Blood supply may be the Achilles heel of tumours
Danish research shows that the arteries supplying blood to cancerous tissue act differently than other arteries in the body. Tumours may be targeted with medicine that alters blood flow thereby effectively killing them or making them more susceptible to radiation therapy.
The tissue surrounding malignant tumours contains arteries that constantly supply the cancer cells with blood, oxygen and nutrients. For many years, the pharmaceutical industry has been trying to design medicine that inhibits tumours from developing a blood supply, but success has been limited for most types of cancer.
However, new Danish research shows that the feed arteries that supply tumours act differently than other arteries.
Since these feed arteries are different from normal arteries, the pharmaceutical industry might not need to produce medicine that inhibits their formation but could instead develop medicine that effectively exploits the differences between these arteries, thereby starving the malignant tumours of their blood supply.
One of the researchers behind the discovery hopes that this will metabolically starve the cancer cells so that they eventually die.
“The feed arteries supplying a tumour with blood are like an Achilles heel for cancer, because shutting down the blood supply will eliminate the tumour. Researchers previously tried to counteract the formation of new tumour arteries but mostly failed. This may be because the medicine was administered too late, after the arteries had already formed. We have instead searched for functional differences in the existing arteries that we might be able to target with medicine,” explains Ebbe Bødtkjer, Associate Professor, Department of Biomedicine, Aarhus University.
The new research results were recently published in Breast Cancer Research.
Induced breast cancer in mice
Ebbe Bødtkjer and colleagues induced breast cancer in female mice by overexpressing the ErbB2 gene. This corresponds to the human HER2 gene, which is associated with 10–15% of all breast cancer cases among women.
The overexpression of ErbB2 resulted in the development of breast cancer, and the researchers then extracted the tumour tissue and examined the arteries in the tissue immediately surrounding the tumour.
These feed arteries are not really part of the tumour but are located in the surrounding healthy tissue. However, they maintain the blood supply to the tumour.
Arteries differ in several ways
The arteries that supply blood to tumours had several structural and functional differences from normal arteries.
First, the tumour feed arteries had less capacity to contract.
Normal arteries can reduce their diameter by contracting smooth muscle cells, which will limit blood flow. In comparison, the tumour feed arteries had lower capacity for contraction.
“From the perspective of a tumour, inhibiting the ability of feed arteries to contract makes good sense because this ensures a constant flow of nutrients to support its aggressive growth,” says Ebbe Bødtkjer.
The feed arteries also expressed fewer α1-adrenoceptors that respond to noradrenaline.
The autonomic nervous system controls the arteries, using noradrenaline and other messengers to signal to the arteries whether they should contract. However, the tumour feed arteries express fewer receptors for noradrenaline, disrupting the ability of the nervous system to regulate the arterial contractility.
“The specialization in structure and function prevents the tumour feed arteries from contracting. Thus, the tumours constantly have a higher blood supply,” explains Ebbe Bødtkjer.
Either open or close the arteries
The research project aimed to find differences between normal arteries and tumour feed arteries. This opens opportunities for designing medicine that can target the tumour feed arteries without compromising the rest of the arteries in the body.
Ebbe Bødtkjer envisions two ways to exploit these differences.
The first is designing medicine that precisely targets the structural or functional differences in tumour feed arteries, making them contract and thereby starving the tumour cells.
The other option is to fully open or dilate the arteries.
For example, radiation therapy is most effective in an oxygen-enriched environment. Radiation therapy produces reactive oxygen metabolites that destroy both proteins and DNA but requires oxygen to produce these oxygen metabolites.
“We envision designing medicine that increases the blood supply to the cancer cells in order to create a tumour environment with a very high concentration of oxygen. This will considerably improve the effectiveness of radiation therapy,” explains Ebbe Bødtkjer.
Presumably applies to all tumours
Although the research is currently only based on a study of breast cancer tissue from female mice, evidence suggests that changes in arteries occur also for other cancer tissue and across species.
In another project involving Ebbe Bødtkjer, researchers examined the differences in arteries from human colon cancer tissue and found exactly the same phenomenon.
“In human colon cancer, the arteries also specialized, with a larger diameter that ensured greater blood supply to the cancer cells. The mechanism is slightly different, but the result is the same. The arteries can dilate more and contract less, and this seems to be an important feature of the feed arteries immediately surrounding malignant tumours,” says Ebbe Bødtkjer.
Discovering why the arteries change
Ebbe Bødtkjer will study this phenomenon more closely, including investigating how the tumours modify the arteries in the adjacent normal tissue.
Among other things, he speculates that this phenomenon may result from the very acidic environment in tumour tissue, with many waste products and growth factors. This special environment promotes the aggressive expansion of the tumours and extends several millimetres into the surrounding normal tissue, affecting such things as the cancer feed arteries.
“The other possibility is that the tumours promote the formation of blood vessels within the tumour, which increases blood flow in the feed arteries. The resulting change in flow pattern probably causes the feed arteries to specialize so that vascular contraction is inhibited, facilitating blood flow as a result. These are the kinds of things, we would like to find out,” says Ebbe Bødtkjer.
“Murine breast cancer feed arteries are thin-walled with reduced α1A-adrenoceptor expression and attenuated sympathetic vasocontraction” has been published in Breast Cancer Research. The Novo Nordisk Foundation awarded Ebbe Bødtkjer, Associate Professor, Department of Biomedicine, Aarhus University, a grant in 2014 for the project Transport and Sensing of Metabolic Acidic Waste Products Contribute to Breast Cancer Metastasis.