Metastasis suppressors genes in cancer

Abstract

The major problem for cancer patients is metastasis of the cancer from the primary tumor to secondary sites. Metastasis is the process by which tumor cells disseminate from the primary tumor, migrate through the basement membrane, survive in the circulatory system, invade into a secondary site, and start to proliferate. In the past, research had concentrated on the biology, taking more of a global view instead of a molecular view. More recently, the focus has been determining the molecular underpinnings, looking at genes that induce or inhibit metastasis. Metastasis suppressors, by definition, inhibit metastasis at any step of the metastatic cascade without blocking primary tumor growth. The expanding list of metastasis suppressors exist with every cellular compartment and have been shown to work by regulating signaling pathways that inhibit proliferation, cell migration and growth at the secondary site. Still, the biochemical basis of their inhibition is not completely known. Here we review the known metastasis suppressors and summarize the suspected mechanisms by which they inhibit metastasis.

Introduction

Metastasis is the most feared, most lethal, and least effectively treated characteristic of cancer and has, at times, been thought to be too complex and random to be studied in detail. Studies from the 1950s through the 1980s revealed that the seemingly random process of metastasis was dependent on a relatively uniform set of events. Using mouse models, the steps of hematogenous metastasis of cancer cells were defined (reviewed in Fidler, 2003). Although this review will focus on hematogenous (i.e., blood-borne) metastasis, readers are reminded that metastases can also develop by lymphatic spread or dissemination across body cavities.

The hematogenous metastatic cascade is composed of sequential, rate limiting steps (Fidler & Radinsky, 1990). The first step requires cancer cells from the primary tumor to invade and migrate through the tumor stroma, followed by intravasation into the vasculature. Circulating tumor cells must survive transport and arrest as a function of hemodynamic properties of the vasculature and recognize endothelium corresponding to various tissues. Until it became possible to visualize cells in vivo using intravital microscopy, it was believed that metastatic cells traversed the endothelial and basement membrane barriers before proliferating. However, tumor cells arrested in the vasculature can proliferate intra-vascularly (Al Mehdi et al., 2000). The cells in vessels will eventually erupt through the basement membrane, but the frequency of the latter scenario is not known. Eventually, tumor cells leave the vessel lumen and traverse the intima by directional migration in response to tissue specific chemoattractants (Craig & Loberg, 2006; Ruffini, Morandi, Cabioglu, Altundag, & Cristofanilli, 2007).

Finally, cells that complete all the steps of the metastatic cascade proliferate, and colonize ectopic tissue. A unanimous definition of metastasis is still under debate (Eccles & Welch, 2007; Welch, 2007). We have advocated that the definition of a “metastasis” be limited to cells that actually proliferate at the secondary site, rather than just remain as single cells. In recent years, the last step in the metastatic cascade – colonization – has become a focal point of research because it offers the possibility of extending the dormant phase at the secondary site and is emerging as a potential area for the development of therapeutic targets.

Once the steps in metastasis were defined, metastasis researchers then began to focus on defining the individual biochemical processes allowing tumor cells to migrate from the primary tumor to secondary sites. Molecules involved in cellular proliferation, motility, adhesion, invasion, resistance to apoptosis, and angiogenesis were identified and since have been extensively studied. Readers are referred to several excellent reviews for details concerning individual mechanisms (Coussens & Werb, 2002; Folkman, 2006; Friedl, Hegerfeldt, & Tilisch, 2004; Hehlgans, Haase, & Cordes, 2007; Jain, 2003; Jain, Duda, Clark, & Loeffler, 2006; Page-McCaw et al., 2007, Ruoslahti, 2002). As we begin to understand more about the biochemical basis underlying the individual steps of the metastatic cascade, it has become evident that genes that specifically modify metastasis exist.

Since coordinated expression of genes is required for successful metastasis, identifying metastasis promoting genes can lead to potentially false-positive candidates (i.e., unless the full complement of molecules/abilities co-exist within a single cell, addition of a bona fide metastasis promoter might be incorrectly categorized because the cells are defective for another property). We do not imply that metastasis promoting genes have not been discovered. We only emphasize that their discovery can be challenging. However, since every step in the metastatic cascade is considered rate-limiting, a gene or protein that inhibits any step in the cascade will do so regardless of the other genes or proteins expressed in a cell.

The principle of coordinated gene expression is highlighted by the fact that tumor cells can still be detected in the circulation, even after primary tumor removal (Melchior et al., 1997; Roberts, Watne, McGrath, McGrew, & Cole, 1958). And, it is increasingly evident that circulating cancer cells that migrate to secondary sites do not necessarily proliferate (Goldberg, Harms, Quon, & Welch, 1999; Hickson et al., 2006, Nash et al., 2007), meaning that they are still subject to growth controls in the new environment. These as yet not defined inhibitory or stimulatory growth signals that could induce dormancy/death or proliferation, respectively, may also be considered potential rate-limiting steps in the metastatic cascade.

This review will summarize the currently known metastasis suppressors, a growing family of molecules that inhibit metastasis without blocking tumorigenicity. The focus will be to describe the biological and biochemical mechanisms of action.