Are Glucosylceramide-Related Sphingolipids Involved in the Increased Risk for Cancer in Gaucher Disease Patients? Review and Hypotheses

Abstract

The roles of ceramide and its catabolites, i.e., sphingosine and sphingosine 1-phosphate, in the development of malignancies and the response to anticancer regimens have been extensively described. Moreover, an abundant literature points to the effects of glucosylceramide synthase, the mammalian enzyme that converts ceramide to β-glucosylceramide, in protecting tumor cells from chemotherapy. Much less is known about the contribution of β-glucosylceramide and its breakdown products in cancer progression. In this chapter, we first review published and personal clinical observations that report on the increased risk of developing cancers in patients affected with Gaucher disease, an inborn disorder characterized by defective lysosomal degradation of β-glucosylceramide. The previously described mechanistic links between lysosomal β-glucosylceramidase, β-glucosylceramide and/or β-glucosylphingosine, and various hallmarks of cancer are reviewed. We further show that melanoma tumor growth is facilitated in a Gaucher disease mouse model. Finally, the potential roles of the β-glucosylceramidase protein and its lipidic substrates and/or downstream products are discussed.

In-Depth Phenotyping for Clinical Stratification of Gaucher Disease

“…Eighty-ve patients had a family history of Parkinson disease and/or dementia. [51] 122 [49] 13 [50] 13 [50] 115 [51] 109 [49] 120 [54] 103 [46] 8 [30] 19 [ [15] 67 [27] 34 [14] 36 [14] 9 [4] 6 [2] 15 [6] 32 [13] 13 [5] 1 [< 1]…”

The Lipoprotein Transport System in the Pathogenesis of Multiple Myeloma: Advances and Challenges

“…What is impressive is that abnormal glucosphingolipids have more recently been implicated in the origin of MM even outside the setting of Gaucher disease ( 93 ). Most importantly, the oncogenic potential of glucosphingolipids appears not to be restricted in MM but to be extended to melanoma and other cancers ( 92 , 94 ). Finally, and most interestingly, substrate debulking in Gaucher disease, achieved with the administration of Enzyme Replacement Therapy (ERT), appears to be capable to attenuate the generation of monoclonal immunoglobulins, implying a potential attenuation of cancer signaling in patients, in whom the amount of glucosphingolipids is reduced ( 95 ).…”

New Insights into the Role of Sphingolipid Metabolism in Melanoma

“…These observations suggest the involvement of some genetic determinants of the ceramide metabolism in melanoma predisposition. Interestingly, a defect in glucosylceramidase 1 (GBA1) resulting in Gaucher inborn disorder (GD), owing to a defect in GlcCer hydrolysis into ceramide, is associated with an increased risk of malignancies, including melanoma [ 37 , 38 ]. Indeed, accumulation of GlcCer as well as glucosylsphingosine, which arises from the cleavage of excess GlcCer by AC [ 39 , 40 ], occurs in macrophages and could severely alter the immune and inflammatory responses.…”

“…Indeed, accumulation of GlcCer as well as glucosylsphingosine, which arises from the cleavage of excess GlcCer by AC [ 39 , 40 ], occurs in macrophages and could severely alter the immune and inflammatory responses. This could create a favourable microenvironment to promote melanomagenesis (for review see [ 38 ]).…”