The Breast Cancer Drug Cyclophosphamide May Paradoxically Help Cancer Cells Spread

Although chemotherapy helps fight cancer, it sometimes has harmful effects on other cells. Effects that can also contribute to the spread of cancer.

Cancer Patient

Chemotherapy is a widely used cancer treatment, either before or after surgery or as an adjunct to radiotherapy. Chemotherapy drugs act systemically on both cancer cells and healthy cells, which can have serious consequences. The side effects of the treatment depend on the dose, the molecule administered, and the patient’s state of health, but also on changes at the cellular level which, paradoxically, can promote the spread of cancer.

This is the conclusion of a study recently published in the International Journal of Molecular Sciences by Ohio State University. Researchers monitored the effects of the breast cancer drug cyclophosphamide (CTX) on the lining of blood vessels and the attachment of cancer cells to them.

Weakening of cell cohesion

It all started with observations from an earlier study by the same team: mice treated with CTX four days after intravenous injection of breast cancer cells had more cancer cells in their lungs than mice that had not received CTX. The aim is to identify the mechanism behind this phenomenon.

CTX increases the permeability of the blood vessels in the lungs, which means that the endothelium of the blood vessels, the layer of cells in direct contact with the blood, is no longer as cohesive. The basement membrane, the base on which the endothelium is anchored becomes accessible. The basement membrane as a result provides attachment sites for the cancer cells circulating in the blood. CTX increases serum levels of metalloproteinase 2, a proteolytic enzyme capable of remodeling the basement membrane and increasing its adhesiveness. The cancer cell still needs to be able to anchor to the basement membrane. To do this, it has ‘hooks’ on its surface. These are proteins belonging to the integrin family. Without them, cancer cells cannot benefit from CTX-induced destabilization of the vascular endothelium.

Understanding this mechanism will give researchers more options for limiting the potential adverse effects of cyclophosphamide therapy. By affecting metalloproteinase 2, integrins, and laminins in the basement membrane, the researchers observed that cancer cells no longer attached as readily to the vascular endothelium. Attachment to blood vessels is one of the key steps that allow cancers to spread and colonize new organs.