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Collaborative Research: Discovery of Survival Mechanism for Pancreatic Cancer May Improve Treatment

Publication Date: 4/2/2019

Research conducted by scientists from Israel and the US shows how cancer cells, considered among the most lethal of human cancers, undergo a kind of metabolic "reprogramming" for their survival. This discovery will contribute to research into more effective treatment of pancreatic cancer.

Professor Gil in his laboratory. Photography: Miki and Gal Koren.Professor Gil in his laboratory. Photography: Miki and Gal Koren.

Researchers at Rambam Health Care Campus, the Technion–Israel Institute of Technology, and the University of California have uncovered a critical defense mechanism for pancreatic cancer cells, which provides them with protection from the lack of oxygen and nutrients. This discovery could help treat one of deadliest of cancers. A recently published study (February, 2019) in the prestigious scientific journal, Nature Communications, demonstrated how pancreatic cancer cells actively “reprogram” to enable their development and survival in both humans and in mice.

“Over the past 40 years, medicine only succeeded to improve the survival rate of pancreatic cancer patients by one percent,” says Professor Ziv Gil, director of Rambam’s Department of Otolaryngology, Head and Neck Surgery, and head of the Laboratory for Applied Cancer Research in the Technion’s Faculty of Medicine. Professor Gil led the study, in collaboration with Professor Mei Kong of the University of California’s School of Biological Sciences. He explains, “Currently, all we can offer pancreatic cancer patients is tumor resection for early stage disease, and chemotherapy in the advanced stages. Pancreatic cancer does not respond to more innovative treatments such as immuno-oncologic drugs. There is much research being done, but to date, there have been no breakthroughs for these patients.”

More about Pancreatic Cancer

Pancreatic cancer is the fourth leading cause of cancer deaths in the Western world. The survival rate among patients within the five years after diagnosis is around eight percent. In Israel, some 500 patients are diagnosed annually and it is the third leading cause of cancer-related death in Israel.

Pancreatic cancer is complex for a number of reasons: An internal organ, the pancreas is difficult to monitor in routine examinations, making early detection of the cancer, critical for treatment, nearly impossible. In addition, the cellular composition of pancreatic tumors makes treatment difficult. Professor Gil explained that pancreatic cancer is characterized by significant involvement of supporting cells that make up most of the tumor. They develop into a dense mass that presses on the cancer cells and blood vessels, and reduces the amount of oxygen and food available for growth. He added, “This cellular envelope is one of the reasons why chemotherapy does not reach the growth.”

More about the Research

The study dealt with a fundamental question regarding cancerous tumors: How do they develop in a hostile environment, when the body is attempting to isolate them and reduce their sources of energy, and survive?

The researchers tried to track alternative metabolic pathways of cancer tumors. This question relates to the biological mechanism that allows the existence of cancer cells and tumors in general. Although this mechanism exists in many types of tumors, Professor Gil explained that the research team believed that pancreatic cancer was best suited for the study, due to the environment in which it grows.

“This is an environment characterized by a particularly high level of stress for the cells,” he said. “The body itself tries to fight: it isolates the growth environment, creates a capsule environment, and affects the growth environment. The capsule reduces available essential amino acids, and generally limits the ability of nutrients to reach the cancer cells. The cancerous cells abandon the glycolysis pathway, which is the standard metabolic pathway for providing energy to the body's cells.”

However, despite the sophisticated efforts of the body and the depletion of the living environment of the tumors, pancreatic tumors are able to survive and develop. Professor Gil and his colleagues found that the resistance of pancreatic cancer stems, among other things, from the ability of tumor cells to find new ways to supply energy by what they call "reprogramming" of their metabolic pathways, that is, metabolism and energy production in the cell.

The researchers found that the lack of nutrients – especially essential amino acids – causes pancreatic cancer cells to produce microRNAs that suppress production of oxygen-dependent energy (aerobic glycolysis) in the production of energy without oxygen (anaerobic glycolysis). This, in turn, reduces their dependence on essential amino acids and oxygen. “In the study, we discovered an unknown pathway, in fact a bypass route where cancer cells respond to a lack of nutrients and oxygen by converting the usual energetic pathways into alternative pathways that allow them to continue to thrive.” Professor Gil concluded by explaining the direct application of their research. “Based on our research, more effective treatments based on a combination of chemotherapy and microRNAs could be developed.”