Over 200 anti-cancer drugs have been approved for clinical application. These drugs inhibit tumor cell proliferation, inhibit tumor angiogenesis, or enhance immune function. In the era of targeted therapy, some anti-cancer drugs have multiple effects, such as inhibiting tumor cell proliferation and tumor angiogenesis. Expectations have been high for personalized medicine, which uses genomic information to guide drug application; however, so far for most solid cancer patients, limited survival benefits have been achieved [10, 11]. The primary reason is that metastasis kills most of patients, and very few of these drugs inhibit cancer metastasis.

From a pharmaceutical point of view, many approaches to evaluate the anti-proliferation properties of candidate compounds have been applied with widely accepted standards, from screening the compound using 50% inhibitory concentration (IC₅₀) in vitro to measuring tumor growth inhibition rate in vivo. These standardized pharmacologic tests have been routinely required by the U.S. Food and Drug Administration (FDA) for pre-clinical evaluation. However, the dilemma is that the FDA does not require that the drugs under approval show any anti-metastatic effects.

Multiple obstacles hamper the development of anti-metastatic drugs. First, pharmaceutical companies have few effective, high-throughput technologies to screen their compound library for potential anti-metastatic compounds. A recent pioneering study by Polireddy et al. [12] using E-cadherin as a marker to identify inhibitors of cancer cell invasion was a credible attempt to address this issue. Second, most pharmaceutical companies have not developed standard techniques for using appropriate animal models for pre-clinical anti-metastatic assessment, whereas these models are well-established in academic laboratories [13–16]. Third, to better enable the development of anti-metastatic drugs, clinical trial designs might need to be adjusted to set metastasis-free survival as the primary endpoint. Obviously, more efforts are needed to overcome these obstacles, and high-throughput technologies should be developed and optimized to speed the pace of anti-metastatic drug development.

Epithelial–mesenchymal transition (EMT) has been recognized as an important event to strengthen the metastatic ability of cancer cells. A review article discusses the functions of MTA3 as a master suppressor of EMT and metastasis [17]. E-cadherin has been widely used as an epithelial marker in evaluating EMT. In this issue of the CJC, a novel role of E-cadherin as a sensitizer of chemoresistant prostate cancer cells by inhibiting Notch signaling is revealed [18]. However, our understanding of the role of EMT in metastasis is based mainly on the evidence of single-cell motility. When cancer metastasis is caused by cancer cell clusters, EMT of the tumor cells is not necessary [19, 20]. In terms of forming metastatic lesions, cancer cell clusters are more aggressive than single cancer cells [21]. Moreover, cancer cell clusters in circulation can better survive when they are enveloped by endothelial cells [22]. Obviously, more appropriate in vitro and in vivo models for studying cell cluster mobility and metastasis should be developed.

In summary, better prevention and inhibition of cancer metastasis is currently limited by our insufficient understanding of its nature. However, we are confident that through multidisciplinary efforts and the development of more effective, high-throughput technologies to identify metastasis inhibitors, we can better predict, prevent, and treat cancer metastasis.