metastasis

Definition: Metastasis can be viewed as an evolutionary process, culminating in the prevalence of rare tumour cells that overcame stringent physiological barriers as they separated from their original environment and developmental fate.

Types

 lymphatic dissemination

• nodal metastasis
• carcinomatous lymphangitis

Localization

 visceral metastasis

• pulmonary metastasis
• hepatic metastasis
• digestive metastasis

 cerebral metastasis
 osseous metastasis (bone metastasis)
 placental metastasis

This phenomenon brings into focus long-standing questions about the stage at which cancer cells acquire metastatic abilities, the relationship of metastatic cells to their tumour of origin, the basis for metastatic tissue tropism, the nature of metastasis predisposition factors and, importantly, the identity of genes that mediate these processes.

The ability of a malignant tumor to become metastatic begins with the hallmarks of motility and invasiveness. When individual cells or clusters of cancer cells acquire the ability to separate and move away from the primary tumor mass, migrate through the surrounding tissue, and enter the lymphatic system and/or blood circulation, the metastatic trait of a given tumor becomes manifest.

Tumor cells that escape their primary microenvironment need to escape anoikis and might be challenged by the host’s immunologic defenses. Although the rate of tumor cell release in cancer patients is unknown, experimental models indicate that millions of tumor cells are continuously dispersed through the body, although only few of these cells might reach a distant organ, survive in a dormant state, evade the immune system and systemic therapy, and eventually grow into an overt metastasis.

Adaption to a new microenvironment and proliferation of a single tumor cell in a distant site requires special traits (plasticity) that the cell must already have or acquire in order to develop to an overt metastasis detectable by clinical procedures.

Metastatic cascade

Tumor cells may enter the bloodstream passively or actively via biological events such as EMT or centrosomes amplification. Disseminating tumor cells must overcome several hurdles including anoikis, shear stress in the bloodstream, and the immune system in-and outside of the blood circulation. Once at a distant site, tumor cells may extravasate, undergo MET, and grow locally to become a metastasis or remain in dormancy.

Cancer dormancy

Tumor cells may stop cell division processes after dissemination but may persist in a quiescent status until environmental conditions provide appropriate signals to start proliferation again. This quiescent state, for which the underlying mechanisms are largely unknown, is called clinical "cancer dormancy" and may last more than 10 years.

There is now increasing evidence that the microenvironment plays a critical role in this process (e.g., osteoclasts as regulators of osteolytic bone metastases, in addition to changes in the tumor cells themselves (e.g., acquisition of new mutations).

CTC migration: mobility and motility

Cancer metastasis has been correlated with specific genetic biomarkers such as mutations, chromosomal aberrations, and gene expression patterns. Nevertheless, whether CTCs enter the blood circulation through an active migration process, by passive means, or both, remains clinically and scientifically an unresolved question. The terms "motile cells" and "mobile cells" have been used to describe the differences between active and passive migration of the tumor cells.

Motile cancer cells are cells that are able to move on their own accord and that has thus gained the ability to move through the extracellular matrix and penetrate basement membranes and endothelial walls upon intravasation and extravasation. These active migration mechanisms imply modification of cell morphology, position, and surrounding tissue. Furthermore, cancer cells may infiltrate as single entities, in clusters, in strands, or in single (Indian) files as observed in lobular breast carcinoma. Single cells must weaken or completely lose their adhesive bonds with neighboring tumor cells for infiltration, whereas collective migration requires stable cell–cell adhesion and multicellular coordinated movement. These clusters frequently comprise of different cell morphologies, that is, both epithelial-and mesenchymal-like. Collective migration may require a leader cell with mesenchymal features, able to create a path for the trailing tumor cells through the surrounding tissue.

Mobile cancer cells are moved by external forces such as growth of the tumor, mechanical forces, or friction which cause them to be dragged or pushed out of place. Although a vast amount of literature is available about the processes involved in active migration of cancer cells through the extracellular matrix, less is known concerning the passive dissemination of cancer cells and how they may be forced into the blood circulation.

