Dormancy of cutaneous melanoma

Abstract

Many cancer-related deaths including melanoma result from metastases that develop months or years after the initial cancer therapy. Even the most effective drugs and immune therapies rarely eradicate all tumor cells. Instead, they strongly reduce cancer burden, permitting dormant cancer cells to persist in niches, where they establish a cellular homeostasis with their host without causing clinical symptoms. Dormant cancers respond poorly to most drugs and therapies since they do not proliferate and hide in niches. It therefore remains a major challenge to develop novel therapies for dormant cancers. In this review we focus on the mechanisms regulating the initiation of cutaneous melanoma dormancy as well as those which are involved in reawakening of dormant cutaneous melanoma cells. In recent years the role of neutrophils and niche components in reawakening of melanoma cells came into focus and indicate possible future therapeutic applications. Sophisticated in vitro and in vivo melanoma dormancy models are needed to make progress in this field and are discussed.

Keywords: Dormant cancer; Immunotherapy; Melanoma; NETs; Neutrophils.

Fig. 1

Metastatic process of melanoma. 1. Melanoma cells may detach from the tumor in parallel to the growth of the primary tumor or in a linear process in which tumors first accumulate genetic and epigenetic alterations after which tumor cells disseminate. They undergo an epithelial-mesenchymal-like transition for higher invasive potential before entering the lymphatic or vascular system. 2. Melanoma cells circulate within the body and may adapt an endothelial phenotype within the vascular niche. 3. Melanoma cells occupy their niche and interact with the tumor microenvironment (TME) which includes extracellular matrix (ECM), cellular components and cytokines. They may undergo apoptosis, or either enter a proliferative or dormant state (created with BioRender.com)

Fig. 2

Mechanisms of dormancy induction. Dormancy can be classified into angiogenic (A), immune-mediated (B), and tumor microenvironment (TME)-mediated (C) dormancy and can be influenced by growth arresting and reawakening factors (created with BioRender.com). More information can be found in the text

Fig. 3

Neutrophils and NETs in cancer. A Neutrophils exert their effect in a cytolytic way. Neutrophils extravasate upon MET receptor upregulation, and HGF triggers nitric oxide release to induce cell death in melanoma cells. Hydrogen peroxide (H₂O₂) allows cytotoxic Ca²⁺ influx via TRPM2 into breast cancer cells. Neutrophils promote detachment of the basement membrane to make oxygen inaccessible in uterine cancer cells. IFNγ upregulates TRAIL in neutrophils to induce apoptosis in leukemic T cells. IL-1β by neutrophils induces upregulation of ZEB1 (EMT marker) to induce a phenotype switch. B Tumor cells may release cytokines or extracellular vesicles (EV) to activate neutrophils. In turn, effectors such as ROS or NETs are released to promote tumor growth. C Evidence in melanoma supports a proliferation-promoting role of NETs, impeding invasiveness and cell viability. Other tumor types suggest an invasive phenotype upon NET release (created with BioRender.com)