Tumors are often much more poorly supplied with oxygen than healthy tissue. Swiss researchers have now shown in mice that cell clusters that migrate through the body and form metastases are particularly often split off from tumor areas with an oxygen deficiency. If the researchers provided a better oxygen supply with medication, they reduced the risk of metastases. However, the primary tumors treated in this way became significantly larger. The findings could help to develop new approaches for cancer therapies.
Many solid tumors have very few blood vessels in some areas to supply them with oxygen and nutrients. However, in order for the tumor to grow, it needs an adequate blood supply. Cancer cells with low oxygen saturation therefore increasingly produce a protein that stimulates the growth of blood vessels, the so-called Vascular Endothelial Growth Factor (VEGF). Some chemotherapy drugs target this area. They prevent new blood vessels from growing into the tumor, thus slowing the growth of the cancerous tumor. Depending on the type of tumor, this strategy can also have disadvantages. It has been shown that tumors with a lack of oxygen are more likely to form metastases, which significantly worsens the patient’s chances of survival.
Human breast cancer mice
Researchers led by Nicola Aceto from the University of Basel have now investigated the mechanisms underlying metastasis. To do this, they injected human breast cancer cells into mice. These formed tumors in the breast tissue of the test animals that correspond to those of humans. With the help of a marker that makes oxygen-poor tumor cells glow yellow, Aceto’s team was able to show that clearly demarcated areas inside and around the edges of the tumor suffered from a lack of oxygen. There were very few blood vessels in these areas – but not none at all. This finding is relevant because metastatic cancer cells spread through the bloodstream. If the oxygen-poor areas had no connection to the blood system, the cancer cells would not be able to reach other areas of the body.
When a tumor begins to spread, both individual cancer cells and clusters of multiple cancer cells break away. These clusters of circulating tumor cells (CTCs) have the highest potential to metastasize when compared to individual cells. As Aceto and his colleagues found out, such clusters mainly originate from tumor tissue that is undersupplied with oxygen. “It’s like too many people crowding into a narrow space. Then some look for some fresh air and go outside, ”says Aceto. His team was also able to show that CTC clusters with little oxygen are more aggressive than those with normal oxygen saturation. “The insufficient supply of a tumor with oxygen leads to the detachment of these CTC clusters, which have a particularly great potential for the development of metastases,” says Aceto. As his group was able to show, the lack of oxygen also causes the cancer cells to produce more proteins that enable them to connect to form clusters.
The Swiss researchers also found that the oxygen-poor cell clusters have a specific genetic signature. This was evident both in the cancer cells obtained from mice and in samples from real breast cancer patients. With the help of data from the cancer genomatlas – a project in which the genome of many different tumors has been recorded since 2005 – the researchers were able to show that the prognosis of breast cancer patients can be predicted on the basis of the gene signature they have identified. A significantly larger proportion of patients whose cancer cells did not have the signature indicating a lack of oxygen survived than patients whose cancer cells had the corresponding signature.
Larger tumors, fewer metastases
In addition, Aceto’s research group examined possible implications for cancer therapy. Some of the mice were given an approved chemotherapeutic agent that inhibits the growth of blood vessels leading to the tumor. As expected, the tumors in these mice remained smaller. However, they scattered more often, which shortened the life of the animals. Instead, they administered an agent to another group of mice with the opposite effect: it stimulated the growth of blood vessels leading to the tumor, thus ensuring an adequate blood supply in all areas of the cancerous ulcer. The tumors in these mice grew much faster and became significantly larger overall. However, they did not scatter, so that these mice survived longer despite the larger size of their tumors. “This is a provocative result,” says Aceto. “If we give the tumor enough oxygen, the cancer cells have no reason to leave the tumor and form metastases. On the other hand, this also accelerates the growth of the primary tumor. “
Agents that promote the growth of blood vessels are already used in cancer therapy. It is known that tumors with sufficient blood supply are more sensitive to radiation therapy and certain chemotherapeutic agents. The researchers were also able to reproduce this on the test mice. Thanks to the additional blood vessels, the administered chemotherapeutic agent could be transported more effectively into the tumor and thus had a stronger effect. The combination also successfully combated tumors and metastases in the mice in the late stages of cancer.
“The next challenge now is to transfer these results to a clinical setting,” the researchers write in their publication. The optimal strategy depends on the individual patient, the type of tumor and many other factors. “We speculate that therapies that combat the lack of oxygen in the tumor, alone or in combination with chemotherapeutic agents, could represent a new way of weakening metastasis,” the researchers say.
Source: Cinzia Donato (University of Basel) et al., Cell Reports, doi: 10.1016 / j.celrep.2020.108105