Murray Korc, MD, an internationally regarded expert in the field of pancreatic cancer and therapy, and a professor in the Department of Experimental and Molecular Medicine and Department of Pharmacology and Toxicology at Dartmouth Medical School, gave a talk regarding his study of pancreatic cancer and explored its relation to Ciliopathy at the weekly Norris Cotton Cancer Center Ground Rounds Lecture.

 

Pancreatic carcinoma is usually fatal, with 43,000 new diagnoses and 38,000 deaths in 2010. Pancreatic cancer’s five-year survival rate of 4 percent is the worst of any known cancer, and its mortality rate has remained roughly the same for the past four decades, with the median time following diagnosis being four to five months. While heredity, diet, and smoking are known to increase risk of pancreatic carcinoma, many unknowns remain, to which Korc stated, “We must have the resolve to move the field forward, prolong survival, and prevent the untimely death of our patients and colleagues.”

 

Korc highlighted hereditary syndromes and genes associated with pancreatic cancer. For instance, Hereditary pancreatitis is caused by a mutation in PRSS1, which is not an oncogene, but causes inflammation that is symptomatic of the disease and may lead to pancreatic cancer. Other genetic mutations found to be associated with pancreatic cancer are familial atypical multiple mole melanoma syndrome (associated with a germline mutation of p16), BRCA2 mutation, and Peutz-Jeghers syndrome.

 

Korc also stated that he was “a strong believer of gene-environmental interactions.” A dramatic increase in rate of pancreatic cancer was observed for certain causative factors, such as smoking, alcohol, hyperlipidemia, hypercalcemia, gallstone disease, and duct strictures.

 

According to Korc, pancreatic cancer poses a problem because “there is no other cancer that has so many [molecular] alterations.” 95 percent of cancers have K-ras mutations, 75 have p53 mutations, 55 percent have Smad4 mutations, 85 percent have p16 mutations, and the other 15 percent are epigenetically silenced. In addition, scientists have observed an overexpression of growth factors and receptors and excessive production of chemokines and cytokines. This stimulates an inflammatory response, motility proliferation of fibroblasts, apoptosis resistance, etc.—all of which pose problems through cancer cell proliferation, immune suppression, extracellular matrix alterations, enhanced angiogenesis, and stimulate fibroblast/stellate cell proliferations, demonstrating multiple pathways and various combinations/alterations to pancreatic cancer. A unified approach to cancer to pancreatic patient, therefore, is inefficient.

 

Korc moved on to the second portion of his lecture by presenting primary (non-motile) cilia, which are present in almost every cell and involved in mechanosensation, chemosensation, and signal transduction that are important for the cell. Loss of normal function often leads to a spectrum of diseases and conditions, such as primary ciliary diskinesia, Polycystic kidney disease, Alstrom syndrome, infertility, cardiac abnormalities, obesity, etc. Researchers observed that pancreatic carcinogen lacked primary cilia, which led Korc and his team to wonder whether primary cilia loss correlated to the formation of pancreatic ductal adenocarcinoma (PDAC). Later, however, Korc noted that acinar and PanIN cells also lacked primary cilia, which prompted the other researchers to hypothesize that pancreatic cancer cells originate from progenitors of acinar cells, to which Korc stated “we don’t know yet.” For closing, Korc emphasized that a great deal of work remains to be done to determine whether PDAC is a ciliopathy, demonstrating a continuous resolve to further scientific knowledge in the face of uncertainties and challenges of pancreatic cancer research.