Exploring the Role of Metabolites in Cancer and the Associated Nerve Crosstalk

Abstract

Since Otto Warburg's first report on the increased uptake of glucose and lactate release by cancer cells, dysregulated metabolism has been acknowledged as a hallmark of cancer that promotes proliferation and metastasis. Over the last century, studies have shown that cancer metabolism is complex, and by-products of glucose and glutamine catabolism induce a cascade of both pro- and antitumorigenic processes. Some vitamins, which have traditionally been praised for preventing and inhibiting the proliferation of cancer cells, have also been proven to cause cancer progression in a dose-dependent manner. Importantly, recent findings have shown that the nervous system is a key player in tumor growth and metastasis via perineural invasion and tumor innervation. However, the link between cancer-nerve crosstalk and tumor metabolism remains unclear. Here, we discuss the roles of relatively underappreciated metabolites in cancer-nerve crosstalk, including lactate, vitamins, and amino acids, and propose the investigation of nutrients in cancer-nerve crosstalk based on their tumorigenicity and neuroregulatory capabilities. Continued research into the metabolic regulation of cancer-nerve crosstalk will provide a more comprehensive understanding of tumor mechanisms and may lead to the identification of potential targets for future cancer therapies.

Keywords: amino acid metabolism; cancer; cancer–nerve crosstalk; lactate; metabolites; perineural invasion; tumor innervation; vitamins.

Figure 1

Complex mechanisms induced by glucose, glutamine, and lactate uptake encompass the metabolism of tumor cells. 3-PG: 3-phosphoglycerate, 3-PH: 3-phosphohydroxypyruvate, ASL: arginosuccinate lyase, ASNS: asparagine synthetase, ASS: arginosuccinate synthase, αKG: alpha-ketoglutarate, GDH: glutamine dehydrogenase, GS: glutamine synthetase, LDH: lactate dehydrogenase, MCT1/4: monocarboxylate transporter 1/4, NOS: nitric oxide synthase, PDH: pyruvate dehydrogenase, PHGDH: phosphoglycerate dehydrogenase, PSAT: phosphoserine aminotransferase, PSPH: phosphoserine phosphatase, ROS: reactive oxygen species, SHMT: serine hydroxymethyltransferase, TXNRD1: thioredoxin reductase 1.

Figure 2

Metabolism-related cancer–nerve crosstalk. (A) Vitamin C transporter SLC2A3 is shown via immunohistochemistry to be upregulated in colorectal cancer patients with perineural invasion (PNI) [206]. mRNA (B) and immunohistochemistry (C) analyses found that asparagine synthetase (ASNS) is upregulated in PNI-positive oral squamous-cell carcinoma patients. Dotted circles represent nerve trunks, and stars indicate the tumor region [28]. (D) Lactate importer MCT1 is colocalized with Sox2- and KLF-positive (cell-proliferation markers) in cases of PNI in pancreatic adenocarcinoma [205]. Scale is 50 μm. Figures are modified from Gao et al., Fu et al., and Sandforth et al., respectively. Figure rights for reuse are available via the Creative Commons Attribution (CC BY) License.