9.1 Introduction to Metastasis

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What is Metastasis?

 

Metastasis is the process of cancer cell dissemination and colonization to distant sites in the body. It is responsible for as much as 90% of cancer related deaths (1). Establishment of pro-metastatic phenotypes is the first step in escaping the primary tumor and invading other tissues in the body to form secondary tumors. Widely recognized pro-metastatic cell phenotypes include increased proliferation, mobility, invasion, resistance to apoptosis, and ability to induce angiogenesis (2). Invasion is described as the movement through the extracellular matrix (ECM) and basement membrane. Angiogenesis is the process through which new blood vessels develop.

 

In a healthy state, epithelial cells are bound to the basement membrane and to each other by cell-ECM and cell-cell junctions, respectively. Thus, normal epithelial cells exist primarily in a stationary state. Yet the majority of life-threatening metastasizing carcinoma tumors originate from cells that have undergone a transition to become independent, migratory mesenchymal cells, also known as invasive cancer cells (3). This transition, referred to as the epithelial-to-mesenchymal transition (EMT), is the process in which epithelial cells overcome the limitations of these junctions and acquire the ability to move through the ECM and invade localized blood vessels (1). Once in the blood stream, the cancer cells must then resist apoptosis and survive long enough to invade a different, often distant, site in the body where a secondary tumor can be established. In this chapter, the key steps in the processes of the metastatic invasion cascade will be discussed in the general order which they occur in cancer metastasis, as summarized in Figure 12.1.1. Accordingly, the following sections will present the current knowledge regarding each step and highlight potential therapeutic strategies.

 

Figure 9.1.1 The metastatic cascade. Released under the Creative Commons Attribution-ShareAlike 4.0 International license (CC BY-SA 4.0).

 

References

1. Chaffer, C. L., & Weinberg, R. A. (2011). A perspective on cancer cell metastasis. Science Signalling331(6024), 1559.

2. Cole Jr., G. W., Alleva, A. M., Zuo, J. T., Sehgal, S. S., Yeow, W., Schrump, D. S., Nguyen, D. M. (2006). Suppression of Pro-metastasis Phenotypes Expression in Malignant Pleural Mesothelioma by the PI3K Inhibitor LY294002 or the MEK Inhibitor UO126. Anticancer Research26, 809-822.

3. Wang, X., Zhu, Y., Ma, Y., Wang, J., Zhang, F., Xia, Q., Fu, D. (2013). The role of cancer stem cells in cancer metastasis: New perspective and progress. Cancer Epidemiology, 37, 60-63.

4. Prenzel, N., Fischer, O. M., Streit, S., Hart, S., Ullrich, A. (2001). The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocrine-Related Cancer8, 11-31.

5. De Luca, A., Maiello, M. R., D'Alessio, A., Pergameno, M., Normanno, N. (2012). The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert Opinion on Therapeutic Targets2, S17-27.

6. Rawlings, J. S., Rosler, K. M., Harrison, D. A. (2004). The JAK/STAT signaling pathway. Journal of Cell Science, 117, 1281-1283.

7. Hermann, P. C., Huber, S. L., Herrler, T., Aicher, A., Ellwart, J. W., Guba, M., ... & Heeschen, C. (2007). Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell stem cell1(3), 313-323.

8. Pang, R., Law, W. L., Chu, A. C. Y., Poon, J. T., Lam, C. S. C., Chow, A. K. M., Cheung, L. W. H., Lan, X. R., Lan, H. Y., Tan, V. P. Y., Yau, T. C., Poon, R. T., Wong, B. C. Y. (2010). A Subpopulation of CD26+ Cancer Stem Cells with Metastatic Capacity in Human Colorectal Cancer. Cell Stem Cell, 6, 603-615.

9. Brabletz, T., Jung, A., Spaderna, S., Hlubek, F., & Kirchner, T. (2005). Migrating cancer stem cells—an integrated concept of malignant tumour progression. Nature Reviews Cancer, 5(9), 744-749.

10. Klarmann, G. J., Hurt, E. M., Mathews, L. A., Zhang, X., Duhagon, M. A., Mistree, T., ... & Farrar, W. L. (2009). Invasive prostate cancer cells are tumor initiating cells that have a stem cell-like genomic signature. Clinical and Experimental Metastasis26(5), 433-446.

11. López‐Novoa, J. M., & Nieto, M. A. (2009). Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Molecular Medicine1(6‐7), 303-314.

12. Rhim, A. D., Mirek, E. T., Aiello, N. M., Maitra, A., Bailey, J. M., McAllister, F., & Stanger, B. Z. (2012). EMT and dissemination precede pancreatic tumor formation. Cell148(1), 349-361.

13. Hoogwater, F. J. H., Nijkamp, M. W., Smakman, N., Steller, E. J. A., Emmink, B. L., Westendorp, B. F., Raats, D. A. E., Sprick, M. R., Schaefer, U., Van Houdt, W. J., De Bruijn, M. T., Schackmann, R. C. J., Derksen, P. W. B., Medema, J., Walczak, H., Rinkes, I. H. M. B., Kranenburg, O. (2010). Oncogenic K-Ras Turns Death Receptors Into Metastasis-Promoting Receptors in Human and Mouse Colorectal Cancer Cells. Gastroenterology138, 2357-2367.