Metastasis is a multi-step process in the spread of cancer. This topic was covered in a previous article. The very nature of its complexity, and an understanding of the elements necessary for the tumor to thrive and proliferate, provide ample clues towards new therapeutic approaches.
How Cancer Cells Modify Its Environment - a New Paradigm of Cancer Spread
Researchers have extensively studied how cancer cells differ from normal cells. In order to fully understand the problem of cancer spread, attention is now directed to how cancer cells modify their neighboring and distant microenvironments. Wels 2008 The cancer cell is able to recruit normal processes for its own uses. The following are two examples:
- The epithelial-mesenchymal transition is a normal process in wound healing that is necessary for reconstruction of the epithelium and to grow new capillaries in the stroma.
- Macrophages are immune cells usually involved in destroying abnormal cells. However, in the stroma they help to promote angiogenesis within the growing tumor, and disrupt tissue structures to allow space for the growing tumor mass.
The Problem of Cancer Relapse
The initial tumor is genetically very heterogeneous. When tumor cells metastasize, only a small number succeed in establishing new colonies. These new colonies are more homogenous, since they have shown the ability to colonize. In time, these colonies form new micrometastases. Micrometastases can be detected by the use of antibodies that react with cytokeratins that are present only in epithelial cells. The vast number of micrometastases remain dormant, or grow only to microscopic size. After the primary tumor is removed and the cancer seems to be cured, many years later the micrometastases may begin to proliferate and form clinically detectable tumors.
Treatment Approaches
Inhibiting metastasis requires drugs that target both the metastasizing cell and its supporting environment. These anti-metastasis agents need to be used at the same time as the primary therapy, since changes in the tumor microenvironment occur very early in the tumorgenesis process. The agents typically act against enzymes or growth factors involved in the cancer signaling process. Olle2003 Examples of drug targets include the following:
- Identify and inhibit signals that promote cellular migration to new metastatic sites
- Promote apoptosis (programmed cell death) by enhancing expression of the protein FAS and its ligand on the cancer cell surface. (Weinberg)
- Inhibit angiogenesis (blood vessel growth) within the tumor. Angiostatin and endostatin have been extensively studied for this purpose.
- Inhibit proteases that are overexpressed in tumors. An example is a drug that inhibits cathepsin-B on the cell membrane but not the internal stores of the protease. Normal cells, therefore, are unaffected by the drug. Matrix metalloproteinases can be an inviting drug target, since they plays a key role in tumor progression. Van Noorden
- Another approach would be to block the extravasation process. Studies (Wels 2004) have shown that inhibition of vascular endothelial growth factor (VEGF) activity stabilizes the endothelial barrier of the blood vessel and suppresses tumor cell extravasation. Tumors secrete large amounts of VEGF, as it is also a growth factor.
A Promising Future to Overcome Metastasis
Metastatic spread of cancer has been the greatest challenge in overcoming the disease. A great knowledge base has been amassed in understanding the process, studying both the metastasizing cell as well as its microenvironment. The complex interplay between the tumor cell and its environment provides many options for developing effective cancer therapies.
References
- Hujanen, E and Terranova, V. Migration of Tumor Cells to Organ-derived Chemoattractants. Cancer Res. 1985 Aug; 45: 3517-3521.
- Olle, D. Metastasis Suppressors. Suite101.com. 2003 Jan 29
- Olle, D. Understanding and Controlling Metastasis. Suite101.com. 2002 Aug 28
- Van Noorden, C. et.al. Metastasis. American Scientist. 1998 March-April; 86(2)
- Weinberg,R. Moving Out: Invasion and Metastasis. In: The Biology of Cancer. New York: Garland Science; 2007: 587-653.
- Wels, J. et al. Migratory Neighbors and Distant Invaders: Tumor-associated Niche Cells. Genes & Development. 2008; 22: 559-574.
- Wels, J. et al. Endothelial Barrier Disruption by VEGF-mediated Src Activity Potentiates Tumor Cell Extravasation and Metastasis. J Cell Biol. 2004 Oct 25; 167 (2): 223-229
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