The emerging molecular machinery and therapeutic targets of metastasis

Abstract

Metastasis is a 100-year-old research topic. Technological advances during the past few decades have led to significant progress in our understanding of metastatic disease. However, metastasis remains the leading cause of cancer-related mortalities. The lack of appropriate clinical trials for metastasis preventive drugs and incomplete understanding of the molecular machinery are major obstacles in metastasis prevention and treatment. Numerous processes, factors, and signaling pathways are involved in regulating metastasis. Here we discuss recent progress in metastasis research, including epithelial-mesenchymal plasticity, cancer stem cells, emerging molecular determinants and therapeutic targets, and the link between metastasis and therapy resistance.

Keywords: cancer stem cell; circulating tumor cell; epithelial–mesenchymal plasticity; metastasis; therapy resistance.

Figure 1. Schematic of the invasion-metastasis cascade

Metastasis involves a succession of discrete steps, beginning with local invasion, then intravasation of cancer cells into blood and lymphatic vessels, transit of circulating tumor cells (CTCs) through the vasculature, followed by extravasation to the parenchyma of distant organs, and finally proliferation from micrometastases into macrometastases.

Figure 2. The epithelial-mesenchymal transition (EMT)

Hypoxia, inflammation, and extracellular factors present in the tumor stroma, such as TGF-β, HGF, TNF-α, Wnt, and PDGF, can activate the expression of transcription factors including Twist, Snail, Slug, ZEB1, and ZEB2, which are regarded as the core EMT regulators. Inducing EMT in carcinoma cells leads to loss of epithelial markers and cell-cell adhesion and acquisition of mesenchymal markers, motility, invasiveness, and cancer-stem-cell (CSC) properties including self-renewal, chemoresistance, and radioresistance.

Figure 3. The Hippo-YAP pathway regulates organ growth, tumorigenesis, and metastasis

Cell membrane receptors LIFR and GPCRs regulate the MST-LATS-YAP/TAZ phosphorylation cascade. Phosphorylation of YAP leads to its cytoplasmic retention and functional inactivation, whereas dephosphorylated YAP translocates to the nucleus and acts as a transcriptional co-activator. Therapeutic agents targeting the Hippo-YAP pathway include the small-molecule YAP inhibitor verteporfin, the peptide mimicking the YAP antagonist VGLL4, and FG-3019, a monoclonal antibody that neutralizes the functional YAP target CTGF.

Figure 4. Circulating tumor cells (CTCs) exist as single-cell CTCs and CTC clusters

Platelets can protect CTCs from NK cell-mediated lysis, whereas Kupffer cells (specialized macrophages in the liver) activated by anti-tumor monoclonal antibodies can eliminate CTCs through phagocytosis.

Figure 5. Regulation of extravasation and survival of disseminated tumor cells (DTCs) in the lung

(A) Breast cancer cells can secrete factors, including angiopoietin-like 4, epiregulin, MMP1, and MMP2, which increase vascular permeability and facilitate extravasation by disrupting pulmonary endothelial cell-cell junctions. (B) DTCs expressing VCAM1 interact with pulmonary macrophages via counter receptor α4-intergrin, which triggers activation of a VCAM1–Ezrin–PI3K–AKT pro-survival pathway.

Figure 6. Cancer stem cells (CSCs) and therapy resistance

CSCs exhibit chemoresistance, radioresistance, and resistance to targeted therapies, and are responsible for generating primary and metastatic tumors. Plasticity is likely to exist between non-CSCs and CSCs. For instance, induced expression of ZEB1 can drive differentiated epithelial cancer cells to undergo EMT and convert from non-CSC state to CSC state, and promote DNA damage response, radioresistance, and drug resistance.