Mapping a new mechanism

JOENSUU and HELSINKI, Finland—A new study from Finland has shed fresh light on how melanoma cells interact with other cells via the extracellular vesicles they secrete. Researchers have found that extracellular vesicles secreted by melanoma cells use the so-called hedgehog signaling pathway to intensify the malignant properties of the cells they are targeting.

The study, entitled “HAS3-induced extracellular vesicles from melanoma cells stimulate IHH mediated c-Myc upregulation via the hedgehog signaling pathway in target cells,” was published in Cellular and Molecular Life Sciences. Research was carried out in collaboration between researchers from the University of Eastern Finland and the University of Helsinki.

Many of the mechanisms regulating body function have remained unchanged throughout evolution — the same genes regulate the development and function of all multicellular animals. One such example of gene survival is the so-called hedgehog signaling pathway. The gene family associated with this signaling pathway gets its unique name from a mutation it caused in fruit fly larvae, making them look spiky like hedgehogs.

Members of the hedgehog gene family are essential regulators of fetal development, but they’re also associated with stem cell division in later stages of development and in adult tissue regeneration. Recent studies suggest that their expression is also associated with many different types of cancer, including skin cancers like melanoma.

"It is quite a coincidence that these signal-carrying vesicles originate from cells that are also known as hedgehog cells due to their microscopically small, spike-like protrusions. These protrusions, however, don’t have anything to do with fruit fly larvae; instead, they are typically found in cells that are active in producing hyaluronan, the most common sugar molecule in the extracellular matrix,” said Docent Kirsi Rilla from the University of Eastern Finland, who with her research group has been studying the biology of extracellular vesicles since 2013. “Hyaluronan also plays a key role in vesicle mediated signaling, as hyaluronan found on the surface of vesicles protruding from the cell surface facilitates their binding to the target cell.”

Traditionally, signaling in the body was thought to take place via freely circulating signals like growth factors and hormones. But according to a more recent view, it’s believed that some signals are packaged for transportation to protect them against breakage and to ensure their delivery to the correct address. Extracellular vesicles are small, bubble-like packages made of cell membrane which serve as natural carriers of signals in the body. They regulate the function of the body during the fetal stage, and via breast milk.

Cancer cells are capable of using extracellular vesicles to deliver signals and to modify their environment, making it favourable to growth. Extracellular vesicles can also be used as diverse carriers of drugs to combat diseases and to repair tissue damage. This is why they are being studied so actively at the moment.

In the newly published study, the researchers discovered a new link between extracellular vesicles and hedgehog molecules. They found that vesicles secreted by melanoma cells intensify the malignant properties of the cells they are targeting, such as division and spreading, via the hedgehog signaling pathway. The researchers used cultured human melanoma cells and normal skin cells, confirming their findings from the cell culture by analyzing tissue samples from patients with melanoma.

“About 40–50% of melanoma patients have mutations in valine at position 600 (Val600) of BRAF protein…” the article notes. “BRAF V600E oncogenic mutation is detected in lymph-derived melanoma EVs, and the increase in mutation frequency in patients correlates with risk of relapse. These results indicate that EVs can be a powerful tool to assess melanoma progression and to predict therapy response. As shown in our study, one of the mitogens from hedgehog signaling pathway, IHH, is significantly enriched in melanoma derived HAS3-EVs [hyaluronan synthase 3-extracellular vesicles]."

“Considering the fact that HA [hyaluronan] content increases at the initial stages of melanoma, and that there is a direct feedback regulation between HA synthesis and hedgehog signaling, one could speculate that melanoma EVs with enriched hedgehog mitogens like IHH may be a good predictor for the progression and therapy response at early stages of melanoma,” continues the article. “In addition, it would be interesting to see if inhibitors of hedgehog signaling combined with the available immune therapeutics improve the survival of melanoma patients.”

The hedgehog signaling pathway holds promise as a target for drug therapy in melanoma and other cancers. The regulation mechanism discovered by the researchers may be able to help with development of better treatment and diagnostics for melanoma in the future.