IPSC is the key to early diagnosis of pancreatic cancer
The first model of human pancreatic cancer progression was created from induced pluripotent stem cells
LifeSciencesToday based on Penn Medicine: Pluripotent Stem Cells Made From Pancreatic Cancer Cells Are The First Human Model of the Cancer's Progression, Penn Study FindsThe prognosis of "pancreatic cancer" is disappointing.
According to the American National Cancer Institute, the five-year relative survival rate of such patients in 2003-2009 was only 6 percent. Scientists and doctors do not even have a non–invasive way to detect early cells - harbingers of further disease progression. There is no PSA-like test for pancreatic cancer, and this is one of the main reasons why this type of cancer is diagnosed fatally late. Therefore, a model of the progression of the disease at its early stage, reproduced on human cells, is so necessary. To obtain a cell line from the cells of a patient with progressive pancreatic duct adenocarcinoma, scientists at the University of Pennsylvania (UPenn) used induced pluripotent stem cells (iPSCs).
This first–of-its-kind cellular model of the progression of human pancreatic cancer is described in an article published in the journal Cell Reports by the laboratory of Professor of Cell Biology and Developmental Biology of the Perelman School of Medicine UPenn Kenneth Zaret, PhD - Jungsun Kim et al., An iPSC Line from Human Pancreatic Ductal Adenocarcinoma Undergoes Early to Invasive Stages of Pancreatic Cancer Progression.
On the left: a scheme for obtaining induced pluripotent stem cells (iPSCs) from pancreatic duct adenocarcinoma cells used to reproduce cancer progression and identify early markers of the disease.
On the right: an invasive stage of a tumor that developed within 9 months in the body of an immunotolerant mouse from human induced pluripotent stem cells derived from pancreatic cancer cells.
(Photo: Kennet Zaret, PhD, Perelman School of Medicine, University of Pennsylvania)."This is the first example of the use of induced pluripotent stem cells (iPSCs) obtained directly from solid tumor cells to simulate the progression of cancer and the first human cell line simulating the progression of pancreatic cancer from its onset to invasive stages," comments Professor Zaret, Deputy Director of the Institute of Regenerative Medicine (Penn Institute for Regenerative Medicine) of the Perelman School of Medicine.
"We were able to predict the appearance of characteristic features of cells and protein markers in the intermediate stages of pancreatic cancer, which do not manifest themselves in the terminal stages. We have received new information about what this deadly type of cancer is, and we have seen something that no one has yet observed on human cells. Our analysis revealed known molecular networks that are activated during the progression of pancreatic duct adenocarcinoma, as well as a new molecular network that is activated at intermediate stages. This will allow us to look at biomarkers of the early stage of the disease in a new way."
Professor Zaret and postdoctoral fellow of his laboratory Jungsun Kim, PhD, suggested that if you reprogram human pancreatic duct adenocarcinoma cells into pluripotent cells, and then differentiate them back into pancreatic tissue, they can go through the early stages of cancer development. Experiments on such pluripotent cells confirmed the researchers' assumption: the cells really repeated the stages of pancreatic cancer development – from early to intermediate. By isolating early-stage cells and growing them in vitro, the scientists identified the proteins secreted by them, which may possibly serve as biomarkers of the early stage of the disease.
In collaboration with John Hoffman, a surgeon at the Fox Chase Cancer Center (FCCC), the scientists applied this method to tumor cells in a total of nine patients. However, as Professor Zaret emphasizes, there are many examples of how just one human cell line has served as an extremely useful model of the disease.
"Our iPS cells demonstrated pluripotency, like other stem cells, but after being introduced into the body of immunodeficient mice, they mainly differentiated into cells of the early stage of pancreatic cancer," Zaret continues. In his opinion, this approach is another example of the use of induced pluripotent stem cells of patients to model diseases based on information about their genome. However, while many laboratories have already obtained similar types of cell lines for neurological and cardiovascular diseases, Zaret's study is the first case of using iPS cells to model solid cancerous tumors.
The visual characteristics of these cancer cells during their progression from early to late stages of the disease coincide with those observed in the cells of cancer patients. At an early stage, abnormal cells expressing specific proteins appear in the ducts of the pancreas. Over time, some of these aberrant cells begin to proliferate rapidly, lose the characteristic features of duct cells and become invasive.
Human iPS cells from pancreatic cancer cells developing in mice secrete proteins corresponding to protein networks expressed during the progression of this cancer in humans, namely, molecules associated with three key proteins – HNF4, integrin and TGF-beta.
"Our proposal is to find out whether biomarkers, which are products of the molecular networks we found, are present in the blood of people with suspected pancreatic cancer or patients with a relatively early stage of this disease," says Professor Zaret.
The approach developed by him allows us to directly study human cells, rather than investigate the features of the progression of pancreatic cancer on his animal model, followed by an assessment of how these data are applicable to humans.
Cancer patients' cells were reprogrammed into stem cells using four factors of Nobel Prize winner Yamanaki delivered in a lentivirus adapted in the laboratory of Zareta.
To understand what happens to the reprogrammed cells at the genetic level, the researchers compared the genome structure of early IPS cells of pancreatic cancer with the tumor cells from which this cell line was isolated. They found 23 chromosomal aberrations in the primary tumor cells compared to 20 of the same chromosomal aberrations in the iPS cancer cell line, which confirmed that the iPS cell line was derived from the cells of the original tumor.
On the other hand, no chromosomal aberrations were observed either in the cells from the cancer-free part of the pancreas of patients, or in the iPS cells obtained from them.
These comparative data allowed the researchers to directly observe the differences between a line of pancreatic cancer cells and a line of normal cells with the same genetic background.
In the field of pancreatic cancer research, a persistent search is underway for unique markers indicating the early stages of the disease, and Professor Zaret and his colleagues hope that their approach will provide a new way to detect early molecular markers of this disease.
"Since in our model it is possible to detect secreted protein markers of at least three different networks characteristic of the early stage of the disease, we believe that the search in the blood for markers indicating the simultaneous activation of these three pathways, instead of one marker, can give a big gain in diagnosis. In addition, our new model can be used to test drugs that block the intermediate stages of the disease," the scientist concludes.
Portal "Eternal youth" http://vechnayamolodost.ru24.06.2013