Understanding Cancer Cell Movement and Metastasis

The Mechanisms of Metastasis

Metastasis represents a critical stage in cancer progression, where cells from a primary tumor acquire the capability to spread to other parts of the body, leading to new tumor formations. This advancement is particularly dangerous, as most treatments prove ineffective at this phase. For a cell to successfully metastasize, several complex processes must occur. Initially, the cell must detach from the original tumor. Next, it enters the bloodstream or lymphatic system, where it must survive the journey through the circulatory system. Finally, the cell must navigate out of the bloodstream and adapt to a new environment.

Cancer cells do not exist in isolation; they are surrounded by a complex three-dimensional network known as the extracellular matrix, composed of fluids, proteins, fats, enzymes, and various other molecules. To metastasize, cancer cells must effectively maneuver through this matrix, making their ability to move and migrate a pivotal aspect of the process.

Directional Choices of Cancer Cells

A recent study conducted in the United States and published in Nature Communications aimed to investigate how cancer cells navigate through the extracellular matrix, with a focus on their directional choices. Researchers created Y-shaped, three-dimensional collagen microtracks of varying widths to analyze spatial confinement, cell-matrix interactions, and cell motility.

Findings revealed that cancer cells often choose the path of least resistance, with approximately 70% preferring to travel down the wider branch of the microtracks. The researchers posited that this preference arises because navigating a narrow path requires more energy, necessitating shape changes or deformation of the tunnel, both of which demand significant energy expenditure. The analogy of traversing a dense jungle illustrates this point—either climbing over obstacles or cutting through them requires energy, while walking along a clear path is far less taxing.

Energy Consumption and Cancer Cell Migration

The study further examined the energy consumption of cancer cells as they navigated through microtracks of different widths. Results indicated that cells confined to narrower spaces consumed more glucose and exhibited increased energy production. Professor Cynthia Reinhart-King, the principal investigator of the study, remarked, “These cells are lazy. They want to move, but they will find the easiest way to do it.”

To enhance their understanding, the scientists developed a computational model to predict cancer cell movement based on minimizing energy expenditure. The model suggested that stiffer cells or those within a rigid extracellular matrix would be less likely to traverse narrow paths. The team tested this hypothesis by chemically manipulating cell stiffness, discovering that stiffer cells exhibited decreased migration into confined spaces and required more energy to move.

Additional experiments involved stiffening the microtracks, revealing that cells were less inclined to navigate through these rigid pathways and took longer to travel through them. This research highlighted the significant increase in energy required for movement in confined environments.

Implications for Future Cancer Treatments

This study underscores the critical role of cell metabolism in metastasis, providing foundational insights for the development of novel treatments targeting metastatic disease. However, several limitations should be acknowledged. The investigation focused solely on a single breast epithelial cancer cell line, raising questions about the applicability of the results to other types of cancer. A comparative analysis with healthy control cells would have offered valuable insights into the specific behaviors of cancer cells. Furthermore, testing a range of cancer cell lines could determine if the observed effects are consistent across various tumor types.

The cells were cultured in Petri dishes, and the simplified model used may not fully represent the complexity of the extracellular matrix in vivo, making it challenging to ascertain the relevance of these findings to humans and animals.

References

Paul, C. D., Mistriotis, P. & Konstantopoulos, K. Cancer cell motility: lessons from migration in confined spaces. Nature Reviews Cancer 17, 131 (2017).
Charras, G. & Sahai, E. Physical influences of the extracellular environment on cell migration. Nature reviews Molecular cell biology 15, 813 (2014).
Spill, F., Reynolds, D. S., Kamm, R. D. & Zaman, M. H. Impact of the physical microenvironment on tumor progression and metastasis. Current opinion in biotechnology 40, 41-48 (2016).
van Helvert, S., Storm, C. & Friedl, P. Mechanoreciprocity in cell migration. Nature Cell Biology 20, 8-20, doi:10.1038/s41556-017-0012-0 (2018).
Zanotelli, M. R. et al. Energetic costs regulated by cell mechanics and confinement are predictive of migration path during decision-making. Nature Communications 10, 4185, doi:10.1038/s41467-019-12155-z (2019).
Turney, S. Cancer cells prefer a ‘comfort cruise,’ follow predictable paths of least resistance (2019).
Photo credit: Reinhart-King Lab / Vanderbilt University.