Implications of In Vitro Cell Migration and Invasion for Disease Therapy

Normal processes of cell migration/invasion include gastrulation, embryonic morphogenesis, branching morphogenesis (eg, mammary ducts), nervous system development, vascular sprouting, placental development, wound healing, or immune cell trafficking. There are also pathological conditions in which dysregulated cell movement is important. For example, tumor cell migration and invasion are most clinically relevant.

Cancer is the second leading cause of death, with 7.6 million deaths worldwide as of 2008. Metastasis is a major problem in cancer treatment, heralding a poor prognosis and having a huge impact on patient survival. Several models of tumor invasion and metastasis have been proposed. For example, these are based on multistep progression, 'intrinsic' transfer or transfer propagation, although no well-defined mechanism is available. Metastasis involves multiple processes, such as invasive growth through the extracellular matrix (ECM), cell migration through blood or lymphatic vessels, and the rise of distant colonies.

It is closely related to the tissue invasion of the primary tumor. Matrix metalloproteinases (MMPs) have been identified to break down the ECM. Therefore, small molecular weight compounds that block the function of MMPs have been developed. Unfortunately, these treatments failed in clinical trials. Since then, new insights into the mechanisms by which cancer cells spread have shown that tumor cells can escape MMP inhibition by using protease-independent mechanisms through the ECM.

Therefore, understanding the rationale and molecular pathways that are altered in cancer cells to drive the first step in metastatic spread is of great interest and potential therapeutic importance.

Migration is often used as an umbrella term in biology to describe any directed cell movement in the body. The ability to migrate allows cells to change their location within tissues or between different organs.

In pathology, cancer invasion is defined as the penetration of tissue barriers, such as through the basement membrane and infiltration (invasion) by malignant cells into the underlying interstitial tissue. For example, bowel cancer is classified as an invasive cancer when the tumor mass passes through the basement membrane and into the submucosa. Defining the aggressiveness of non-epithelial carcinomas is more difficult because, for example, mesenchymal cells are not clearly separated by the basement membrane. In many areas of biology described in vivo that deal with directed cell movement, there is no clear distinction between migration and invasion.

Despite the difficulties in defining different migration patterns, it is a fact that migratory ability is a prerequisite for invasion; cells cannot invade without migrating, but can move without invasive. And so on, migration can be seen as walking on a sidewalk, while invasion corresponds to walking through a thorny hedge (requiring all the tools a bush needs, including the ability to walk).

The basic features that occur in migrating cells have been elucidated. These cells display directional polarity, with a leading edge in front of the cell body and a lagging edge behind the cell body. Common to all modes of migration is actomyosin cytoskeleton-mediated changes in cell body shape. However, external cues such as physical and molecular features of the environment and intrinsic cellular determinants can influence migration patterns. The two main types are collective migration of multicellular compartments and single-cell movement.

Migration of individual cells can be subdivided into amoeboid and mesenchymal-type movements. Metastasis is by far the leading cause of cancer mortality. 90% of solid tumor deaths can be attributed to metastatic spread. Clearly, new therapeutic strategies are needed clinically to avoid metastatic spread. Only by understanding the basic principles of metastasis can new anti-metastatic drugs be developed. To date, the major challenges of clinical monitoring of migration, invasion and metastasis inhibition are far from resolved. Because metastasis is a multi-stage process and can last for months or even years, it is difficult to obtain a definitive clinical readout, which will be a major challenge for clinical testing of anti-metastatic drugs.

As mentioned above, metastasis involves multiple processes; however, it is closely related to the initial tissue invasion at the primary tumor site. Therefore, it is necessary to understand how cancer cells acquire aggressive phenotypes and to understand the respective molecular mechanisms. Functional perturbation of different modes of invasion is necessary to counteract the different strategies cancer cells have evolved to move through tissues and organs. These interventional therapeutic strategies need to be established, which can be achieved through the use of in vivo and/or in vitro models.

Furthermore, they often allow for examination and phenotyping during the assay. Furthermore, in vitro assays are suitable for high-throughput drug testing (high-throughput screening, HTS) and are less expensive than in vivo assays. Furthermore, animal experiments raise ethical concerns, which can be reduced by using in vitro models. However, it should be noted that none of the detection methods described so far can well generalize all the fundamental steps in transfer, but only some of them. It seems that in the near future, comprehensive in vitro metastases detection will be technically far from being achievable.