hopkins University developed a new fluorescent hypoxia mapping system to understand how hypoxic cells survive in the bloodstream and support metastasis. This system showed that cells exposed to hypoxia were protected against reactive oxygen species (ROS = reactive oxygen species), thereby increasing their ability to metastasize.

Reactive oxygen species (ROS) are byproducts derived from oxygen molecules that form during energy production in cells. Under normal conditions, they help regulate cellular functions, but when they accumulate excessively, they can damage cells, leading to DNA mutations and the development of diseases such as cancer.

The Role of HIF and MUC1 Proteins in Metastasis

Studies found that breast cancer cells accumulate higher levels of ROS than normal cells and that hypoxia increases this accumulation. Hypoxia-Inducible Factor (HIF) and MUC1 proteins regulate the cells' redox balance so they can survive this stress. The MUC1 protein promotes the production of antioxidant enzymes, particularly by entering the cell nucleus through a subunit called MUC1-C. This allows circulating cancer cells to survive and increases the risk of metastasis. High HIF-1α expression was also observed in 76% of patients with metastatic breast cancer, suggesting that hypoxia signaling may remain active even after cancer cells enter the circulation.

• Related Topic: Belzutifan, an Inhibitor of Hypoxia-Inducible Factor—the Subject of the 2019 Nobel Prize in Medicine—Receives FDA Approval

Study Methods and Findings: Hypoxia Memory and Gene Expression

In this study, researchers developed a system that uses green fluorescent protein expression at <1% O2 to identify hypoxic cells. The transcriptional profile of hypoxic cells was compared with that of cells in well-oxygenated tumor regions. These analyses showed that cells exposed to hypoxia had a gene expression profile like that observed in cells exposed to chronic hypoxia. This finding revealed a phenomenon called “hypoxia memory.” The continued activity of these hypoxia-induced genes after cancer cells entered the circulation was considered a mechanism sustaining metastasis.

The MUC1 gene was activated in hypoxia-memory (HB) cells in a HIF-1α- and NF-kB-dependent manner, increasing the expression of antioxidant enzymes such as superoxide dismutase (SOD) and providing resistance to ROS. This resistance allowed hypoxic cells to survive in circulation and increased their metastatic potential. MUC1-C inhibitors, such as GO-203, are considered potential treatment options that could be investigated in the future to eliminate these cells and prevent metastasis.

Targetable Genes in Hypoxic Cancer Cells: Identifying 16 Genes

Researchers identified 16 genes that allow hypoxic cells to survive in the bloodstream. These were observed to be hypoxia-related genes that continued to be expressed even when oxygen levels increased in cells entering the circulation. Their continued activity has been associated with a condition called “hypoxia memory.” Dr. Gilkes stated that this reveals differences between laboratory conditions and conditions in the human body. In the laboratory, cells exposed to hypoxia quickly return to normal when oxygen levels rise, whereas hypoxia can persist more chronically in tumors. In this context, the research findings provide clinically important information beyond laboratory findings.

The Prominent Role of MUC1 and Potential Future Treatments

One of the study's notable findings concerns the MUC1 protein. In triple-negative breast cancer , MUC1, which is associated with a high rate of relapse (cancer recurrence), was found at higher levels, particularly in cells with metastatic potential. The researchers aimed to reduce the spread of cancer to the lungs by blocking MUC1 with an inhibitor called GO-203. Reducing MUC1 levels decreased the chances of hypoxic cells surviving in the bloodstream and reduced the rate of metastasis in mouse models. A phase I/II clinical trial targeting MUC1 is currently ongoing in patients with advanced cancer. This research shows that MUC1 could be considered a potential treatment target, particularly in cancer types with a high risk of recurrence.

Conclusion: How Hypoxia Opens New Horizons in Cancer Treatment

Cancer cells that survive in hypoxic conditions are more likely to metastasize, making cancer harder to treat. New studies shed light on how genes that remain active in hypoxic cells, particularly the MUC1 protein, help circulating cancer cells survive. Understanding these mechanisms is a promising step toward developing new treatment strategies and preventing metastasis. Treatments developed for cells with hypoxia memory may improve treatment success, especially in cancers with high metastatic potential, such as breast cancer. Research into hypoxia signaling and key proteins such as MUC1 is therefore regarded as a sign of potentially groundbreaking advances in cancer treatment.