For patients with solid tumors, metastatic disease often represents a turning point in their journey. It remains the most significant hurdle in cancer treatment, accounting for 90% of all deaths resulting from solid tumors (1). Research during the past 20 years has begun to elucidate multiple events that take place during metastatic progression. In the primary tumor itself, genomic instability and selective pressure within the tumor microenvironment can lead to mutations that allow cells to survive in acidic and hypoxic conditions. Tumor cells also interact with surrounding normal tissue, promoting the growth of new blood vessels and modifying immune cells to escape detection. The molecular events that occur after tumor cells escape the primary tumor are one of the least understood aspects of metastasis. Although Paget’s “seed and soil” hypothesis of cancer metastasis is over 100 years old, only within the past decade have researchers begun to understand how the “soil”, now termed the premetastatic niche, is primed.
microRNAs (miRNAs) are small non-coding regulatory RNA molecules that display differential expression in a wide variety of human cancers compared to normal tissue (2). miRNAs, depending on their target, can either promote or suppress tumorigenesis. Perhaps unsurprisingly, evidence continues to accumulate suggesting that miRNAs play a significant role in metastasis. The miR-200 family is a well-characterized regulator of the epithelial-mesenchymal transition (EMT), although whether it promotes or suppresses metastasis may depend on cellular context (3). miR-10b is overexpressed in breast cancer tissue and is required for invasion and proliferation induced by TGFβ-1 in breast cancer cell lines (4). Both the miR-200 family and miR-10b have been implicated in cancers from several tissue types, suggesting that there may be a set of miRNAs that are common to the metastatic phenotype. Tumor-derived exosomes transporting miRNAs have also been implicated in premetastatic niche formation. Exosomes isolated from metastatic versus non-metastatic cell lines show differential expression of miRNAs involved in EMT, cellular adhesion, and angiogenesis. High miR-122 levels are associated with breast cancer metastasis, and miR-122 was shown to alter energy metabolism in multiple cell types in vitro by downregulating pyruvate kinase (5).
Several factors make miRNAs attractive for future research. Circulating miRNAs are quite stable and can be readily isolated with existing techniques, two important criteria for biomarker development and use in liquid biopsy. Lists of circulating miRNAs associated with cancer are abundant in the literature and continue to expand. Perhaps most significantly, the realization that tumor-derived exosomes can transport miRNA to distant sites has opened a new avenue for exploring the possibility that miRNAs play a role in promoting metastasis.
1. Gupta, G.P. and Massagué, J. (2006) Cancer Metastasis: Building a Framework. Cell 127, 679.
2. Lu, J. et al. (2005) microRNA expression profiles classify human cancers. Nature 435, 834.
3. Park, S.M. et al. (2008) The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 22, 894.
4. Han, X. et al. (2014) Critical role of miR-10b in transforming growth factor-β1-induced epithelial-mesenchymal transition in breast cancer. Cancer Gene Ther. 21, 60.
5. Fong, M.Y. (2015) Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat. Cell Biol. 17, 183.