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A New CSC-targeted Strategy to Treat Melanoma?



Review of  “Immunomodulatory Factors Control the Fate of Melanoma Tumor Initiating Cells” from Stem Cells by Stuart P. Atkinson

Melanoma, the highly aggressive skin cancer, displays an intra-tumor heterogeneity which may contribute to malignancy and resistance to targeted therapy [1, 2]. One theory to explain such heterogeneity is the presence of cancer stem cells/tumor initiating cells (CSCs/TICs) [3] that can switch status to a more differentiated phenotype, and vice-versa, by so-far-unknown mechanisms.

In order to define the interplay between CSCs and more differentiated melanoma cells, researchers from the laboratory of Chiara Castelli (IRCCS Istituto Nazionale Tumori, Milan, Italy) have taken advantage of a previously described melanoma CSC culture model [4]. Their new study, published in Stem Cells, now describes how specific inflammatory modulators present in the tumor microenvironmental can control the switch between self-renewing CSC and differentiated states [5]. Have Tuccitto et al uncovered a new means to target and treat melanoma?

Initial cytokine and chemokine secretion profiles of melanospheres (3D spheroid cultures), which contain high levels of CSCs/TICs, and differentiated melanoma adherent cells demonstrated many interesting differences. The authors chose to concentrate their study on the differential effects of interleukin-6 (IL-6 – an inflammatory cytokine) and interleukin-10 (IL-10 – an anti-inflammatory cytokine) on melanoma CSC self-renewal.

IL-6 released from differentiated melanoma cells reduced CSC self-renewal and induced differentiation, as shown in the adjoined figure which shows increased blue staining of senescence-associated heterochromatin foci (SAHF). However, IL-10 released from CSC-enriched cultures acted in the opposite way and promoted CSC self-renewal. But can we use this information treat melanoma? To this end, the authors demonstrated that by IL-10 gene silencing and antibody-mediated blocking of the IL-10 receptor, the authors could sensitize melanoma CSCs to IL-6 mediated differentiation.

This study highlights the IL-6/IL-10 axis, suggesting that inflammatory factors within the tumor microenvironment can “tip the balance” and enhance CSC stemness and, therefore, stimulate tumor aggressivity. However, the study also highlights a possible solution: tipping the balance back via anti-inflammatory factors. This would lead to an environment in which CSCs lose their self-renewal capacity and switch to a more differentiated phenotype which is easier to therapeutically target.

Discussion Points

  • How do IL-6 and IL-10 mediate their effects on stemness in CSCs?
  • Can we therapeutically target Il-6 and IL-10 to treat melanoma?
  • Do these inflammatory mediators represent a common control mechanism in CSC-associated tumors?


  1. Fidler IJ. Tumor heterogeneity and the biology of cancer invasion and metastasis. Cancer Res 1978;38:2651-2660.
  2. Ennen M, Keime C, Kobi D, et al. Single-cell gene expression signatures reveal melanoma cell heterogeneity. Oncogene 2015;34:3251-3263.
  3. Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem cells. Nature 2001;414:105-111.
  4. Perego M, Tortoreto M, Tragni G, et al. Heterogeneous phenotype of human melanoma cells with in vitro and in vivo features of tumor-initiating cells. J Invest Dermatol 2010;130:1877-1886.
  5. Tuccitto A, Tazzari M, Beretta V, et al. Immunomodulatory Factors Control the Fate of Melanoma Tumor Initiating Cells. Stem Cells 2016;34:2449-2460.