CD38 Inhibition Decreases Melanoma Expansion and Ameliorates Metastatic Burden

Melanoma has the highest propensity to metastasize to the brain and in many reports is the third most frequent cause of metastatic brain tumors.

The tumor microenvironment contains different types of cells including cancer-associated fibroblasts (CAFs). Numerous studies showed that CAFs support the growth and angiogenesis of various types of cancers including melanoma. CD38 is a multifunctional ectoenzyme that uses NAD⁺ as a substrate to generate second messengers. We have recently shown that targeting CD38 in the tumor microenvironment may serve as a novel approach to treat glioma.

Using the syngeneic B16-F10 model of melanoma progression in wild-type and CD38 null mice, we show that CD38 deficiency or treatment with the novel CD38 inhibitor K-rhein, which was identified by us, significantly attenuates melanoma expansion both subcutaneous and in the brain, and prolonged the survival of melanoma bearing mice. This reduction in tumor growth was associated with decreased necrotic area and angiogenesis in Cd38^-/- tumors. CD38 deficiency inhibited also primary tumor volume and pulmonary and brain spontaneous metastases in Ret melanoma injected mice

When B16-F10 cells were co-injected with WT or Cd38^-/- primary fibroblasts tumor volumes were affected mostly and significantly by the genotype of the co-injected fibroblasts, regardless to the hosts genotype; i.e. the tumors grown in Cd38^-/--enriched microenvironment were significantly smaller. Our results thus suggest that CD38 participates in the tumor-supporting action of the tumor microenvironment and that targeting CD38 might be a potential therapeutic approach for melanoma treatment.