The epigenetic reprogramming of poorly aggressive melanoma cells by a metastatic microenvironment

Abstract

Cancer pathogenesis involves dynamic interactions within the tumor-host microenvironment. Most noteworthy is cutaneous melanoma which is considered one of the few remaining cancers escalating in incidence [1,2], and thus represents a growing public health burden worldwide [3; for review, see 4; 5]. In addition, uveal melanoma is considered the most common primary intraocular cancer in adults [6], where metastasis occurs in an unpredictable manner in approximately 50% of patients with a primary tumor originating in the choroid or ciliary body of the eye [6]. Without question, the clinical manage- AbstractA dynamic, complex relationship exists between tumor cells and their microenvironment, which plays a pivotal role in cancer progression, yet remains poorly understood. Particularly perplexing is the finding that aggressive melanoma cells express genes associated with multiple cellular phenotypes, in addition to their ability to form vasculogenic-like networks in three-dimensional matrix -called vasculogenic mimicry, which is illustrative of tumor cell plasticity. This study addressed the unique epigenetic effect of the microenvironment of aggressive melanoma cells on the behavior of poorly aggressive melanoma cells exposed to it. The data show significant changes in the global gene expression of the cells exposed to 3-D matrices preconditioned by aggressive melanoma cells, including the acquisition of a vasculogenic cell phenotype, upregulation of ECM remodeling genes, and increased invasive ability -indicative of an epigenetic, microenvironment-induced reprogramming of poorly aggressive melanoma cells. However, this epigenetic effect was completely abrogated when a highly cross-linked collagen matrix was used, which could not be remodeled by the aggressive melanoma cells. These findings offer an unique perspective of the inductive properties associated with an aggressive melanoma microenvironment that might provide new insights into the epigenetic regulation of tumor cell plasticity and differentiation, as well as mechanisms that could be targeted for novel therapeutic strategies.

Alternative site of implantation affects tumor malignancy and metastatic potential in mice: Its comparison to the flank model

“…Microenvironment is a key factor in tumor progression. Seftor et al 5 demonstrated that poorly aggressive melanoma cells acquired a vasculogenic phenotype when they were exposed to a microenvironment preconditioned by aggressive metastatic melanoma cells. The opposite effect has also been studied long ago by Illmensee et al 8 who showed that teratocarcinoma cells could be normalized by the blastocyst environment.…”

“…1,2 In the case of osteosarcoma, for instance, although several cell lines have been established and characterized, few reliable animal models mimic all the aspects of human cancer, making it difficult to test valuable therapeutic strategies. 3 Since tumor microenvironment plays a key role in cancer development, [4][5][6] we investigated whether the dermis of a different anatomical site of mice would offer different characteristics than those of the flank. Thus, we chose the dorsal region of the foot and compared it to the flank in terms of cellular influx and reactivity upon antigen injection.…”

Distinctive properties of metastasis-initiating cells

“…After tumor cells escape the primary site, the epigenome is subjected to microenvironmental signal modulation, conferring cellular plasticity and adaptability to new and inhospitable conditions (Seftor et al 2006;Hendrix et al 2007;Tam and Weinberg 2013). Indeed, multiple studies have unveiled evidence of specific epigenetic pathways involved in the metastatic progression of different cancer types (Cunha et al 2014;Gu et al 2015;Okada et al 2015;Tang et al 2015).…”

The Role of the Microenvironment – Models for the Study of Melanoma

“…Poorly aggressive melanoma cells acquired a vasculogenic phenotype when they were exposed to a microenvironment preconditioned by aggressive metastatic melanoma cells (Seftor et al, 2006). The opposite effect has also been studied long ago by Illmensee & Mintz (1976) who showed that teratocarcinoma cells could be normalized by the blastocyst environment.…”