CYNTHIA A. REINHART-KING
Cancer is the second leading cause of death in the United States and is projected to overtake cardiovascular disease as the leading cause of death in the next few years. Few patients die from primary tumors, but once a tumor has spread to other parts of the body (a process called metastasis), it becomes much more difficult to treat—90 percent of cancer deaths are due to metastasis.
The exact mechanisms by which tumors form, grow, and spread are not clear, but significant attention has been paid to the role of genetic mutations in cells that drive uncontrolled growth. While genetics and gene mutations are clearly drivers of cancer, it is now known that they are not the only key players. The chemical and physical environment surrounding tumor cells also contributes to malignancy and metastasis.
Numerous tumors are diagnosed based on their physical properties; as an example, changes in tissue stiffness and density are markers of tumor formation detectable by palpation and medical imaging. Notably, changes in tissue stiffness and density have been shown to enhance tumor progression. As such, research now focuses not only on the causes and treatments of genetic mutations and molecular changes in the cell but also on physical changes in the tissue and cells. This requires a new arsenal of tools aimed at characterizing and controlling the physical properties of cells and tissue. Engineers have made significant strides in developing the tools and models necessary to understand and attack cancer.
OVERVIEW: CANCER, METASTASIS, AND STAGING
Tumors are generally thought to form from one initial rogue cell that undergoes genetic changes that result in its uncontrolled growth and proliferation (Hahn
and Weinberg 2002). As this proliferation occurs, the tumor is considered benign as long as the cell mass remains in the tissue in which it formed. In this case, it is not considered cancer, but it can sometimes be dangerous if its size compresses nerves, arteries, or other tissues. If, however, the cells invade the surrounding tissue, it is considered cancerous. The cells can spread to surrounding tissues, often traveling through the bloodstream and/or lymph systems to other organs in the body. As such, there is immense interest in determining
- What triggers the initiating steps that lead to uncontrolled proliferation?
- What are the determinants of invasion? and
- How can the spread of tumor cells in the lymph system and blood stream be prevented?
Staging of cancer is done to categorize the extent of the spread of the tumor in a common clinical language that all physicians can understand and use to establish a prognosis, determine a course of action, and determine the fit for a clinical trial. It is based on factors such as the location and size of the primary tumor, and whether the tumor has spread to the lymph nodes or other areas of the body. The TNM staging system is based on categorizing the size and extent of the primary tumor (T), the spread to regional lymph nodes (N), and the presence of secondary metastatic tumors in other organs (M). Each of these (T, N, and M) is then used to determine the numerical stage of the cancer (I–IV).
Staging is specific to cancer type and depends on the type of tumor and its location. Stage I is indicative of a cancer that is the least advanced and has the best prognosis; Stage IV indicates that the cancer has spread to other areas of the body and is typically much more difficult to treat. In general, if a cancer is identified and treated before it has spread, the outcomes are favorable. For this reason, significant attention has been paid to stopping cancer progression before the cells metastasize.
MECHANOBIOLOGY IN CANCER
Most cancer research has focused on identifying genetic drivers and understanding the mechanism by which genes and specific signaling pathways in the cell drive tumor formation. Notably, however, cancer, from tumor initiation through metastasis and the formation of secondary tumors, involves both genetic changes in a cell and physical changes to both the tissue structure and the cancer cells (Carey et al. 2012). More recent work has therefore also focused on the mechanobiology of tumor progression. Mechanobiology is the study of how forces (e.g., pressure, tension, and fluid flow) and mechanical properties (e.g., stiffness and elasticity) affect cellular function.
Recent advances in engineering and the physical sciences have uncovered critical roles of the mechanical and structural properties of cells and tissues in
guiding malignancy and metastasis. Indeed, it is increasingly appreciated that tissue architecture and the mechanical properties of tissues and cells contribute to cancer progression.
