Breakaway breast cancer cells can travel to the brain: scientists devise a way to block entry

One of the most puzzling — and devastating — aspects of cancer is its potentially deadly wanderlust, the spread of the disease from a primary tumor to a new and distant location.

The process is of course formally referred to as metastasis, which is basically recognized as cancer cells in motion. After detaching themselves from a primary tumor, these malignant migrants hitchhike into the blood or lymphatic system to seed new tumors. As countless studies have shown, certain types of cancer have preferential fates.

Scientists from the University of Friborg in Switzerland are studying the development of brain metastases in patients with breast cancer. Knowing how these cancer cells make their way to the brain helps lay the groundwork for interventions that block the tumor cells’ well-trodden path. Blocking the cells from a target tissue is crucial because metastatic cancer is bound to be worse in terms of its aggression and more difficult to treat than a primary tumor, say oncologists.

“Brain metastases are a complication with increasing incidence in patients with advanced breast cancer,” writes Dr. Girieca Lorusso, whose laboratory focuses on experimental and translational oncology. “It is a serious disease characterized by a rapid decline in quality of life and a poor prognosis. There is a critical clinical need to develop effective therapies to prevent and treat brain metastases,” added Lorusso.

registered mail Science Translational MedicineLorusso and her colleagues have shown how proteins called connexins orchestrate the spread of metastatic breast cancer in the brain – an event that drastically worsens patients’ prognosis.

In the lab, the Swiss team performed in vitro and in vivo studies to show that connexins and the enzyme focal adhesion kinase – FAK – likely play an important role in brain invasion by cancer cells. Connexins belong to a family of proteins that form intercellular membrane channels that allow the flow of ions and small molecules between neighboring cells.

The Swiss research shed light on how connexin-mediated activation of the FAK enzyme promoted cell adhesion, tumor-astrocytic interaction and tumor survival in the brain parenchyma. The parenchyma is the functional tissue in the brain, made up of two types of cells involved in sensing and controlling the body. The remaining brain tissue, known as the stroma, is the structural tissue of the organ.

Scientists and clinicians have made tremendous advances in the treatment of breast cancer over the past three decades, and a large percentage of patients have a normal life expectancy after treatment. Advances in various combination treatments and immunotherapy are among the types of approaches that have helped increase the number of breast cancer survivors many-fold.

However, according to Breastcancer.org, an information resource for patients and their families, about 30% of women diagnosed with early-stage breast cancer eventually develop metastatic disease, regardless of where malignant cells spread. Because there are so few cases of male breast cancer, it’s unclear how many of their tumors metastasize, but men are also diagnosed with metastatic breast cancer, additional data from the resource shows.

Among people who develop metastatic breast cancer, about 10% to 15% have brain metastases with stage IV disease. According to Breastcancer.org, the risk of brain metastases is usually highest in patients with more aggressive subtypes of breast cancer, such as B. HER2-positive or triple-negative breast cancer.

Meanwhile, Lorusso and colleagues found that connexins, activated by the enzyme FAK, can in turn stimulate signaling pathways that maintain breast cancer cells in brain tissue. The team demonstrated in three different mouse models that connexin proteins drive the spread of breast cancer cells to the brain. When the mice were treated with inhibitors of FAK, an approach already being tested in human clinical trials, the growth of metastatic breast cancer cells in the brain was suppressed.

“There is a critical clinical need to develop effective therapies to prevent and treat brain metastases,” noted Lorusso, who also emphasized that the team’s animal model of breast cancer metastasis has been instrumental in unveiling molecular mechanisms that govern metastatic spread and colonization control the brain.

With clinical trials of FAK inhibitors already underway, Lorusso and colleagues look forward to further therapeutic applications of these molecules. “Systemic treatment with FAK inhibitors reduced brain metastasis,” Lorusso wrote.

“Given the limited therapeutic options for brain metastases in cancer patients, we propose FAK [inhibition] as a therapeutic candidate for further clinical follow-up”concluded Lorusso and her collaborators.

They suggest that FAK inhibitors are probably the most promising strategy for clinical translation at present, since connexin inhibitors are not yet available for humans and the side effect profile has yet to be determined.

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