Underlying Mechanisms for Distant Metastasis - Molecular Biology

Abstract

Background: The formation of distant metastases constitutes a complex process with a variety of different genes and pathways involved. To improve patient survival, it is necessary to understand the underlying mechanisms of metastasis to allow for targeted intervention.

Methods: This review provides an overview of the general concepts of metastasis, focusing on the most important genes and pathways involved and on interventional strategies.

Results: Cancer cells undergo different steps to form metastasis: most prominently, local invasion, intravasation, survival in the circulation, arrest at a distant organ site and extravasation, micrometastasis formation, and metastatic colonization. In order to pass these steps, different molecular pathways are of major importance: EGF/RAS/RAF/MEK/ERK, PI3K/Akt/mTOR, HGF/Met, Wnt/β-catenin, and VEGF signaling. The HGF/Met regulator MACC1 and the Wnt signaling target S100A4 have been shown to play a major role in the metastatic process. Each gene and pathway provides an opportunity for therapeutic intervention.

Conclusion: Since metastasis represents a highly limiting factor in cancer therapy causing 90% of cancer deaths, it is imperative to reveal the underlying mechanisms. This is fundamental for uncovering prognostic markers and new targeted therapy options.

Keywords: Cancer therapy; Metastasis; Molecular mechanism.

Fig. 1

Invasion-metastasis cascade (modified from Valastyan et al. [6]).

Fig. 2

EGFR signaling: key components of the RAS/RAF/MEK/ERK and PI3K/Akt/mTOR signaling pathways and their influence on the metastatic cascade. An activated receptor tyrosine kinase (e.g. EGFR) starts both cascades resulting in the activation of the downstream effectors Akt, mTORC-1/-2, and ERK. Available therapeutics targeting these signaling cascades are marked (cetuximab, panitumumab, trastuzumab, erlotinib, gefitinib, lapatinib, perifosine, sorafenib, vemurafenib, dabrafenib, selumetinib, trametinib, everolimus, temsirolimus).

Fig. 3

cMet signaling and its influence on the metastatic cascade. HGF binds to the growth factor receptor cMet and activates downstream SHC, PI3K, STAT3/5, C-SRC, SHP2, PCLγ, GRB2, and SOS. This leads to the activation of RAS/RAF, RAS/RAC1m, FAK, and Akt/mTOR, and as a consequence to enhanced tumor proliferation, migration, invasion, EMT, cell survival, and angiogenesis. cMet is targetable by using the receptor antibodies rilotumumab or onartuzumab or the multikinase inhibitor foretinib.

Fig. 4

Wnt signaling and its influence on the metastatic cascade. Wnt ligand binding leads to the inhibition of the destruction complex and consequently to the nucleic accumulation of β-catenin which drives Wnt gene expression. NSAIDs such as sulindac or celecoxib, the antibiotic calcimycin, and the anthelminthic niclosamide target β-catenin-dependent gene transcription.