By Sarah Choi
Metastasis is a multi-step process whereby cancer cells migrate from the primary tumour to a secondary site. This involves: the acquisition of mesenchymal characteristics to gain motility, invasion into blood vessels or lymph vessels, resistance to cell death once in the blood stream, evasion of the immune system, and extravasation out of blood vessels into tissue. Upon arrival at their “new home”, the cancer cells have to then establish themselves at the secondary site, survive there, and enter dormancy or proliferate into a secondary tumour.
To study metastasis, researchers have used in vitro systems, ex vivo organ slices, and animal models – such as zebrafish models, mouse models, or the more recent patient-derived tumour xenografts (van Marion et al., 2016). However, elucidating all the mechanisms involved in the complex process of metastasis has been a continuing challenge. Due to the dynamic relationship between the tumour and its environment, more knowledge was needed on how the cancer cells interacted with components from outside the tumour. This led to the development of techniques that could imitate the cancer cells and their microenvironment in 3D, overcoming the limitations of 2D models.
Metastatic cancer cells have modified genetics and epigenetics that provide the tools necessary for metastasis. The cells’ altered gene expression is attributable to their interactions with the immediate external environment and signals received from the body. Specifically, signals from the extracellular matrix and other cells in the tumour’s surroundings, the microenvironment, are especially important during carcinogenesis and metastasis. These signals instruct cancer cells to differentiate, direct them to a secondary site, and allow their continued survival. Studying the biochemical and physicochemical interactions in living human tumours could therefore provide insight into novel methods of manipulating the microenvironment and signals to prevent tumour growth or the worsening of the cancer.
Recent advancements in technology and the combination of microfluidics and tissue engineering have enabled the in vitro development of 3D multicellular systems imitating the tumour microenvironment. These systems are controllable and can function at the organ level, allowing observations of interactions between cells and tissues (Portillo-Lara and Annabi, 2016). Researchers can use these “on-chip” technologies to study the signals and stresses that originate from the metastatic microenvironment, along with the variety of pathways and interactions between tumour cells and their surroundings. As much is still unknown about the mechanisms that cancer cells use, this knowledge could open new doors for treating patients.
This 3D microculture system can also be used to assess patients’ tumour progression and assist in cancer treatments. By mimicking transport in the tumour-adjacent capillary network, multiple features of metastasis can be observed. For example, loading tumour cells or patient-derived tumour organoids adjacent to the vascular network, allows the passage of nutrients and drugs between tumour and blood to be studied, with potential for drug screening and advancing precision medicine-based treatments. The process of neoangiogenesis, when cancer cells induce the growth of new blood vessels, and the process of intravasation, when cells invade into the bloodstream, can be tested to advance knowledge on these processes. This system can also be used to study and improve cancer treatments such as personalized medicine, chemotherapy and anti-angiogenic therapy (Shirure et al., 2018).
As more variations on this 3D system are explored – such as mimicking the tumour microenvironment in other tissues, or including normal cells in the environment (Trujillo-de Santiago et al., 2019) – many more aspects of cancer and cancer metastasis could be elucidated. With the wide range of possibilities for the models that can be made with this on-chip technique, there are numerous applications including advancing existing cancer treatments as well as novel therapies or prevention strategies as more research is done. As cancer metastasis is the main cause of cancer-related death, gaining insight into this process could tremendously benefit patients and aid recovery.
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Portillo-Lara, R. and Annabi, N. (2016) ‘Microengineered cancer-on-a-chip platforms to study the metastatic microenvironment’, Lab on a Chip. Royal Society of Chemistry, 16(21), pp. 4063–4081. doi: 10.1039/c6lc00718j.
Shirure, V. S. et al. (2018) ‘Tumor-on-a-chip platform to investigate progression and drug sensitivity in cell lines and patient-derived organoids’, Lab on a Chip. Royal Society of Chemistry, 18(23), pp. 3687–3702. doi: 10.1039/c8lc00596f.
Trujillo-de Santiago, G. et al. (2019) ‘The tumor-on-chip: Recent advances in the development of microfluidic systems to recapitulate the physiology of solid tumors’, Materials. MDPI AG. doi: 10.3390/ma12182945.