Stromal CD38 regulates outgrowth of primary melanoma and generation of spontaneous metastasis.

Hananya Vaknine,Reuven Stein,Eran Blacher,Bar Ben Baruch,Neta Erez,Einav Mantsur,Hila Schwartz

doi:10.18632/oncotarget.25737

Abstract

The outgrowth of primary melanoma, the deadliest skin cancer, and generation of metastasis is supported by the tumor microenvironment (TME) which includes non-cancerous cells. Since the TME plays an important role in melanoma pathogenesis, its targeting is a promising therapeutic approach. Thus, it is important to identify proteins in the melanoma TME that may serve as therapeutic targets. Here we show that the nicotinamide adenine dinucleotide glycohydrolase CD38 is a suitable target for this purpose. Loss of CD38 in the TME as well as inhibition of its enzymatic activity restrained outgrowth of primary melanoma generated by two transplantable models of melanoma, B16F10 and Ret-mCherry-sorted (RMS) melanoma cells. Pathological analysis indicated that loss of CD38 increased cell death and reduced the amount of cancer-associated fibroblasts (CAFs) and blood vessels. Importantly, in addition to inhibiting outgrowth of primary melanoma tumors, loss of CD38 also inhibited spontaneous occurrence of RMS pulmonary and brain metastasis. The underlying mechanism may involve, at least in the brain, inhibition of metastasis expansion, since loss of CD38 inhibited the outgrowth of B16F10 and RMS brain tumors that were generated by direct intracranial implantation. Collectively, our results suggest that targeting CD38 in the melanoma TME provides a new therapeutic approach for melanoma treatment.

Highlights

Melanoma is the deadliest skin cancer [1]
Using mouse melanoma models we demonstrate that targeting CD38 in the melanoma tumor microenvironment (TME) inhibited outgrowth of primary melanoma and reduced the occurrence of spontaneous pulmonary and brain metastases
This conclusion is based on the following findings: i) Loss of CD38 inhibited primary melanoma outgrowth in two different mouse models. ii) Treating B16F10 melanomabearing WT mice with a CD38 inhibitor restrained primary melanoma growth when applied together with tumor cells www.oncotarget.com www.oncotarget.com www.oncotarget.com www.oncotarget.com or after tumor occurrence. iii) In the RMS experimental model of spontaneous metastasis, the metastatic load was significantly lower in lungs and brains of Cd38‒/‒ mice. iv) Loss of CD38 inhibited the progression of brain tumors generated by intracranial injection of B16F10 or RMS melanoma cells

Summary

Introduction

Melanoma is the deadliest skin cancer [1]. While early-detected melanoma is mostly curable by surgical excision, diffused metastatic disease is inevitably fatal [24]. The melanoma tumor mass is comprised of tumor cells and stroma, known as tumor microenvironment (TME). The interaction between tumor cells and TME modifies the microenvironment properties towards a phenotype that supports tumor progression and invasiveness [5, 6]. The TME regulates the formation of metastasis [7]. The TME in cancers, including melanoma contains different types of cells including, endothelial cells, infiltrating immune cells and cancer-associated fibroblasts (CAFs) [5, 8, 9]

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Results

Conclusion