Melanoma is the most aggressive and life-threatening skin cancer. Due to the high propensity to metastasize, over 90% of skin cancer deaths are due to melanoma. Melanoma is treated with surgical removal. The main goal of treatment is to reduce the risk of metastasis.

Postoperative interferon (IFN) therapy improves relapse-free and overall survival in patients at high risk of melanoma recurrence. Systemic interferon treatment was the only effective strategy before the advent of immune checkpoint inhibitors and targeted therapies.

Interferons have antiviral, antiproliferative, and antitumor activity. Despite the proven benefit of type I IFNs, they have significant side effects at high doses. In addition, the optimal dosage and duration of treatment with interferons is unknown.

To Reduce The Risk of Metastasis, Cancer Stem Cells Destruction is Necessary

Melanoma resists chemotherapy and can spread to organs distant from the original focus due to melanoma cancer stem cells (CSC). CSCs can appear when normal stem cells or cells of various tissues mutate. Cancer stem cells can divide asymmetrically. After division, some of the cells remain cancerous stem cells, replenishing the CSC population, while the other part acquires the properties of various tumor cells. One cancer stem cell can create a new tumor. CSCs can survive treatment with drugs that inhibit cell division and development since they are in a dormant state part of the time. They do not divide and do not develop but remain metabolically active.

Cancer stem cells promote tumor metastasis by secreting exosomes – extracellular vesicles containing biologically active lipids, proteins, and RNA. These biologically active molecules contribute to forming a subject-static niche and tumor spread. For more information about the mechanisms of metastasis, see the article “Tumor secretes vesicles that suppress the protective response of interferon.”

Spanish scientists studied how IFN-α affects:

  • the ability of melanoma cells, containing cancer stem cells, to form spherical structures (melanospheres) and divide;
  • on exosomes that secrete CSCs.

Study Results

  • IFN-α reduced the number, diameter, and proliferation of melanospheres and the ability of CSCs to form colonies.
  • IFN-α decreased stem properties of melanoma. CSCs have a higher migration capacity. IFN-α disrupted CSC migration and stimulated melanoma cell death.
  • IFN-α altered the expression of genes and miRNAs associated with stemness and cancer processes such as vessel formation, cell division, and cell death.
  • IFN-α reduced the ability of melanoma CSCs to form new tumors. The scientists experimented on mice injected subcutaneously with CSC: on one side – treated with a low dose of interferon and untreated on the other. After 27-53 days, mice developed tumors on both sides. However, tumors from untreated CSCs had significantly greater volume and weight than tumors treated with interferon. In addition, interferon reduced tumor stemness markers.
  • Low doses of IFN-α reduced the secretion of exosomes by cancer stem cells, reduced the diameter of exosomes, and altered their contents.

Conclusions

Cancer stem cells from melanoma are resistant to chemotherapy and radiation therapy and often contribute to the recurrence of the disease.

Even at low doses, IFN-α inhibits the formation of melanospheres and their cell division and significantly reduces the number of cancer stem cells. IFN-α inhibits the ability of CSC to migrate and substantially reduces the ability of CSC to form tumors.

Low-dose IFN-α therapy is a possible strategy for treating melanoma. Future studies aim to study the effectiveness of IFN-α therapy in combination with immunotherapy and targeted therapy for melanoma.

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