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The Hyenas in our Bodies: How Scavenging Allows Cancer Cells to Thrive in Nutrient-Poor Conditions
Department of Biology
Lake Forest College
Lake Forest, Illinois 60045
Cancer cells have a high demand for nutrients. Vasculature proximal to tumours is generally leaky and tortuous, leading to ineffective inflow of nutrients to the tumour.. A process called desmoplasia, where interstitial pressure is increased due to the deposition of extracellular matrix (ECM) proteins by stromal cells, further decreases vascular perfusion. Yet, cancer cells have upregulated expression of several nutrient transporters, particularly in the later stages of the disease, and can still obtain the nutrients they need to support their unusually high proliferation rates.
Recently, several studies have shown that cells across several types of cancer are able to effectively scavenge nutrients from the tumour microenvironment (TME) for re-use within the cell. In fact, desmoplasia increases the richness of the extracellular environment, leading to larger potential for scavenging. The cell uses integrins to interact with ECM proteins such as laminin, vitronectin, collagen and albumin, which are then internalized via receptor-mediated endocytosis and directed to the lysosome for degradation. Albumin is especially important, as it binds hydrophobic nutrients and signalling molecules in the blood, allowing them to be transported through aqueous environments. The leakiness of tumour blood vessels, coupled with insufficient lymphatic drainage, leads to a build-up of albumin in the tumour microenvironment. The albumin and the nutrients bound to it are then scavenged by the cell through receptor-mediated scavenging and macropinocytosis.
Macropinocytosis is a non-selective form of endocytosis through which cells obtain extracellular fluid and nutrients through the formation, and intake, of large uncoated vesicles. Activating mutations in HRAS, NRAS, KRAS or SRC kinases result in constitutive macropinocytosis, although the amount of macropinocytosis is dependent upon cell types, pointing to a possible epigenetic regulation of macropinocytosis. Amongst other things, cancer cells macropinocytose dead cell debris. Studies using isotopically labelled necrotic cell debris showed that in lower protein conditions, macropinocytosed necrotic cell proteins made up 35-71% of the amino acids for protein synthesis in cancer cells. Tumour cells can also consume their intact, living neighbours in a process known as entosis. Entosis has been observed in breast cancers, melanomas, lung, cervical, colon and stomach cancers. Following entosis, the vesicle-enclosed whole ingested cell can be released, but it is often fused with a lysosome, resulting in degradation and recycling of the cannibalized cell’s components.
Nutrient scavenging by tumour cells can be targeted through the disruption of a number of pathways. Several small macropinocytic inhibitors exist, the most notable ones being class I PI3K inhibitors. Because PI3Ks are needed for macropinosomes to be able to form, PI3K inhibitors can be used even in cancers that do not result from a PI3K mutation. P21-activated kinase (PAK) inhibitors are effective against a variety of cancers, and their activity may be related to their effects of macropinocytosis. Therapeutics that affect integrin-mediated scavenging typically limit ligand binding. Unfortunately, the receptors responsible for albumin scavenging are unknown and hence cannot be targeted therapeutically at the moment.
Tumour cells are incredibly versatile and quickly adapt to the loss of an individual pathway. In heterogenous tumours, this can occur through an increased proliferation in pre-existing resistant clones. In homogenous tumours, this is typically a result of an upregulation in compensatory pathways that eliminate the dependence of the cell on the lost pathway or molecule. Therefore, the inhibition of several pathways at once through a combination of therapies is the approach that will most likely result in starvation of cancer cells.
Finicle, B. T., Jayashankar, V., & Edinger, A. L. (2018). Nutrient scavenging in cancer. Nature Reviews Cancer, 1.
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