Reversing cancer cry | EurekAlert! Science News

In new findings published online March 18, 2021 in the journal Cancer cell, an international team of researchers, led by scientists at the University of California San Diego School of Medicine and the Moores Cancer Center, describes how pancreatic cancer cells use another way to find essential nutrients , goes against conventional therapies, to help them grow and spread.

Pancreatic cancer accounts for about 3 percent of all cancers in the United States, but it is among the most invasive and fatal, resulting in 7 percent of cancer deaths each year. Pancreatic cancer is particularly deadly once it metastasizes, with the number of people surviving five years later declining from 37 percent to just 3 percent.

All cancer cells need a constant supply of nutrients. Some cancers accomplish this by creating their own viral networks to draw nutrients from the guest’s blood supply. But other cancers, especially pancreatic ductal adenocarcinoma, are surrounded by a thick layer of connective tissue and extracellular molecules (the so-called tumor stroma) that function not only as a kind of dividing line between malignant cells and normal host cigarettes, but also as a barrier to cancer cells having adequate resources, including blood supply.

As a result, pancreatic and other malignant cancers use nutritional modalities to avoid starvation death, a particularly high risk in fast-growing tumors. One such way is autophagy or self-eating. Autophagy allows nutrient-weighted cancers to digest intracellular proteins, especially degraded or damaged proteins, and use the free amino acid building blocks as an energy source to fuel their metabolism.

Previous research showing that autophagy has increased in pancreatic cancer led to the idea that self-consumption may be inhibited by the use of hunger. However, several clinical trials using fertilizers that prevent autophagic protein contamination in combination with traditional chemotherapy have not yielded any therapeutic benefit other than chemotherapy alone, said Michael Karin, PhD, Distinguished Professor Pharmacology and Pathology at UC San Diego School of Medicine.

In the new study, Hua Su, PhD, a postdoctoral fellow in Karin’s laboratory and first author of the study, and colleagues examined why pancreatic cancers survive autophagy and, indeed, it seems that they thrive. They found that inhibition of autophagy led to a rapid or increased activity of a different nutrient supply pathway known as macropinocytosis, which came from the Greek for “heavy drinking or gulping.”

Macropinocytosis enables cancer cells affected by autophagy and nutritional stress to take up exogenous proteins (found outside the cell), digest them and use the amino acid for energy generation. “This explains why autophagy defenders don’t suffer from pancreatic starvation and can’t recover,” Su said. “Once autophagy is prevented, cancer cells simply use different equipment to feed themselves.”

In experiments using mouse cancer models and human pancreatic cancers grown in mice, Su and colleagues found that a combination of autophagy and macropinocytosis inhibitors resulted in rapid and almost complete tumor recurrence. .

“These results provide another example of the plastic nature of pancreatic cancer metabolism,” said lead author Karin. “It also shows that blocking the two main pathways of nutrient supply can block energy supply that leads to tumor starvation and consequent reduction.”

Study co-author Andrew Lowy, MD, head of the Department of Surgical Oncology at Moores Cancer Center at UC San Diego Health and a professor of surgery at UC San Diego School of Medicine, said the new data shows the promise of focus on tumor metabolism as a treatment strategy and success may need to bring together several agents for several targets.

“I believe these decisions are encouraging and support the view that we will soon make a significant impact against this difficult disease,” Lowy said.

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Co-authors include: Fei Yang, Rao Fu, Xiaohong Pu and Beicheng Sun, Nanjing University School of Medicine; Xin Li and Yinling Hu, National Cancer Institute; Randall French, Evangeline Mose, Brittney Trinh, Junlai Liu, Laura Antonucci, Yuan Liu, Avi Kumar and Christian M. Metallo, UC San Diego; Jelena Todoric, UC San Diego and Vienna Medical University; Maria Diaz-Meco and Jorge Moscat, Weill Cornell Medicine.