Lung cancer, illustration

A recent discovery by researchers at the University of Arizona Medical School – Phoenix has shown that nanoparticle delivery of frizzled-4 (FZD4) to lung endothelial cells slows lung cancer progression and metastases.

“We have identified the novel protein FOXF1 that stabilizes blood vessels inside the lung tumors, decreases intertumoral hypoxia and prevents lung cancer metastases,” said Tanya Kalin, MD, PhD, professor of Child Health and Internal Medicine at the University of Arizona College of Medicine – Phoenix.

Research from Kalin’s lab have shown the that use of FOXF1—or FZD4 activating—therapies can enhance the delivery of chemotherapies or immune checkpoint inhibitors for lung cancer treatments. To search for more therapeutic approaches to treat non-small cell lung cancer(NSCLC)—which have a low, 20 percent five-year survival rate when found in advanced stages—Kalin’s team developed a nanoparticle to deliver FZD4 to the pulmonary endothelium. In preclinical models of lung cancer the team showed this method decreased tumor growth and metastasis.

“Since targeting the FOXF1/FZD4 signaling using gene therapy had efficiently decreased lung cancer progression and normalized tumor blood vessels, our next step will be to develop pharmacological approach to activate this signaling pathway and to move this therapy into clinical trials,” Kalin said.

In the current study, published in the journal EMBO Molecular Medicine, the investigators showed that FOXF1 is expressed in normal lung endothelial cells, but is decreased in the tumor associated vasculature in lung cancers. Tapping data from the Cancer Genome Atlas, their analysis found that higher FOXF1 mRNA expression was associated with higher survival rates compared with those people whose cancers had lower FOXF1 levels.

Using this information, the researchers used gene editing techniques to knock out the FOXF1 gene from endothelial cells, which showed impressive results. Models with FOXF1 removed promoted lung tumor growth and metastasis, caused functional and structural abnormalities in tumor vasculature, and led to a lack of FZD4. The FZD4 protein plays a critical role in the Wnt/β-catenin signaling pathway. Wnt regulates various cellular processes such as cell proliferation, differentiation, and migration and is involved in both normal development and disease development, including cancer.

The team then increased FOXF1 gene expression in endothelial cells using a transgenic lung cancer model and found this effectively inhibited lung tumor growth and metastases while also stabilizing tumor-associated blood vessels. An important new finding was that FOXF1 directly activated FZD4, one of the Wnt/β-catenin signaling receptors.

“Our study identifies the novel molecular mechanisms used by lung endothelial cells to regulate tumorigenesis which involves FOXF1/FZD4/WNT signaling. We have demonstrated that maintaining FOXF1/FZD4 signaling in pulmonary endothelial cells via genetic or gene therapy is beneficial to normalize tumor vessels and inhibit lung cancer progression,” the researchers wrote. “Nanoparticle delivery of FZD4 cDNA represents a promising therapeutic strategy to treat NSCLC.”

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