Defective Cell Extrusion May Lead to Formation of Tumors in Pancreas, Lungs, or Colon

The disruption of normal S1P2 (sphingosine-1-phosphate receptor 2) receptor activity in epithelial cells prevents the pro-apoptotic extrusion of cells from overcrowded tissue and leads to the formation of cancerous growths in the pancreas, lung, and colon.

When epithelial tissues become too crowded, some cells are extruded that later die. To extrude, a cell produces the lipid, sphingosine 1-phosphate (S1P), which activates S1P2 receptors in neighboring cells that seamlessly squeeze the cell out of the epithelium. Tumors or epithelia lacking S1P2 cannot extrude cells in the normal fashion, which can contribute to carcinogenesis and tumor progression.

Investigators at the University of Utah (Salt Lake City, USA) studied the extrusion process in a zebrafish model system. They reported in the January 26, 2015, online edition of the journal eLife that when S1P2 signaling was disrupted, cells built up and formed masses that resisted apoptosis—even when it was triggered by chemotherapy—or they slipped into underlying tissues where they could potentially begin to grow. Furthermore, some cells died without being extruded, creating poor barrier function in the epithelium, which could cause chronic inflammation.

Inducing S1P2 expression was found to be sufficient to restore extrusion and cell death and reduced pancreatic tumors and their metastases. An inhibitor of the enzyme FAK (focal adhesion kinase) was found to enable cells to bypass extrusion defects and could, therefore, target pancreatic, lung, and colon tumors that lacked S1P2 without affecting normal tissues.

"This kind of altered extrusion may be a common hallmark of invasive tumor types," said senior author Dr. Jody Rosenblatt, associate professor of oncological sciences at the University of Utah. "While the mechanisms that drive tumor cell invasion are not yet clear, the results suggest that S1P2-mediated extrusion may play an important role in metastatic cell invasion. Some FAK inhibitors are already being tested in clinical trials for other types of cancers. Hopefully, they may also be a better therapy for recalcitrant tumors such as pancreas cancers and some lung cancers."

Related Links:
University of Utah