Blocking the interaction between cancer cells and their microenvironment could be a viable strategy to eliminate cancer cells that stray from the primary tumor, thereby preventing cancer’s spread, according to a study.
While treatments with chemotherapy and hormone therapy after surgery significantly improve the lives of breast cancer patients, nearly 10% of these patients will relapse within five years. This is caused by cancer cells that manage to stray from the primary tumor before being detected and invade other tissues in the body, called disseminated tumor cells (DTCs).
Once DTCs migrate and establish themselves in distant tissues, systemic conventional chemotherapy “with regimens that include dose-dense Adriamycin (also known as doxorubicin) plus cyclophosphamide (AC) and/or paclitaxel (also known as Taxol)” fails to eliminate them.
Scientists long believed the reason DTCs resist chemotherapy is that most of them remain in a quiescent (non-proliferative) state. Now, a team of researchers from the Fred Hutchinson Cancer Research Center in Seattle, Washington, and their collaborators challenged this idea, arguing that it is the microenvironment, and not cancer cells’ state, that shields DTCs from chemotherapy.
To prove this, researchers first injected green-fluorescent cancer cells into mice, treated them with surgery and chemotherapy, and tracked the cells for five weeks.
Cell tracking revealed that cancer cells that resisted chemotherapy had migrated and settled in the perivascular niche (the vicinity of blood vessels) within the bone marrow.
The cells lining blood vessels — called endothelial cells — are not just passive conduits of blood; they produce a plethora of factors that regulate biological processes, including the development of the immune system and some cancer processes.
Thus, researchers investigated whether these endothelial cells were protecting cancer cells from chemotherapy, and if so, how. They developed a culture system that mimicked bone marrow interactions, including breast cancer cells, endothelial cells, and cells of the bone marrow connective tissue.
Results showed that endothelial cells, but not other bone marrow cells, protected cancer cells from chemotherapy. This protection was mainly mediated by two endothelial factors: von Willebrand factor (vWF), a molecule that contributes to atherosclerosis, and vascular cell adhesion molecule 1 (VCAM-1), a protein that mediates the adhesion between endothelial cells and other types of cells.
Blocking the interaction between breast cancer cells and the blood vessels by inactivating VCAM-1 and other adhesion molecules sensitized the cancer cells to chemotherapy, ultimately preventing cancer from spreading. Of note, this sensitization was achieved without changing the proliferative state of the cancer cells or increasing chemotherapy doses.
“Our work provides critical insight about how therapeutic resistance of [bone marrow] DTCs can be overcome,” researchers said.
However, whether eliminating these disseminated cancer cells in the bone marrow will also prevent metastasis in other regions of the body remains to be addressed. Because breast cancers often spread to the bone, researchers propose studying disseminated cancer cells in other cancers that are more prone to metastasize outside the bone.
“For now, we can conclude that adjuvant chemotherapy can be modified to target the perivascular niche, resulting in depletion of the BM DTC reservoir and prevention of bone metastasis,” they said.