Cancer Alters the Metabolic Fingerprint of Extracellular Vesicles

Abstract

Cancer alters cell metabolism. How these changes are manifested in the metabolite cargo of cancer-derived extracellular vesicles (EVs) remains poorly understood. To explore these changes, EVs from prostate, cutaneous T-cell lymphoma (CTCL), colon cancer cell lines, and control EVs from their noncancerous counterparts were isolated by differential ultracentrifugation and analyzed by nanoparticle tracking analysis (NTA), electron microscopy (EM), Western blotting, and liquid chromatography-mass spectrometry (LC-MS). Although minor differences between the cancerous and non-cancerous cell-derived EVs were observed by NTA and Western blotting, the largest differences were detected in their metabolite cargo. Compared to EVs from noncancerous cells, cancer EVs contained elevated levels of soluble metabolites, e.g., amino acids and B vitamins. Two metabolites, proline and succinate, were elevated in the EV samples of all three cancer types. In addition, folate and creatinine were elevated in the EVs from prostate and CTCL cancer cell lines. In conclusion, we present the first evidence in vitro that the altered metabolism of different cancer cells is reflected in common metabolite changes in their EVs. These results warrant further studies on the significance and usability of this metabolic fingerprint in cancer.

Azoxymethane Alters the Plasma Metabolome to a Greater Extent in Mice Fed a High-Fat Diet Compared to an AIN-93 Diet

“…Epidemiological and experimental data suggest that obesity increases colon cancer risk [ 2 , 3 , 6 , 7 , 8 , 9 ]. Our previous data demonstrate that a HFD promotes colonic ACF formation with increased levels of circulating proinflammatory cytokines in a mouse model [ 7 ].…”

“…We therefore posit that determining plasma metabolomic responses may lead to a greater understanding of the metabolic regulation concerning a HFD and colonic ACF formation. As small-molecule metabolites exhibit an organisms’ physiological condition at a given moment, these metabolites represent a dynamic situation in response to biochemical and pathological changes [ 8 , 9 ]. Thus, untargeted metabolite profiling (e.g., metabolomics) is an effective approach that aids in determining these underlying biochemical changes [ 10 ].…”

The role of the metabolite cargo of extracellular vesicles in tumor progression

“…Onecarbon units are required for nucleotide synthesis, methylation, and reductive metabolism, all of which contribute to the rapid proliferation of cancer cells. Also in cell line-derived EVs from PCa and CTLC, Palviainen et al have detected elevated levels of creatinine [48].…”

“…Succinate, together with the three other oncometabolites, is a small molecule that accumulates in cancer cells as a result of gain-of-function or loss-of-function mutations in genes encoding energy metabolism enzymes. Elevated levels of succinate were measured in EVs from prostate, CTCL, and CC cell lines (PC-3, Mac-2A, RKO) compared to their respective control EVs (PNT2, PBMC, CCD841) [48]. In addition, succinate promotes tumorigenesis through a number of ways, such as generating epigenetic modifications and increasing cancer cell angiogenesis, invasion, and migration [104,105].…”

“…Numerous studies have reported the increased expression of AAs or their derivatives in tumors, but so far, no clear consensus on a shared set of AAs across various malignancies has been achieved. Palviainen and colleagues observed that proline was upregulated in all EVs derived from prostate cancer (PCa), cutaneous T-cell lymphoma (CTCL), and colon cancer (CC) cell lines (PC3, Mac-2A, RKO) when compared to their respective controls [ 48 ]. Proline is a unique AA that plays a key function not only in protein biosynthesis but also in cancer metabolism as a regulatory AA.…”