Migrastatics-Anti-metastatic and Anti-invasion Drugs: Promises and Challenges

Abstract

In solid cancers, invasion and metastasis account for more than 90% of mortality. However, in the current armory of anticancer therapies, a specific category of anti-invasion and antimetastatic drugs is missing. Here, we coin the term 'migrastatics' for drugs interfering with all modes of cancer cell invasion and metastasis, to distinguish this class from conventional cytostatic drugs, which are mainly directed against cell proliferation. We define actin polymerization and contractility as target mechanisms for migrastatics, and review candidate migrastatic drugs. Critical assessment of these antimetastatic agents is warranted, because they may define new options for the treatment of solid cancers.

Keywords: contractility; invasion; metastasis; migrastatics; solid cancer; treatment.

Figure 1

The Plasticity of Cancer Cell Invasion. Cancer cells can invade either collectively or as individual cells when utilizing the amoeboid or mesenchymal invasion mode. Cells invading in one mode can undergo the mesenchymal-amoeboid, or amoeboid-mesenchymal mode (MAT and AMT, respectively) in response to current conditions and signaling within the extracellular matrix (ECM). The plasticity of invasion is further regulated by interactions with noncancer cells that contribute to signaling circuits. Tumor-associated macrophages (TAMs) produce proinvasive cytokines that affect invasion directly and sustain the cancer-associated phenotype of proximal fibroblasts. These cancer-associated fibroblasts (CAFs) realign fibers of the ECM, which facilitates cancer cell invasion. The Rho/Rho-kinase (ROCK) pathway is crucial for many of these interactions and, thus, its inhibition downregulates cancer cell invasion (for more details, see the main text).

Figure 2

Key Figure: Target Mechanisms of Migrastatics. Cell invasion is affected by various extracellular stimuli and encompasses many signaling pathways that ultimately regulate actomyosin contractility and actin polymerization, which are two essential mechanisms driving cell migration. Since the signaling pathways regulating cell invasion are highly redundant, inhibition of any of these pathways can be overcome and will result in resistance, stemming from another signaling circuit by-passing the inhibited pathway. Thus, migrastatics should target the essential mechanisms (cell contractility and actin polymerization) to efficiently inhibit cell invasion.

Figure 3

Regulators of Actomyosin Contractility Are Targets for Migrastatics. Rho-kinase (ROCK) mediates the phosphorylation of myosin light chain (MLC) to directly enhance contractility. In addition, ROCK and myotonic dystrophy kinase-related CDC42-binding kinase (MRCK) phosphorylate and, thus, inhibit MLC phosphatase (MLCP), which counteracts MLC phosphorylation. Thus, drugs targeting ROCK or MRCK are candidates for efficient migrastatics because they act to inhibit actomyosin contractility, which is necessary for of all cell invasion modes. Candidate drugs are depicted in blue, whereas enhancers of actomyosin contractility are in red.

Figure 4

Potential Candidates for Migrastatics. Drugs targeting the actin cytoskeleton are suitable candidates for the inhibition of cell invasion because they impair both amoeboid and mesenchymal invasion. Chosen groups of migrastatic agents are depicted. Drugs interfering with actin dynamics include actin cytoskeleton-destabilizing drugs (cytochalasins, latrunculins, and geodiamolide H) and actin filament-stabilizing drugs (jasplakinolide, chondramide, and cucurbitacin). TR100, a tropomyosin inhibitor, disrupts the actin cytoskeleton by affecting its stability. Other drugs target actomyosin contractility, such as blebbistatin (an inhibitor of non-muscle myosin II) or inhibitors (e.g., Y-27632, BDP5290, CCT129254, or AT13148) that target kinases involved in the regulation of actomyosin contractility. The group of kinase inhibitors is emphasized because they have shown the potential to inhibit cell invasion in in vivo experiments. For more detail on certain drugs, refer to the main text.