Gaucher's Disease and Cancer: A Sphingolipid Perspective

Abstract

Gaucher’s disease is a sphingolipidosis characterized by a specific deficiency in an acidic glucocerebrosidase, which results in aberrant accumulation of glucosylceramide primarily within the lysosome. Gaucher’s disease has been correlated with cases of myeloma, leukemia, glioblastoma, lung cancer, and hepatocellular carcinoma, although the reasons for the correlation are currently being debated. Some suggest that the effects of Gaucher’s disease may be linked to cancer, while others implicate the therapies used to treat Gaucher’s disease. This debate is not entirely surprising, as the speculations linking Gaucher’s disease with cancer fail to address the roles of ceramide and glucosylceramide in cancer biology. In this review, we will discuss, in the context of cancer biology, ceramide metabolism to glucosylceramide, the roles of glucosylceramide in multidrug-resistance, and the role of ceramide as an anticancer lipid. This review should reveal that it is most practical to associate elevated glucosylceramide, which accompanies Gaucher’s disease, with the progression of cancer. Furthermore, this review proposes that the therapies used to treat Gaucher’s disease, which augment ceramide accumulation, are likely not linked to correlations with cancer.

Mechanistic interplay between ceramide and insulin resistance

“…Sphingolipid metabolism is a complex system that takes place in different parts of the cell, from the ER to the cell membrane1835. Regarding the specific compartmentalization of the metabolites, to the best of our knowledge, there is no data available that is suitable for modeling.…”

Fabry disease: Four case reports of meningioma and a review of the literature on other malignancies

“…Ceramide is bound within the chemical structure of the accumulating glycosphingolipid which cannot be metabolized into it individual components to release free ceramide, as occurs in normal cells. Ceramide is a molecule with pro-apoptotic and anti-proliferative properties, and recent reviews examine the role of ceramide as an anti-cancer molecule [24], [25] and the association of elevated glucosylceramide with Gaucher-associated malignancies [26]. Similar links between low ceramide and colon cancer have also been suggested in the setting of Niemann-Pick type B disease [22].…”

Gaucher disease and comorbidities: B‐cell malignancy and parkinsonism

“…One of the byproducts of β‐glucosylsphingosine, sphingosine, can build up as a result and is considered by some to have carcinogenic properties . Although this appears to be an attractive hypothesis, the topic is clearly controversial, as reported in a recent review article . For example, the idea that therapies used in Gaucher disease might induce certain cancers in these patients has been advanced.…”

“…However, this seems highly implausible since there is no evidence that cancer in Gaucher disease was less frequent before the advent of therapy; indeed, in relation to the most commonly associated malignancy, multiple myeloma, this has been found to be a common cause of death in the era before enzyme therapy was introduced. In fact, there are studies suggesting that the prevalence has remained stable, if not decreased, and that most cancer‐afflicted Gaucher patients with the N370S genotype were diagnosed with cancer before treatment for Gaucher disease was started .…”