Stop cannibalism
An international team of researchers, led by scientists from the University of California, San Diego School of Medicine and the Moore Cancer Center, has described an alternative way to feed pancreatic cancer cells, which is used to survive despite chemotherapy.
Pancreatic cancer accounts for approximately 3% of all cancers in the United States and is one of the most aggressive tumors with a five-year survival rate of less than 5% in case of metastasis.
All cancer cells need a constant supply of nutrients. Some of the malignant tumors create their own vascular networks to take nutrients from the host's blood supply. Other cancers, including pancreatic adenocarcinoma, are surrounded by a thick layer of tumor stroma – connective tissue and extracellular molecules that act not only as a kind of dividing line between malignant cells and normal host tissues, but also as a barrier for cancer cells to obtain resources for active growth.
As a result, in pancreatic cancer and other tumors subject to alimentary stress, cancer cells use a number of adaptive mechanisms to avoid death from starvation, and this risk is especially high in fast-growing tumors. One of these mechanisms is autophagy. It allows cancer cells to digest intracellular proteins, especially denatured or damaged ones, and use the resulting amino acids as an energy source for nutrition and metabolism.
Data on autophagy in pancreatic cancer gave researchers the idea that the suppression of this process can be used to stop feeding cancer cells. However, numerous clinical studies using compounds that inhibit autophagic protein breakdown, combined with traditional chemotherapy, have not yielded any additional effect compared to chemotherapy alone.
In a new study, Hua Su and his colleagues studied why pancreatic cancer survives therapy that inhibits autophagy. They found that inhibition of autophagy leads to an increase in the activity of another pathway for obtaining nutrients – macropinocytosis (from the Greek "big swallowing").
Macropinocytosis allows cancer cells deprived of autophagy to absorb exogenous proteins outside the cell, digest them and use amino acids for energy production. This explains why autophagy inhibitors are ineffective in pancreatic cancer.
In experiments using mouse models of human pancreatic cancer, Su and colleagues found that a combination of autophagy inhibitors and macropinocytosis inhibitors leads to rapid and almost complete tumor regression.
These results prove the plasticity of pancreatic cancer metabolism and demonstrate the effectiveness of tactics of joint inhibition of the two main ways of obtaining nutrients for the treatment of tumors.
Article H.Su et al. Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis is published in the journal Cancer Cell.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on UC San Diego: Reversing Cancer's Gluttony.