The ability of cells to exert force against their surroundings, as one example, enables the rearrangement of tissue fibers and the creation of paths through the tissue that facilitate metastatic cell movements (Kraning-Rush et al. 2011, 2013). The ability to generate these forces is enhanced in tumor cells compared to their healthy counterparts (Kraning-Rush et al. 2012), suggesting that metastatic cells are better at invading tissue because, in part, they are better at physically rearranging it to create paths in which they can move.
Metastatic cells have also been shown to be more deformable than nonmetastatic cells (Agus et al. 2013; Guck et al. 2005). This deformability may help metastatic cells squeeze through tissue to escape the primary tumor and enter the circulatory system to move to secondary sites.
In addition to changes in the physical properties of the cells, changes in the physical properties of the tissue have been shown to promote cancer progression. Solid tumor tissue is stiffer than normal tissue, and research suggests that this stiffness can promote tumor cell growth and invasion. Conversely, decreasing tissue stiffness has been shown to delay tumor progression (Cox et al. 2016; Venning et al. 2015). These results indicate that tissue mechanics plays a critical role in cancer and that, clinically, approaches to intervene with cancer mechanobiology may benefit cancer treatment.
TISSUE-ENGINEERED PLATFORMS TO STUDY MECHANOBIOLOGY IN CANCER
To investigate and manipulate the mechanobiology of cancer, tissue-engineered platforms have been critical. Because it is known that there are distinct differences between how tumors form and grow in the human body compared to how cancer cells grow in culture dishes or in animal models, tissue-engineered platforms serve as bridges to better understand and manipulate the drivers of cancer.
Using principles from biomaterials science, mechanics, and chemistry, engineers have been working to create platforms that recreate the architecture, chemistry, and mechanical properties of the tumor microenvironment (Carey et al. 2012; Mason and Reinhart-King 2013). These platforms will enhance understanding of the physical forces and features that drive tumor progression, and have also in many cases been adapted for use in drug testing.
Tissue-engineered platforms can be created to mimic both the dimensionality of tumors, overcoming the limitation of conventional cell culture, and the stiffness and porosity of native tissue at various stages of tumor progression. More specifically, several bioengineering groups have developed tunable materials that mimic the changing mechanical properties of the tumor microenvironment. Materials that
can be activated to stiffen or soften through various chemical techniques have been created and used to study how cells respond to the dynamic mechanical environment in tumor tissue (Gill et al. 2012; Magin et al. 2016). They may be useful for parsing the effects of genetic changes from those induced by changes in the mechanical environment of the cell.
TRANSLATING MECHANOBIOLOGY TO THE CLINIC
One of the biggest hurdles in the field of cancer mechanobiology is the translation of findings to the clinic. For instance, because it is known that metastatic cells exert higher forces and are more deformable than nonmetastatic cells, there may be clinical value to assaying patient samples to correlate forces and deformability with patient prognosis. It has been suggested that new mechanobiological assays be incorporated in clinical protocols, and significant efforts are being made to develop assays that are user-friendly and translatable to clinical settings (Kiessling et al. 2013).
Clinically targeting mechanically related molecules may also be feasible. There are numerous signaling pathways and associated proteins in cells that control cellular force profiles, cell contractility, and cell deformability. In fact, many of these pathways have been either directly or indirectly pharmacologically targeted for the treatment of other diseases, including arthritis, diabetes, cardiovascular disease, and pulmonary diseases.
Additionally, approaches to alter the mechanical properties of tissues have been developed for targeting tissue stiffening in wound healing and cardiovascular disease. Thus clinically treating changes in the mechanical properties of cell and tissues is feasible and within reach.
The field of cancer mechanobiology has grown significantly over the past decade as the role of mechanical forces in cancer has been increasingly appreciated. It is now well accepted that mechanical changes in both cells and tissues can contribute to malignancy and metastasis, but the mechanisms by which these changes promote cancer are not yet fully understood. Engineers have the unique skills to build platforms to measure, probe, and manipulate cell and tissue mechanics to better understand cancer mechanobiology and translate it to the clinic.
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