Carcinomas induce the formation of new blood vessels by the secretion of the vascular endothelial growth factor (VEGF) to facilitate the supply of nutrients and oxygen for growth. This process called angiogenesis, often results in leaky vessels caused by weak interconnections of the vessel’s endothelial cells and intercellular openings. Due to outward pushing of the tumor during growth, single or clusters of tumor cells can be forced through the leaky vessels, thus ending up in the blood circulation as ‘accidental CTCs’. Furthermore, tumor cells may be passively moved through the micro-tracks created by other tumor cells by proteolysis or through other pre-existing tissue structures.

Because the ‘accidental CTCs’ from epithelial malignancies are more likely to have retained their original phenotype, detection with epithelial-specific markers such as the epithelial cell adhesion molecule (EpCAM) would be feasible.

On the other hand, tumor cells that have transformed to a more mesenchymal-like phenotype, and thus exhibit greater plasticity, may prove to be less easily detected by conventional EpCAM-based detection methods. Nevertheless, new evidence shows that a phenotypical transformation is not always required for tumor cell motility.

CTCs in circulation

Once in the bloodstream, CTCs face several natural obstacles that hinder the metastatic process.

First are the enormous shearing forces and collisions with blood cells, generated by blood flow. Although shear stresses decrease the number of viable cancer cells dramatically, tumor cells that underwent EMT seem to be more resistant against these forces compared to epithelial tumor cells (Mitchell & King, 2013).

Second, CTCs must survive in the bloodstream without their cell–matrix interactions, an occurrence that would normally trigger apoptosis through a process called anoikis. Resistance against anoikis, however, is made possible in CTCs by activated tropomyosin-related kinase B (TrkB) that suppresses caspase-associated apoptosis and enables the cells to survive in liquid suspension (Douma et al, 2004).

The third obstacle that CTCs face in the blood is the activity of the immune system. In colorectal cancer, immune escape is obtained by up-regulation of CD47 that prevents CTCs from macrophage and dendritic cell attack (Steinert et al, 2014).

Finally, cancer cells must eventually leave the blood circulation, which requires binding to the endothelium lining the vessels. Because platelets enhance this binding, inhibition of platelet aggregation by for instance aspirin can decrease stable tumor cell binding to activated platelets (Uppal et al, 2014).

Tumor cell homing and dormancy

Extravasation starts when CTCs slow down in small capillaries, attach to the endothelium, and finally undergo transendothelial migration (Reymond et al, 2013).

One of the most frequent CTCs homing sites are the bones, including for primary malignancies such as colorectal and lung cancer that less typically metastasize to the bone (Pantel & Brakenhoff, 2004; Braun et al, 2005; Riethdorf et al, 2008). It is therefore thought that the bone marrow functions as a reservoir for disseminated tumor cells (DTCs) (Wikman et al, 2008; Kang & Pantel, 2013).

In breast cancer, it may take many years up to decades after surgery of the primary tumor until metastases become evident (Goss & Chambers, 2010; Uhr & Pantel, 2011). During this time, bone marrow DTCs (Janni et al, 2011) as well as CTCs derived from the DTCs (Meng et al, 2004) may be found in these patients. DTCs in bone marrow may linger in a dormant state, thus evading systemic therapy while waiting for the appropriate trigger to resume proliferation (Bragado et al, 2013; El Touny et al, 2014).

The basis for tumor cell dormancy may be the initial EMT process itself. In squamous cell carcinoma, spatiotemporal regulation of the epithelial–mesenchymal transition is essential for the dissemination and eventual metastasis (Tsai et al, 2012).

The mesenchymal phenotype of CTCs that underwent EMT promotes motility but does not favor growth (Celia-Terrassa et al, 2012). Indeed, cancer cells must undergo a reverse mesenchymal-to-epithelial transition (MET) to acquire the ability to proliferate and thus form a metastatic tumor. It has therefore been suggested that tumor cells with an intermediate phenotype can most efficiently disseminate and grow at the distant sites (Bednarz-Knoll & Weinberg, 2012; Tam & Weinberg, 2013).

See also

 circulating tumoral cells
 metastasis of unknow origin
 epithelial–mesenchymal plasticity
 epithelial–mesenchymal transition (EMT)

Open reviews

 Pantel K, 2015. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309663/

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