By Sarah Choi
Cancer is a disease that touches and affects many people and their loved ones. The National Cancer Institute estimates that nearly 40% of men and women will be diagnosed with cancer in their lifetime, and in 2020 alone, around 16,850 individuals aged 0 to 19 will receive a cancer diagnosis. Furthermore, of these 16,850 young people, 1,730 cases will prove fatal (National Cancer Institute, 2020). As cancer metastasis is the chief culprit behind cancer-related deaths (Beans, 2018), there have been numerous efforts to discover and develop treatments against metastasis.
While primary and secondary tumours are still to this day mostly treated in the same way (for example, with chemotherapy and radiation therapy), it is argued that this should not be the case as this could encourage metastasis instead. Metastasizing cells display different characteristics and express different genes than stationary proliferating tumour cells. Therefore, it is justifiable that there should be treatments specifically for metastasizing, or circulating, tumour cells. Cancer metastasis is the process where cells from the primary malignant tumour move to a secondary site away from the original site and manage to develop secondary malignant growths. There are several steps to metastasis and cancer cells must overcome many obstacles before successfully metastasizing. By removing resources that cancer cells use to overcome obstacles, or targeting specific steps for example intravasation, the process where cells squeeze into blood vessels or lymph vessels in order to travel to secondary sites, researchers are attempting to reduce the impact of metastases and diminish the chances of a successful metastasis. With the discovery of novel pathways or of involvement of certain molecules in the metastasis of certain cancers, new treatments have been proposed as new methods to prevent metastasis.
While the blood-brain barrier makes invasion into the brain much more difficult, once cancer cells do this, it is also harder to target them using drugs, as the chemicals will also need to pass the blood-brain barrier. One study found that cancer cells metastasising to the brain can hijack astrocytes to aid in metastasis (Chen et al., 2016). Astrocytes are glial cells in the central nervous system that are involved in various functions, including the formation of the blood-brain barrier. Human breast and lung cancer cells express the protein protocadherin 7 (PCDH7), which is involved in the formation of gap junctions between cancer cells and astrocytes, thereby forming physical channels between the cells. The cancer cells can then transfer cGAMP, a second messenger, to astrocytes. This triggers a cascade within the astrocytes, leading to the activation of pathways that promote tumour growth and chemoresistance within the brain. Eliminating the trigger, cGAMP, would allow the pro-metastasis cascade within astrocytes to be avoided. One way of doing this would be by blocking the gap junctions. This way, cGAMP would have no accessible entry point to the astrocytes, and the cascade of reactions would not ensue. Drugs that inhibit gap junctions, such as meclofenamate and tonabersat, could therefore be explored as treatments for brain metastases.
After cancer cells invade a new tissue or organ, they need to establish their oxygen and nutrient supply again. This is accomplished by the process of angiogenesis, or in the case of cancer cells, neoangiogenesis. This is when tumour cells induce nearby capillaries to grow extra blood vessels to the tumour cell. The protein vascular endothelial growth factor-A (VEGF-A) initiates angiogenesis by binding to its receptor and mediating signalling pathways. By blocking these pathways, angiogenesis can be impeded, and tumours will have less chance of successfully establishing themselves at secondary sites. Bevacizumab, a humanized immunoglobulin G monoclonal antibody, inhibits VEGF-mediated pathways by binding to VEGF. Bevacizumab can therefore be used to prevent metastases, and has been shown to increase survival in patients with metastatic colorectal cancer when used in conjunction with chemotherapy (Krämer and Lipp, 2007). When used in combination with other treatments, bevacizumab has also shown promising results for other solid cancers such as breast cancer and pancreatic cancer (Shih and Lindley, 2006). Therefore, this antibody can be used in therapies to improve cancer treatments.
There are numerous other novel therapies to explore and develop, each targeting different aspects of tumours and cancer metastasis. Tumour cells interact with their environment, surrounding cells and extracellular matrix. Upon arrival at a distant site, they will also need to interact with their surroundings to establish themselves and grow into a secondary tumour. By denying cancer cells the conditions they need in order to grow new blood vessels or form metastatic cells, secondary tumour growths could be avoided (Yoo, Fuchs and Medarova, 2018). As neoangiogenesis is induced in response to the lack of oxygen, novel therapies increasing the oxygen in tumor tissue have been demonstrated to induce apoptosis. The use of the drug salinomycin may also inhibit breast cancer metastasis, due to its toxicity to only breast cancer stem cells which are similar to the cells that metastasize. Moreover, inhibition of microRNA-10b could increase chances of apoptosis during the process of metastasis and prevent metastasis formation. It may also be beneficial to stabilize the primary tumour by modulating destructive immune responses that are unable to fully destroy the primary tumour.
Cancer metastasis remains an area full of mystery and undiscovered knowledge. There is a need for more resources and funds to be put into researching cancer metastasis and novel therapies which target this process. By preventing successful metastases, the number of cancer-related deaths can be largely decreased, and relapses can be better prevented.
Beans, C. (2018) ‘Targeting metastasis to halt cancer’s spread’, Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences, 115(50), pp. 12539–12543. doi: 10.1073/pnas.1818892115.
Chen, Q. et al. (2016) ‘Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer’, Nature. Nature Publishing Group, 533(7604), pp. 493–498. doi: 10.1038/nature18268.
Krämer, I. and Lipp, H. P. (2007) ‘Bevacizumab, a humanized anti-angiogenic monoclonal antibody for the treatment of colorectal cancer’, Journal of Clinical Pharmacy and Therapeutics. J Clin Pharm Ther, pp. 1–14. doi: 10.1111/j.1365-2710.2007.00800.x.
National Cancer Institute (2020) Cancer Statistics – National Cancer Institute. Available at: https://www.cancer.gov/about-cancer/understanding/statistics (Accessed: 28 September 2020).
Shih, T. and Lindley, C. (2006) ‘Bevacizumab: An angiogenesis inhibitor for the treatment of solid malignancies’, Clinical Therapeutics. Clin Ther, pp. 1779–1802. doi: 10.1016/j.clinthera.2006.11.015.
Yoo, B., Fuchs, B. C. and Medarova, Z. (2018) ‘New directions in the study and treatment of metastatic cancer’, Frontiers in Oncology. Frontiers Media S.A., p. 1. doi: 10.3389/fonc.2018.00258.