Target FOXC1 in Pancreatic Cancer?

The FOXC1 gene plays a “significant role” in pancreatic cancer growth and metastatic potential, according to preclinical research published in Oncogenesis.

“FOXC1 is a potent oncogenic transcription factor, which promotes pancreatic cancer growth and metastasis,” reported senior study author Rajkumar Lakshmanaswamy, PhD, of the Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center in El Paso, Texas, and colleagues. “FOXC1 increased the metastatic abilities of pancreatic cancer cells by enhancing cell proliferation, migration, invasion, epithelial-to-mesenchymal transition, and angiogenesis.”

Targeted therapies have prolonged patient survival times for many types of cancer, but mortality remains very high for pancreatic ductal adenocarcinoma, an aggressive and metastasis-prone malignancy. Five-year survival rates are a daunting 7%. By 2020, pancreatic cancer is expected to become a leading cause of cancer deaths, the authors noted.

Insulin-like growth factor 1 receptor (IGF-1R) is involved in cancer cell proliferation, metastasis, and treatment resistance, the authors noted. The research team previously found that IGF-1R is overexpressed by pancreatic cancer cell lines and facilitates epithelial-to-mesenchymal transition, and that targeting IGF-1R inhibits pancreatic cancer growth.

However, IGF-1R inhibitors have not yielded benefits in clinical studies. The authors studied interactions between IGF-1R and the IGF-1R signal regulator FOXC1, seeking a more promising target in the IGF-1R pathway, using genetic engineering experiments to manipulate overexpression or silencing of FOXC1 in pancreatic cancer cell lines.

“Our results demonstrate that IGF-1R and FOXC1 seem to positively regulate each other,” the authors reported. “Targeting FOXC1 could be a potential therapeutic strategy against pancreatic cancer.”

Silencing FOXC1 decreased expression of P13K/AKT/mTOR pathway genes, whereas FOXC1 overexpression hastened cancer cell proliferation. FOXC1 also regulates pancreatic cancer cell migration, invasion, and anchorage-independent growth, the research team reported.

“The data from xenograft experiments further established the importance of FOXC1 in pancreatic tumorigenesis,” the team reported.

To validate the in-vitro cell-line findings, the authors xenografted FOXC1-silenced and -overexpressing pancreatic cancers to athymic mice. FOXC1-overexpressing xenograft tumors grew more rapidly.

Previous reports have linked FOXC1 to breast, colon, liver, lung, and prostate cancer, the authors noted.