Pharmacologic downregulation of c-FLIP(L) restores juxtacrine death receptor-mediated apoptosis in cancer cells in a peritoneal carcinomatosis model.

Metastasis occurs when circulating cancer cells implant in normal secondary tissues. Paradoxically, many cancer cells express death receptors while many normal tissues express the cognate death receptor ligands, suggesting that cancer cells possess mechanisms to inhibit death receptor signaling. Pharmacological restoration of juxtacrine-mediated death receptor signaling could prevent cancer cells from implanting in normal tissues such as the peritoneum. The results showed that BAY 11-7085 significantly inhibited peritoneal carcinomatosis in mice following the introduction of colon and pancreatic cancer cell lines into the intra-abdominal cavity. Treatment with BAY 11-7085 restored juxtacrine death receptor signaling during the adhesion of the cancer cells to mesothelial cells, which line the peritoneum. BAY 11-7085 rapidly inhibited c-FLIP(L) expression in colon and pancreatic cancer cell lines during adhesion to mesothelial cells. Pancreatic cancer cells sorted for high c-FLIP(L) expression formed peritoneal implants much more readily than cells with low c-FLIP(L) expression, and RNAi inhibition of c-FLIP(L) in colon cancer cells dramatically reduced peritoneal implantation. This is a novel demonstration that the restoration of death receptor-mediated apoptotic signaling in cancer cells through the pharmacological inhibition of c-FLIP(L) can inhibit tumor implantation in a clinically relevant model of peritoneal carcinomatosis, a fatal disease. Pharmacological inhibitors of FLIP hold promise as a way to curtail cancer cell colonization of secondary tissues.

Inherited polyposis syndromes: molecular mechanisms, clinicopathology, and genetic testing.

The inherited polyposis syndromes are a group of conditions in which multiple gastrointestinal polyps occur in the lumen of the gastrointestinal tract, most exhibit an increased risk of colon cancer. Benign and malignant extraintestinal tumors might also be observed. Recent elucidation of the underlying gene mutations has contributed to our understanding of the cell biology and molecular mechanisms associated with gastrointestinal tumorigenesis. Developments have also allowed genetic testing to become an integral component in accurate diagnosis, categorization, and management of inherited polyposis syndromes. In this review, we will focus on familial adenomatous polyposis, mutY human homologue-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis, and Cowden syndrome. It is essential that both physician and patient understand the benefits and limitations of genetic testing before submission of samples to the laboratory. There are many issues accompanying molecular diagnosis of cancer syndromes, and genetic counseling is an essential prelude to genetic testing.