Priority Research Papers:
Stromal CD38 regulates outgrowth of primary melanoma and generation of spontaneous metastasis
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Bar Ben Baruch1,*, Eran Blacher1,*, Einav Mantsur1, Hila Schwartz2, Hananya Vaknine3, Neta Erez2 and Reuven Stein1
1 Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
2 Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
3 Department of Pathology, Wolfson Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Holon, Israel
* These authors have equally contributed to this work
Reuven Stein, email: [email protected]
Keywords: CD38; melanoma; tumor microenvironment; primary tumor; metastasis
Received: May 09, 2018 Accepted: June 19, 2018 Published: August 07, 2018
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.
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