After establishing a beachhead in the epidermis, and before accessing blood vessels on its way to other parts of the body, melanoma invades the dermis. This intermediate stage is crucial to the spread of melanoma. If the penetration of the dermis were better understood, melanoma might become more vulnerable to countermeasures and, most important, less deadly. As matters now stand, melanoma causes the death of one person every 52 minutes.

In hopes of learning how to prevent the dermis from being overrun, scientists based at Tel Aviv University (TAU) have closely studied the interactions between melanoma cells and the dermis. These scientists have discovered that before spreading to other organs, a melanoma tumor sends out tiny vesicles containing molecules of microRNA (miRNA). These miRNA-containing vesicles amount to a microscopic artillery barrage that softens resistance in the dermis, inducing morphological changes in preparation for receiving and transporting the cancer cells.

The TAU researchers also considered the feasibility countermeasures. The researchers found chemical substances that can stop the process and are therefore promising drug candidates.

Details appeared August 22 in the journal Nature Cell Biology, in an article entitled, “Melanoma miRNA Trafficking Controls Tumour Primary Niche Formation.” The article describes how the TAU researchers began by examining pathology samples taken from melanoma patients. “We looked at samples of early melanoma, before the invasive stage,” reported Carmit Levy, Ph.D., a researcher in the Department of Human Genetics and Biochemistry at TAU's Sackler School of Medicine. “To our surprise we found changes in the morphology of the dermis—the inner layer of the skin—that had never before been reported. Our next task was to find out what these changes were, and how they related to melanoma.”

The TAU researchers revealed that melanoma cells directly affect the formation of the dermal tumor niche by miRNA trafficking before invasion. The researchers paid particular attention to melanocytes, cells of melanoma origin, that are specialized in releasing pigment vesicles, termed melanosomes.

“In melanoma in situ, we found melanosome markers in distal fibroblasts before melanoma invasion,” wrote the authors of the Nature Cell Biology article. “The melanosomes carry microRNAs into primary fibroblasts triggering changes, including increased proliferation, migration and pro-inflammatory gene expression, all known features of cancer-associated fibroblasts (CAFs).”

The melanosomes, the scientists explained, induce morphological changes in the dermis in preparation for receiving and transporting the cancer cells. “Specifically, melanosomal microRNA-211 directly targets IGF2R [insulin-like growth factor 2 receptor] and leads to MAPK [mitogen-activated protein kinase] signaling activation, which reciprocally encourages melanoma growth.”

Having discovered the mechanism, the researchers proceeded to look for substances that could intervene and block the process in its earliest stages. They found two such chemicals: one (SB202190) inhibits the delivery of the vesicles from the melanoma tumor to the dermis; and the other (U0126) prevents the morphological changes in the dermis even after the arrival of the vesicles. Both substances were tested successfully in the lab, and may serve as promising candidates for future drugs. In addition, the changes in the dermis, as well as the vesicles themselves, can be used as powerful indicators for early diagnosis of melanoma.

“Our study is an important step on the road to a full remedy for the deadliest skin cancer,” concluded Dr. Levy. “We hope that our findings will help turn melanoma into a nonthreatening, easily curable disease.”








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