![]() Pharmacological and genetic inhibition of macropinocytosis can inhibit cell line proliferation and xenograft tumor growth, presenting a potential therapeutic target for a subset of tumors 7, 8. Macropinocytosis is a conserved, actin-dependent, endocytic process that results in non-specific bulk internalization of extracellular material, including protein and other macromolecules, into the cell 7, 8, 17. Direct catabolism of albumin by the tumor itself might also contribute to hypoalbuminemia, but the extent to which this occurs in vivo remains controversial due to the lack of reliable methods to trace albumin fate. Decreased albumin levels observed in cancer patients and tumor-bearing animals has been posited to be a result of decreased hepatic synthesis or increased degradation by the liver or other organs such as skeletal muscle 13– 16. ![]() Hypoalbuminemia is observed in many patients with cancer and epidemiological studies suggest that levels of serum albumin prior to therapy can be a predictor of survival 11, 12. However, the source of amino acids contributing to cancer cell proliferation within intact tumors is less well studied.Īlbumin is the most abundant extracellular protein in blood and in tissues, and has been previously shown to be internalized into lysosomes of cells in tumors 9, 10. Some cancer cells can also obtain key amino acids through catabolism of extracellular protein via macropinocytosis to fuel anabolic pathways required for growth 3, 7, 8. Amino acids, particularly glutamine and serine, have been shown to be essential nutrients for many cancer cell lines 5, 6. Altered metabolic processes are involved in the pathogenesis of cancer, but which nutrients support inappropriate cancer cell growth within intact tumors is incompletely understood 2– 4. Mammalian tissues rely on a variety of nutrients to support physiological function 1. These data provide evidence for albumin catabolism by tumors and also suggest a method for testing therapies that take advantage of the propensity of pancreatic cancer cells to scavenge extracellular protein. Local release of a macropinocytosis inhibitor leads to a drastic reduction in amino acids levels in tumor tissue arguing that the direct uptake and catabolism of extracellular protein is necessary to provide amino acids to pancreatic cancer cells in tumors. In addition, we implement a device to deliver large molecules directly into the tumor and observe protein catabolism and macropinocytosis by cancer cells within pancreatic tumors. We demonstrate that albumin-derived peptides and amino acids accumulate in tumors in a Kras-driven mouse model of pancreatic ductal adenocarcinoma. We provide direct evidence that extracellular protein is a fuel source for pancreatic cancer cells in vivo. Protein scavenging by macropinocytosis can serve as a source of nutrients for pancreatic cancer cells.
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