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Advanced pancreatic cancer is often asymptomatic, resulting in a late diagnosis only after the spread of metastases in the body. In addition, the tumor cells are enclosed in a "protective shield", a microenvironment conferring resistance to many anticancer drugs. Researchers at the Salk Institute and an international team of collaborators have discovered the role of a signaling protein that could be the Achilles heel of pancreatic cancer.
The results, published in Nature on April 17, 2019, show that stellate cells of the pancreas – resident cells that are generally dormant in normal tissues – are activated and secrete proteins to form an envelope around the tumor for the purpose of wallowing and containing it. Activated stellate cells also secrete a signaling protein called LIF, which transmits stimulation signals to tumor cells to stimulate the development and progression of pancreatic cancer. The results also suggest that LIF may be a useful biomarker to help diagnose pancreatic cancer faster and more effectively.
"The treatment of pancreatic cancer has not advanced much as it is difficult to diagnose and treat cancer," says Salk's American Cancer Society professor, Tony Hunter. "Understanding this communication network between cancer cells and stellate cells can enable us to develop more effective therapies, as well as tools for earlier diagnosis."
According to the National Institutes of Health (NIH) project, pancreatic cancer will be the second leading cause of cancer deaths in the United States by 2030. NIH reported last year about 55,000 new cases of pancreatic cancer , with more than 44,000 deaths disease.
"Most solid cancers are not caused by an abnormality in one type of cell.Tumor cells live and work in cooperation with the surrounding normal cells located in the tissue.They can also" spoil "together as a tumor. an impious alliance that can lead to cancer, "said Yu Shi, a postdoctoral researcher at Salk and the journal's first author." If we can understand how different types of cells interact with each other in the microenvironment of the tumor, we can then find a good target to eventually cure the disease. "
To understand the method of communication between stellate cells of the pancreas and cancer cells, researchers first developed cell cultures to badyze proteins exported from stellate cells. They suspected that the stellate cells were communicating with the tumor cells with the help of specific signaling proteins, but until now they did not know which ones.
"We wanted to know what kind of signaling was activated in pancreatic cancer tumor cells," said Shi. "LIF is an important factor that normally helps stem cells maintain their developmental potential during the embryonic period, but it usually disappears in adulthood.We have found that activated stellate cells secrete LIF, which acts on neighboring cancer cells. "
After identifying the LIF as the essential communicator, researchers wanted to better understand the function of LIF during pancreatic cancer progression to evaluate the protein as a potential therapeutic target. By observing the effects on tumor growth of LIF blockade or destruction (both of which render the protein non-functional) in a mouse model of pancreatic cancer, researchers could examine how LIF affects tumor progression and response. treatment. Both techniques independently showed that, without a functional LIF signal, tumor progression was slowed down and responses to chemotherapeutic drugs used in the treatment of human cancer (such as gemcitabine) were improved.
"Previous studies have shown that if you kill the stellate cells of the pancreas, the tumors get worse," said Hunter, Renato Dulbecco's Salk Chair. "This means that you do not want to destroy the stellate cells of the pancreas that secrete signaling factors, but rather to prevent them from transmitting the stimulation signals to the tumor cells."
In addition to verifying the consequences of LIF blockade in mice, the researchers also examined the levels of LIF in the tumor tissues and blood of patients with human pancreatic cancer. They found high levels of LIF in the tumors and blood of the patients. They also found a significant correlation between LIF levels, tumor progression, and the patient's response to chemotherapy. These early results suggest that LIF is promising as a biomarker of pancreatic cancer stage and response to treatment.
"We were pleased to see that high LIF levels were significantly correlated with tumor cell status and response to chemotherapy," Shi added. "These findings are consistent in the mouse model and human pancreatic cancer."
Currently, the only FDA-approved biomarker for pancreatic cancer is a carbohydrate called CA19-9. This study found that LIF was an accurate and independent measure of pancreatic cancer and was a better indicator of the therapeutic response than CA19-9.
"One possibility would be to use a combination of both biomarkers to get a better picture of the status and response of the disease," Hunter said. "We also believe that anti-LIF antibody treatment may be useful, in combination with other therapeutic agents, to treat pancreatic cancer.This is a highly translatable research and it is nice to work on a project that can have a direct impact on a deadly human cancer. "
Based in part on Hunter's discovery of the role of LIF in pancreatic cancer, Northern Biologics, a Canadian company, has launched a Phase 1 clinical trial to test the effect of a treatment with a monoclonal (synthetic) antibody binding to the LIF of signaling in advanced pancreatic cancer and others. The results of this test are expected with great interest, according to Hunter.
Weina Gao, Peiwu Huang, Xiao Yuan and Ruijun Tian of the Southern University of Science and Technology also participated in the study. Nikki K. Lytle, Andrew M. Lowy and Tannishtha Reya from the School of Medicine at the University of California San Diego; Miriam Scadeng from the University of California at San Diego; Amanda M. Dann and Timothy R. Donahue of the David Geffen School of Medicine at the University of California at Los Angeles; Maya Ridinger, Kathleen E. DelGiorno, Corina E. Antal, Gaoyang Liang, Annette R. Atkins, Galina Erikson, Huaiyu Sun, Jill Meisenhelder, Elena Terenziani, Gyunghwi Woo, Linjing Fang, Thom Santisakultarm, Uri Manor, Mathias Leblanc, Michael Downes, Ronald M. Evans, and Geoffrey M. Wahl of Salk; Ruilian Xu of the Shenzhen People's Hospital; Carlos R. Becerra of the Texas Oncology-Baylor University Medical Center; Erkut Borazanci and Daniel D. Von Hoff of the Translational Genomics Research Institute and HonorHealth; Paul M. Grandgenett and Michael A. Hollingsworth of the Eppley Institute for Cancer Research and Related Diseases of the University of Nebraska Medical Center; Sarah E. Umetsu and Eric A. Collisson from the University of California at San Francisco; and Tony Pawson, of the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, and the Molecular Genetics Department of the University of Toronto.
The work was funded by grants from the Chinese Ministry of Science and Technology (2016YFA0501403), the National Natural Science Foundation of China (21575057), NIH grants (CA014195, CA082683, CA080100, CA178015, CA227807, CA227267, CA197699, CA197699, CA187643, P50CA127297, U01CA210240, P30CA36727 and 5R50CA211462), the Lustgarten Foundation Scholarship (388246 and 552873), the Leona M. Grant and the Harry B. Helmsley Charitable Grant (2012-PG-MED002), the Grant William Isacoff Research Group for Gastrointestinal Surgery, Dream Team Standing Cancer Research Grant (SU2C-AACR-DT-05-09 and SU2C-AACR-DT-20-16), NRSA F31 Research Fellowship (CA206416) and T32 GM007752, Flinn Foundation, Howard Hughes Medical Institute, Ipsen / Biomeasure and Freeberg Foundation, William Isacoff Foundation for Gastrointestinal Cancer Research, Jeanne Shelby Fund Foundation for Cancer Research in Texas and Charity Trust Leon to Mr. and Harry B. Helmsley.
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