The hidden life of NAD+-consuming ectoenzymes in the endocrine system

Ectoenzymes are a family of cell surface molecules whose catalytic domain lies in the extracellular region. A subset of this family, nucleotide-metabolizing ectoenzymes, are key components in the regulation of the extracellular balance between nucleotides (e.g., NAD+ or ATP) and nucleosides (e.g., adenosine). Their substrates and products are signalling molecules that act by binding to specific receptors, triggering signals that regulate a variety of functions, ranging from the migration of immune cells, to synaptic transmission in the brain, to hormone/receptor interactions in the glands. Almost two decades of accumulated data indicate that these regulatory processes significantly affect the endocrine system, a tightly controlled information signal complex with clear evidence of fine regulation. Functional models discussed in this review include insulin secretion, bone modelling and the association between hormones and behaviour. The emerging pattern is one of a system operating as a scale-free network that hinges around hubs of key molecules, such as NAD+ or ATP. The underlying natural link between nucleotides, ectoenzymes and the endocrine system is far from being clearly demonstrated. However, the body of evidence supporting the existence of such connection is growing exponentially. This review will try to read the available evidence in a hypothesis-oriented perspective, starting from the description of NAD+ and of ecto- and endoenzymes involved in its metabolism

CD38 and bone marrow microenvironment.

This review summarizes the events ruled by CD38 shaping the bone marrow environment, recapitulating old and new aspects derived from the body of knowledge on the molecule. The disease models considered were myeloma and chronic lymphocytic leukemia (CLL). CD38 has been analyzed considering its twin function as receptor and enzyme, roles usually not considered in clinics, where it is used as a routine marker. Another aspect pertaining basic science concerns the role of the molecule as a member of an ectoenzyme network, potentially metabolizing soluble factors not yet analyzed (e.g., NAD+, ATP, NAM) or influencing hormone secretion (e.g., oxytocin). The last point is focused on the use of CD38 as a target of an antibody-mediated therapeutic approach in myeloma and CLL. A recent observation is that CD38 may run an escape circuit leading to the production of adenosine. The generation of local anergy may be blocked by using anti-CD38 antibodies. Consequently, not only might CD38 be a prime target for mAb-mediated therapy, but its functional block may contribute to general improvement in cancer immunotherapy and outcomes