Oncotarget


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


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The cover for issue 61 of Oncotarget features Figure 3, "The effect of loss of CD38 on blood vessels, necrotic area, peritumoral area and amount of CAFs in late stage tumors effect on blood vessels density," by Baruch, et al.

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 melanoma cells. Collectively, our results suggest that targeting CD38 in the melanoma TME provides a new therapeutic approach for melanoma treatment.

Dr. Reuven Stein from the Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel said, "Melanoma is the deadliest skin cancer."

Figure 3:

Figure 3: The effect of loss of CD38 on blood vessels, necrotic area, peritumoral area and amount of CAFs in late stage tumors (A, B) effect on blood vessels density. Paraffin sections were stained with anti-CD34 Ab. (A) Representative images of CD34 staining in tumors grown in WT and Cd38−/− mice (scale bar = 500 μm). (B) Quantitation of the density of CD34 staining. The results are expressed as the average signal of CD34-positive area in each tumor section (*p = 0.03, Student's t test, n = 10 mice from each group). (C, D) Effect on necrotic area. Necrotic regions were identified in H&E stained sections. (C) Representative images of necrotic area (pink) in tumors grown in WT and Cd38−/− mice (scale bar = 500 μm). (D) Quantification of the percentage of necrotic area. The results are expressed as the average percentage of necrotic region in each tumor. Values are presented as mean ± S.E.M (bars) (***p 3.11 × 10-5; Student's t test, n = 9 WT and 10 Cd38−/− mice). (E, F) Effect on thickness of the peritumoral area. Collagen enriched peritumoral capsules were measured in Masson's trichrome stained sections. (E) Representative images of tumors grown in WT and Cd38−/− mice (scale bar = 250 μm). (F) Quantification of the peritumoral area. The results are expressed as the average area of peritumoral capsule in each tumor section (*p = 0.03; Student's t test, n = 8 for each group). (G, H) Effect on the amount of CAFs. Sections were stained with anti-α-SMA Ab. (G) Representative images of α-SMA in the tumors grown in WT and Cd38−/− mice (scale bar = 500 μm). (H) Quantitation of the density of α-SMA staining. The results are expressed as the average number of α-SMA in the counted regions. (**p = 0.001, Student's t test, n = 9 mice from each group).

The melanoma tumor mass is comprised of tumor cells and stroma, known as tumor microenvironment. The TME in cancers, including melanoma contains different types of cells including, endothelial cells, infiltrating immune cells and cancer-associated fibroblasts. However, due to the heterogeneity of tumor cells, even within a single tumor mass, this task is challenging.

An alternative, yet complementary approach for cancer therapy is to target the TME cells. CD38 is also expressed in TME cells of extracranial tumors e.g., macrophages, T-cells endothelial cells and fibroblasts. The effect of CD38 targeting on B16F10 tumor progression involved increased cell death and reduction in the amount of CAFs and blood vessels, suggesting that loss of CD38 affects melanoma outgrowth through these effects.

The Reuven Stein research team concluded, "Collectively, our results suggest that targeting CD38 in the melanoma TME may be a beneficial approach to treat melanoma both as a neoadjuvant treatment, to reduce tumor growth before resection of primary tumor, as well as for inhibiting the occurrence of metastasis."

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DOI - https://doi.org/10.18632/oncotarget.25737

Full text - https://www.oncotarget.com/article/25737/text/

Correspondence to - Reuven Stein - [email protected]

Keywords - CD38, melanoma, tumor microenvironment, primary tumor, metastasis



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