Defining the Hallmarks of Metastasis

Abstract

Metastasis is the primary cause of cancer morbidity and mortality. The process involves a complex interplay between intrinsic tumor cell properties as well as interactions between cancer cells and multiple microenvironments. The outcome is the development of a nearby or distant discontiguous secondary mass. To successfully disseminate, metastatic cells acquire properties in addition to those necessary to become neoplastic. Heterogeneity in mechanisms involved, routes of dissemination, redundancy of molecular pathways that can be utilized, and the ability to piggyback on the actions of surrounding stromal cells makes defining the hallmarks of metastasis extraordinarily challenging. Nonetheless, this review identifies four distinguishing features that are required: motility and invasion, ability to modulate the secondary site or local microenvironments, plasticity, and ability to colonize secondary tissues. By defining these first principles of metastasis, we provide the means for focusing efforts on the aspects of metastasis that will improve patient outcomes.

Figure 1.

Neoplastic progression is depicted as normal cells become transformed. Transformed cells can acquire additional characteristics to become neoplastic. Transition through a benign phase is depicted here; however, not all cells within a neoplasm acquire additional characteristics sequentially. The generation of a cancer/neoplasm is characterized by 10 “hallmarks of cancer” (4,5). Superimposed upon the hallmarks of cancer are four “hallmarks of metastasis” which are characteristics required for invasive neoplastic cells to establish macroscopic secondary (or higher-order) masses.

Figure 2.

The pathogenesis of hematogenous metastasis. 1. The process of metastasis begins when neoplastic cells grow, recruit inflammatory cells, induce angiogenesis, and begin to initiate establishment of pre-metastatic niches (gray arrow), while generating mutant variants at high frequency. 2. Neoplastic cells then begin to invade through surrounding stroma via a variety of motility mechanisms as either single cells (via EMT) or collective migration. 3. Immune cells infiltrating the primary tumor associate with tumor cells such that neoplastic cells co-opt the invasive functions of the infiltrating immune cells to enter the vasculature (intravasation). Cells which have entered the vasculature typically roll along the endothelium but can form homotypic (tumor cell-tumor cell) or heterotypic (tumor cell-immune cell/platelet) emboli. After surviving sheer forces, tumor cells selectively adhere to endothelium or arrest when vessel diameter is too small to traverse. Note that the extracellular matrix where tumor cells invaded surrounding stroma is also reorganized and can result in the release of matrikines that affect tumor cell and/or stromal behavior. 4. Upon arrest/adhesion tumor cells exit vessels (extravasation) and interact with pre-metastatic niches which are permissive for proliferation and colonization of secondary sites. 5. Colonization is dependent upon a combination of tumor cell and tissue-specific factors. Disseminating cells selectively colonize different tissues and the process of further dissemination (i.e., metastasizing from metastases) can occur. The four proposed hallmarks of metastasis are listed in the red boxes.