Metastasis suppressors in breast cancers: mechanistic insights and clinical potential

Abstract

For the most part, normal epithelial cells do not disseminate to other parts of the body and proliferate, as do metastatic cells. Presumably, a class of molecules-termed metastasis suppressors-are involved in this homeostatic control. Metastasis suppressors are, by definition, cellular factors that, when re-expressed in metastatic cells, functionally inhibit metastasis without significantly inhibiting tumor growth. In this brief review, we catalog known metastasis suppressors, what is known about their mechanism(s) of action, and experimental and clinical associations to date.

Figure 1. Hematogenous metastatic cascade and metastasis suppressors' mechanism of action

Cancer progression and metastasis begin when a subset of tumor cells acquire genomic changes that alter expression of pro and anti-metastatic genes. Tumor cells acquire the ability to migrate and invade surrounding tissues matrices and basement membranes (collectively, the stroma). Blood-borne metastases begin when those invasive cells enter the circulatory system (i.e., intravasation). In the circulation, cells overcome shear forces, anoikis, and immune surveillance as they travel through the vasculature, sometimes forming emboli with platelets, white blood cells and/or red blood cells. Surviving cells arrest at the secondary site through ligand-receptor-based adhesion or physical size constraints. Once attached, cells extravasate and begin to modify the surrounding stroma. If the microenvironment is conducive to growth, the cells begin to multiply, or colonize the secondary tissues. Colonization of the secondary site is the last and most crucial step of the metastatic cascade. While many disseminated cells can seed distant tissue, exceedingly few cells form macroscopic masses. Moreover, certain cancers have predilections to colonize certain organs preferentially (organotropism). For example, the most common sites of breast cancer metastases are bone, lymph nodes, lung, liver and brain. Metastasis requires completion of every step of this multistep cascade. It was long ago recognized that inhibition of any step rendered a cell non-metastatic. Each metastasis suppressor is listed below the step(s) for which experimental evidence demonstrates inhibition of the metastatic process. Solid black boxes are metastasis suppressors that only have experimental data in breast/mammary cancer models. White boxes with solid black lines are suppressors that have been shown to function in multiple cancer types, including breast. Boxes with dashed black borders are suppressors that have been shown to function in multiple cancer types, excluding breast. Note: In Table 1, some of the metastasis suppressors have reported tumor suppressor activities. For simplicity, tumor suppressor function is not depicted in this figure.