Pancreatic cancer cells use multiple mechanisms to avoid starvation, suggesting a new target for treating a very difficult and deadly disease, researchers at UC San Diego School of Medicine and Moores Cancer Center revealed in a report published Thursday.
In findings published online in the journal Cancer Cell, an international team of researchers, led by scientists at UCSD, describe how pancreatic cancer cells use an alternative method to find necessary nutrients, defying current therapies, to help them grow and spread.
Pancreatic cancer accounts for roughly 3% of all cancers in the United States, but it is among the most aggressive and deadly, resulting in 7% of all cancer deaths annually. Pancreatic cancer is especially deadly once it metastasizes, with the number of people who are alive five years later declining from 37% to just 3% once that occurs.
All cancer cells require a constant supply of nutrients. Some types of cancer achieve this by creating their own vascular networks to pull in nutrients from the host’s blood supply. But other cancers are surrounded by a thick layer of connective tissue and extracellular molecules acting not just as a sort of dividing line between malignant cells and normal host tissues, but also as a hindrance to cancer cells obtaining sufficient resources, including blood supply.
As a result, pancreatic and other nutritionally stressed cancers employ a number of adaptive mechanisms to avoid death by starvation — a risk particularly high in rapidly growing tumors. One such mechanism is autophagy or self-eating. Autophagy allows nutritionally stressed cancers to digest intracellular proteins, especially denatured or damaged proteins, and use the liberated amino acid building blocks as an energy source to fuel their metabolism.
Past research indicating autophagy is elevated in pancreatic cancer gave rise to the idea that inhibiting self-eating might be used to starve tumors. Yet, multiple clinical trials using compounds that inhibit autophagic protein degradation combined with traditional chemotherapy, did not produce any added therapeutic benefit compared to chemotherapy alone, said Michael Karin, professor of pharmacology and pathology at UCSD School of Medicine.
Hua Su, a postdoctoral fellow in Karin’s lab and first author of the study, investigated why pancreatic cancers survive autophagy and even appear to thrive. Inhibition of autophagy was found to result in increased activity of a different nutrient procurement pathway called macropinocytosis, derived from the Greek for “large drinking or gulping.”
Macropinocytosis enables nutritionally stressed cancer cells to take up proteins found outside the cell, digest them and use their amino acids for energy generation.
“This explains why autophagy inhibitors fail to starve pancreatic cancer and cannot induce its regression,” Su said. “Once autophagy is inhibited, cancer cells simply resort to a different mechanism 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 micropinocytosis inhibitors resulted in rapid and nearly complete tumor regression.
Study co-author Dr. Andrew Lowy, chief of the Division of Surgical Oncology at Moores Cancer Center and a professor of surgery at UCSD School of Medicine, said the new data demonstrate the promise of targeting tumor metabolism as a treatment strategy and that success will likely require combining multiple agents for multiple targets.
–City News Service